General Practitioner-Community

Fat Hormone Influences Baseline Dopamine Levels And Our Motivation To Eat

2009-08-15T14:07:00.001+07:00

As we all know from experience, people eat not only because they are hungry, but also because the food just simply tastes too good to pass up. Now, a new study in the August 6th Cell Metabolism, helps to explain how leptin, a hormone produced by fat tissue, influences that motivation to eat.

The researchers describe for the first time a new bunch of leptin-responsive (LepRb) neurons in the brain's lateral hypothalamic area (LHA). Those LHA neurons feed directly into the mesolimbic dopamine system seated in the ventral tegmental area (VTA) of the brain, which controls the rewarding properties we assign to things.

"Dopaminergic neurons in the VTA and their downstream targets represent the site of action for drugs of abuse, and also control motivation for food, sex or a fancy car," explained Martin Myers, Jr., of the University of Michigan, Ann Arbor. Put simply, "they control our wanting of stuff."

The study therefore adds to growing evidence that leptin doesn't turn the appetite on and off just by controlling satiety – for instance, whether we feel hungry or full.

"Most who have studied leptin in the brain have focused on an important circuit in the ARC," and the leptin-responsive neurons there, Myers said. ARC stands for arcuate nucleus and is an area in the brain's hypothalamus that controls energy balance by controlling satiety. "It has been assumed that leptin action in the ARC – if not the be all and end all – was responsible for the vast majority of leptin's effect on appetite."

But in fact, neurons bearing leptin receptors exist in many other parts of the brain too. Earlier studies revealed the role of leptin action on the VTA and its influence on dopamine. The new findings show that leptin also has direct effects on the LHA, which in turn exerts greater influence on the dopamine system of the VTA.

The new study shows that leptin injected in the LHAs of rats causes the animals to eat less and lose weight. Leptin action in the LHA also raises dopamine content in the brains of otherwise leptin-deficient animals.

While in general higher dopamine release tends to be associated with wanting things – food or something else – Myers said he suspects the higher dopamine at baseline may in fact dampen the response to food temptations, making them easier to resist.

"Some people may over-eat rewarding food because of a perceived 'reward deficit,'" Myers suggested. "When leptin is turned up, it might fix that deficit and make us feel better about a lot of things."

It's not yet clear how the leptin-responsive neurons in the LHA and VTA work together to control dopamine and with it our motivations, according to the researchers.

"The unique roles played by these subpopulations of LHA LepRb neurons, as well as those played by VTA LepRb neurons, remain unclear, but could include the requirement for leptin to differentially regulate specific populations of midbrain dopamine neurons and/or to distinctly modulate the incentive for feeding relative to other behaviors. Going forward, it will be important to determine how these various populations of mesolimbic dopamine system-interacting LepRb neurons differ in terms of their wiring and the control of different aspects of mesolimbic dopamine signaling."

The new findings do highlight the LHA neurons as a major link between leptin's anorectic action and the mesolimbic dopamine system, they conclude. "These findings reveal important mechanisms that underlie the regulation of the mesolimbic dopamine system by a crucial signal of energy stores. In the future, it will be crucial to address the potential dysregulation of these neurons in states of obesity."

The researchers include Gina M. Leinninger, University of Michigan, Ann Arbor, MI; Young-Hwan Jo, Albert Einstein College of Medicine, Bronx, NY; Rebecca L. Leshan, University of Michigan, Ann Arbor, MI; Gwendolyn W. Louis, University of Michigan, Ann Arbor, MI; Hongyan Yang, University of Michigan, Ann Arbor, MI; Jason G. Barrera, University of Cincinnati, Cincinnati, OH; Hilary Wilson, University of Cincinnati, Cincinnati, OH; Darren M. Opland, University of Michigan, Ann Arbor, MI; Miro A. Faouzi, University of Michigan, Ann Arbor, MI; Yusong Gong, University of Michigan, Ann Arbor, MI; Justin C. Jones, University of Michigan, Ann Arbor, MI; Christopher J. Rhodes, University of Chicago, Chicago, IL; Streamson Chua, Jr., Albert Einstein College of Medicine, Bronx, NY; Sabrina Diano, Yale University, New Haven, CT; Tamas L. Horvath, Yale University, New Haven, CT; Randy J. Seeley, University of Michigan, Ann Arbor, MI; Jill B. Becker, University of Michigan, Ann Arbor, MI; Heike Munzberg, University of Michigan, Ann Arbor, MI; and Martin G. Myers Jr., University of Michigan, Ann Arbor, MI.

Source : http://www.sciencedaily.com/releases/2009/08/090805133009.htm

Clinical Factors Predict Risk of Complicated Community-Acquired Pneumonia

2009-07-24T15:49:00.000+07:00

Seven clinical factors can predict the risk of complicated parapneumonic effusion or empyema in patients presenting with community-acquired pneumonia (CAP), researchers report in the July issue of the journal Thorax.

Pneumonia severity scores have been used to predict 30-day mortality in patients presenting with CAP, the authors explain, but their utility to predict the development of complicated parapneumonic effusion or empyema has not been studied.

Dr. James D. Chalmers and colleagues from the Royal Infirmary of Edinburgh in Scotland set out to identify key factors predicting the development of these complications in patients admitted with CAP.

They report that recognized severity scores poorly predicted complicated parapneumonic effusion and empyema in these patients.

However, seven clinical factors emerged as independent risk factors for these complications on multivariate logistic regression, including serum albumin below 30 g/L, C-reactive protein above 100 mg/L, platelet count above 400 billion/L, sodium below 130 mmol/L, intravenous drug use, and chronic alcohol abuse. A history of chronic obstructive pulmonary disease (COPD) was associated with a lower risk.

When each risk factor was given a value of 1 (except the history of COPD, which was given a value of negative 1), a cutoff of 2 or more points accurately separated patients with a high and low risk of developing complicated parapneumonic effusion and empyema, the investigators say.

The 2-point cut-off was 87.0% sensitive and 68.3% specific and gave a positive predictive value of 17.7% and a negative predictive value of 98.5%. This score was superior to all pneumonia severity scores in predicting complicated parapneumonic effusion or empyema.

"This study," the investigators say, "has provided proof of the concept that complicated parapneumonic effusion and empyema can be predicted by deriving a scoring system with good predictive value."

"Independent validation studies are needed," they add.

"Exactly which biomarker is most appropriate and what cut-off levels should be used to affect the management decisions requires further clarification," writes Dr. Jeremy S. Brown from University College Medical School, London, UK, in a related editorial.

"Furthermore," Dr. Brown concludes, "any changes to CAP guidelines to include the use of biomarkers along the lines described above would ideally need support from prospective trials."

Thorax 2009;64:556-558,592-597.

Source : http://www.medscape.com/viewarticle/706328?sssdmh=dm1.503531&src=nldne

Successful New Treatment For Hodgkin's Lymphoma, Reduces Long-term Risks

2009-07-23T20:53:00.001+07:00

New research led by Cindy Schwartz, MD, of Hasbro Children's Hospital has identified a new chemotherapy regimen for pediatric Hodgkin lymphoma (HL) patients. The new treatment enhances efficacy through dose-dense drug delivery while simultaneously reducing the long-term risks presented by high cumulative dose chemotherapy. Schwartz and the researchers of the Children's Oncology Group have published their findings in the journal Blood (posted in an online first edition).

The Children's Oncology Group's Hodgkin Lymphoma Committee, led by Schwartz, director of pediatric hematology/oncology at Hasbro Children's Hospital, recognized that treatment for HL in the United States was not being treated with the most modern treatment models, in large part because it was one of the first malignancies for which a curative chemotherapy regimen was developed.

Schwartz says, "For decades, the chemotherapy regimens known as MOPP and ABVD had been the standard treatment options for these patients. However, while they yielded excellent survival rates, they often resulted in long-term effects from toxicity, including infertility, second malignancy and cardiopulmonary toxicity. With the new treatment paradigm we've developed, in essence, we've been able to cure the cancer while reducing the risk of long-term effects on our patients."

The group designed a new chemotherapy treatment known as ABVE-PC, combining six different drugs into one "dose-dense" regimen that could limit the cumulative doses of each drug below the recognized thresholds known for resulting in long-term toxicity. Their goal was to reach a rapid early response (RER) in order to further reduce cumulative therapy and to thereby increase event-free survival (EFS). They also combined the chemotherapy treatment with low dose radiation following the completion of the ABVE-PC cycles.

The treatment developed by the researchers was unique given that its focus was on early response after nine weeks, measuring to detect primary chemosensitivity – a favorable response to chemotherapy, indicating that the therapy is working. This approach differs from the traditional evaluation of the response at the end of chemotherapy. Schwartz notes that this is important, because, "This early detection allows for a reduction in therapy for those who respond well to the dose-dense treatment, and therefore, individual response can be tailored for maximum efficacy."

Schwartz, who is also a professor of pediatrics at The Warren Alpert Medical School of Brown University, believes that the study represents a new treatment model for patients with HL. She states, "Our treatment paradigm for advanced HL relied on two treatment principles: dose density enhances therapeutic efficacy and rapid early response is evidence of chemosensitivity and can serve as a basis for reduction of therapy."

The researchers conducted a trial of 216 eligible patients under 22 years of age, with intermediate or high risk HL; there were 76 females and 140 males. The median time from initial treatment to completion of the third cycle was approximately 8.7 weeks, and completion of the fifth cycle was approximately 16 weeks. While the dose densities of the chemotherapy agents exceeded those of the most commonly used regimens, cumulative doses of the chemotherapy were significantly lower, particularly in those with RER. The study was conducted at Children's Oncology Group sites between 1997 and 2001.

Schwartz says, "The results of the study indicate that through this new chemotherapy treatment we have been able to effectively deliver dose-dense chemotherapy while reducing the cumulative exposure to our patients." There are other, more immediate outcomes of the new treatment paradigm that are also of note. Schwartz also adds, "Our patients truly appreciate the rapidity of treatment. Regimens traditionally used for intermediate and advanced disease require six to eight months of chemotherapy, instead of two to three and a half months. A major benefit of this new approach is that children and young adults are able to more quickly return to school and work."

Of the 216 eligible patients, 209 were able to be evaluated for response. Of those patients, 63 percent (132 patients) showed RER, and only two of the patients showed evidence of progressive disease. RER was achieved in 67 percent of intermediate HL patients and 61 percent of high risk HL patients. The five-year event-free survival for intermediate risk HL patients was 84 percent and 85 percent for high risk HL patients. Few relapses occurred beyond three years after enrollment.

Schwartz concludes, "We have successfully achieved five-year event free survival in 84 percent of the patients and overall survival in 95 percent of our patients with this dose-dense, early-response based treatment algorithm. Only nine weeks of chemotherapy were required in 63 percent of our patients. This study has shown conclusively that the new chemotherapeutic treatment of ABVE-PC simultaneously provides high efficacy and reduces the cumulative doses of chemotherapy and radiation. We believe this represents a significant advance in the treatment of HL."

Other researchers involved in the study with Schwartz include Louis S. Constine of the University of Rochester Medical Center in Rochester, NY; Doojduen Villaluna of Children's Oncology Group - Operations Center in Arcadia, CA; Wendy B. London of Children's Oncology Group – Statistics and Data Center, University of Florida in Gainesville, FL; Robert E. Hutchison of SUNY Upstate Medical University in Syracuse, NY; Richard Sposto of Children's Hospital Los Angeles in Los Angeles CA; Steven E. Lipshultz of University of Miami Miller School of Medicine in Miami, FL; Charles S. Turner of Wake Forest University School of Medicine in Winston-Salem, NC; Pedro A. deAlarcon of St. Jude Midwest Affiliate in Peoria, IL; and Allen Chauvenet of West Virginia University HSC in Charleston, WV.

Source : http://www.sciencedaily.com/releases/2009/07/090713160521.htm

One Secret To How TB Sticks With You

2009-07-18T10:05:00.000+07:00

Mycobacterium tuberculosis is arguably the world's most successful infectious agent because it knows how to avoid elimination by slowing its own growth to a crawl. Now, a report in the July 10 issue of the journal Cell, a Cell Press publication, offers new insight into the bugs' talent for meager living.

"Tuberculosis can resist the host immune system and remain latent for decades," said Michael Glickman of the Memorial Sloan-Kettering Cancer Center. To do so, the mycobacterium responsible must resist an arsenal of DNA-damaging mutagens produced within the macrophage, the immune cell in which it lives. "It's incompletely understood how it can do that. We've identified one such mechanism."

The discovery could lead to new drugs that might eliminate strains of TB that have grown resistant to those that are currently available.

A whopping 30% of the world's population is infected with latent TB, the researchers said. In some people, the Tuberculosis bacterium will reactivate, causing an estimated 1.3 million deaths a year, according to the World Health Organization.

One secret to TB's success is a protein that the researchers call CarD, the new study shows. That protein ratchets down transcription of the genes encoding ribosomal RNA (rRNA) by directly binding RNA polymerase, the cellular machinery that transcribes DNA into RNA. rRNA is the central component of the ribosomes that serve as the cell's protein factories, and, Glickman explained, its production accounts for some 90 percent of all transcription.

"The mycobacterium tailors its translational machinery in response to stress within the host and we have identified CarD as a critical mediator of this response" he said.

Loss of CarD is fatal to M. tuberculosis living in cell culture, Glickman and his colleague Christina Stallings show. CarD depletion leaves the pathogen sensitive to killing by oxidative stress, starvation, and DNA damage as it fails to cut its transcription of rRNA.

Importantly, Glickman said, they were able to show in infected mice that the mycobacterium depends on CarD not just when it is in its early, most active phase of growth, but also later in the course of infection. Drugs that target CarD's interaction with RNA polymerase could therefore lead to sorely needed, new TB drugs, the researchers said.

"The TB health crisis is exacerbated by the alarming emergence of multidrug- and extensively drug-resistant strains," Glickman said. "The development of new chemotherapeutic strategies is imperative, which requires insight into the pathways involved in M. tuberculosis infection, persistence, and drug resistance. CarD is one such pathway that we plan on targeting for therapeutic development. "

The findings might also prove to be clinically important for other disease-causing microbes.

Scientists knew before how some bacteria adapted to stress by limiting rRNA transcription, Glickman said. But the new study is the first to show how this is done in a mycobacterium, which lack a key gene responsible in other bugs like E. coli.

CarD is widely distributed in the bacterial world, he said, for instance it is found in Bacillus anthracis, the bacterium that causes anthrax. "This finding may have broader application to other important pathogens," he said.

The researchers include Christina L. Stallings, Sloan-Kettering Institute, New York, NY; Nicolas C. Stephanou, Sloan-Kettering Institute, New York, NY; Linda Chu, Sloan-Kettering Institute, New York, NY; Ann Hochschild, Harvard Medical School, Boston, MA; Bryce E. Nickels, Rutgers University, Piscataway, NJ; and Michael S. Glickman, Sloan-Kettering Institute, New York, NY, Memorial Sloan-Kettering Cancer Center, New York, NY.

Source : http://www.sciencedaily.com/releases/2009/07/090709124741.htm

Current Perspectives on Pneumonia in Clinical Practice

2009-07-12T18:51:00.000+07:00

Introduction to Perspectives on Pneumonia

The increased concerns of drug resistance in managing lung disease affects both hospitalized and outpatient populations. In this expert interview with Michael Niederman, MD, of State University of New York and Winthrop University Hospital conducted by Medscape editor Jennifer Brown, PhD, the risks for pneumonia in special populations are considered. The current management trends to prevent and treat pneumonia caused by ever-evolving pathogens are put into a clinical perspective in the following commentary.

Patients at Risk for Pneumonia

Medscape: Welcome, Dr. Niederman, and thank you for sharing your perspectives on pneumonia. What patient populations are currently considered to be at increased risk for bacterial, viral, or fungal pneumonia?

Dr. Niederman: All 3 forms of pneumonia can affect virtually any individual, but in general the paradigm for any type of pneumonia is the balance between the patient's host defenses, the virulence of the potential pathogen, and the size of the exposure to the pathogen. So in theory, pneumonia can develop even in healthy individuals if they encounter particularly virulent pathogens or very large inoculum. So for example, an individual who gets severe acute respiratory syndrome (SARS) encounters a virus so virulent that it is impossible to have host defenses against it. On the other hand you can have a large inoculum of bacteria, which could overwhelm a healthy defense system. A good example is a young, otherwise healthy individual who gets drunk, vomits, and aspirates such a large quantity of bacteria that pneumonia develops. The majority of the patients we see in the hospital who have pneumonia tend to be individuals with impaired host defenses, either as a result of advanced age, underlying comorbid medical conditions, or medications. Because of their impaired immune systems not only are these individuals more prone to infection, but when pneumonia develops, it is a more severe infection.

Comorbid conditions could be congestive heart failure, chronic obstructive pulmonary disease (COPD), cigarette smoking, or underlying malignancy. A variety of medications that we routinely use increase the risk for infection. Even something as simple as aspirin has been shown to interfere with immune defenses and can predispose some patient populations to pneumonia. Certainly advanced age is also an important factor. There is some controversy about whether it is the age itself or the diseases that develop as a result of getting older. It is probably to some extent the combination of both.

Medscape: Are there special concerns for the immunocompromised, for example, those who take medications that are immunosuppressive?

Dr. Niederman: There are concerns, and the most common immunosuppressive drugs of concern used in clinical practice are probably corticosteroids. Individuals who are chronically treated with corticosteroids, as might be the case in those with COPD, rheumatoid arthritis, or other inflammatory diseases, are more prone to bacterial and viral infections as a result of their steroid therapy. Chemotherapy immune-related suppression can develop in individuals receiving chemotherapy, which particularly predisposes them to bacterial and fungal infections. With the biologic therapies that interfere with cell-mediated immunity, particularly the anti-tumor necrosis factor types of therapies, there has been a much greater concern about tuberculosis than pneumonia. Anything that interferes with immune defenses can predispose a patient to both bacterial and fungal infections.

Medscape: In patients with, for example HIV or a disease that has made them immunocompromised, what are the particular risks for pneumonia?

Dr. Niederman: There is a risk for immunocompromised patients. The way to evaluate that risk is to look at the abnormality the patient has to know, for example, what that does to the immune system. Then you can better predict what types of pathogens are likely to cause infection. So for example, people who are infected with HIV can have predominantly abnormalities of cell-mediated immunity but they can also have antibody formation abnormalities. Therefore, they are on the one hand predisposed to things like tuberculosis and atypical microbacteria and unusual fungal infections. In addition, they're also greatly at risk for pneumococcal pneumonia.

If you look for example at patients who have neutropenia because of cancer and chemotherapy, they are particularly predisposed to Gram-negative bacteria. So if you can define the nature of the immunosuppression and where specifically it affects the immune system, this can help you better predict which specific types of pathogens are likely to be problematic.

Evaluating Causes of Pneumonia

Medscape: In patients with cystic fibrosis in particular, what are the most common causes of pneumonia you see?

Dr. Niederman: The 2 pathogens that have been a problem in cystic fibrosis are Staphylococcus aureus, which tends to be a pathogen earlier in the disease and Pseudomonas aeruginosa, which tends to be a pathogen later in the disease. But there are a variety of unusual Gram-negative bacteria that have been a problem with cystic fibrosis as the disease gets more advanced. Here the factors that predispose patients to infection tend to be the cystic fibrosis itself, which leads to alterations in production of mucous, quality of the mucous, and clearance of the mucous. All of these can predispose to specific bacteria. Inevitably because of their disease, patients with cystic fibrosis are frequently treated with antibiotics. The treatment can then predispose to emergence of particularly resistant forms of Gram negative bacteria that tend to be problematic later in the disease.

Medscape: How would you determine the cause in a patient who has symptoms of pneumonia, whether bacterial, viral, or fungal?

Dr. Niederman: I think one of the issues that people are struggling with right now is this question, is it possible to look at a patient and know whether their infection is bacterial or viral? Efforts in the past included can you tell by the clinical syndrome, can you tell by the radiographic patterns, by the fever, by the white cell count? Many studies have been done but they have not yet shown that clinical features can separate bacterial from viral infections. One of the reasons this is important is if you can predict who has a viral infection with some accuracy, then you could say that this person doesn't need antibacterial therapy. Since we are concerned about the overuse of antibiotics and how that could be driving resistance, it would be helpful in theory to be able to predict who has which.

A particularly promising approach right now involves serum measurements of procalcitonin.^[1] When procalcitonin measurements are low, they exclude bacterial disease, as low procalcitonin levels seem to occur in viral infection. Studies in patients who have x-ray-positive pneumonia and low procalcitonin levels who have been randomized to observation without antibiotics have done very well without antibiotic therapy. This is one potential measurement for the future.

Today, for most patients, we look at their clinical features. If there is any chance that it is bacterial, we treat them with antibiotics and we try to identify the bacterial pathogen. Sputum samples are used if patients are intubated and the tracheal aspirates or bronchoscopic samples are cultured. We examine them microscopically to identify suspicious bacterial infections, and to identify what bacteria.

Medscape: Are agent-specific tests recommended for regular use?

Dr. Niederman: Generally agent-specific tests are not routinely used. Agent-specific tests widely available right now include urinary antigen testing for Legionella and Pneumococcus species. The problem with specific-agent tests in community-acquired pneumonia (CAP) is that it's difficult to know when the test is positive and how it should affect your approach to treatment. There are some new-onset cases and complexities of treatment. For example, there is a dataset of patients who have been in infected with Pneumococcus, who have pneumococcal bacteremia, who seem to benefit by the addition of a second antibiotic. If that is reproducible, then it would be hard to imagine how doing a specific test for Pneumococcus that was positive might change the antibiotic therapy. It might narrow it if you have a broad-spectrum therapy because of the possibility of needing a second antibiotic. But Legionella and Pneumococcus urinary antigen tests are probably the most specific tests in use.

The other common approach is to culture sputum, tracheal aspirates, bronchoscopic samples, or lower respiratory tract samples in patients who have suspected or confirmed pneumonia.

Current Practice for Treating Pneumonia

Medscape: What are the current medications of choice and how is the therapy selection individualized for the patient newly diagnosed with pneumonia?

Dr. Niederman: Guidelines for treating patients with CAP, with healthcare-associated pneumonia (HAP), and with nosocomial pneumonia depend on the severity of illness, the comorbidities of the patients, and the time of onset of the illness in the case of nosocomial infection. There are a variety of different algorithms for therapy, but no single best therapy. The 2005 guidelines for nosocomial pneumonia were a joint effort of American Thoracic Society and the Infectious Disease Society of America, as were the 2007 guidelines for CAP.^[2,3]

In general, with CAP, we treat for pneumococcus and generally the possibility of atypical pathogen co-infection. Some subpopulations are treated for Gram-negative bacteria. For patients who have HAP, coming from a nursing home or the hospital in the previous 3 months, they are at much greater risk for drug-resistant Gram negative infections and methicillin-resistant S aureus, and these patients need therapies directed to those pathogens. In nosocomial pneumonia it depends on how late in the course of the hospital stay pneumonia developed. Have they recently been on antibiotics? What are the pathogens that are common in a given hospital? All of these factors then get considered in terms of choosing an antibiotic therapy.

Strategies for Preventing Pneumonia

Medscape: Considering care of the elderly, could you please comment on strategies to prevent pneumonia in this population?

Dr. Niederman: I think in the elderly, 3 factors may play a role in their increased risk for infection. One is aging itself, and there is some controversy whether that really plays a role. The medications that the elderly get, and also the comorbidities that they have both play a role. For the elderly, many medications and comorbidities are associated with the risk for pneumonia. In terms of prevention, prevention of pneumonia generally involves smoking cessation and vaccination for patients outside of the hospital setting. For the elderly individual who is residing outside of the hospital, whether it's in the nursing home or at home, vaccination, including both pneumococcal and influenza vaccines, are probably the 2 most important preventive strategies that we have right now. In the hospital a whole series of preventive measures is undertaken.

Medscape: A recent report indicated vaccinating even the young had a positive effect for preventing pneumonia in others with HIV in the population.

Dr. Niederman: This is an interesting observation, the concept of herd immunity. When the 7-valent conjugant vaccine for Pneumococcus ^[4] (PCV7) was widely used in children, it had a benefit in elderly individuals, particularly the ones caring for the children. It seemed that if you eliminated the reservoir of Pneumococcus in young children, you might then eliminate the distribution source, if you will, of the Pneumococcus to older individuals who came in contact with the children. Very compelling data showed that with the early use of the vaccine in children there was a decline in the frequency of those strains of Pneumococcus in elderly individuals. This paralleled the decline in children, and the speculation was that they were therefore not transmitting the Pneumococcus at the same rate to the elderly caregivers around them.

Another twist to that data on vaccinating the young should be watched very closely. There have now been reports that with continued use of PCV7, there appears to be a decline in the frequency of the strains covered in that vaccine. They have been replaced at a higher frequency by other strains that aren't covered. In particular there are some very severe, necrotizing strains of Pneumococcus that aren't covered by the current vaccine that have emerged at higher frequency in vaccinated individuals. The concern is that the Pneumococcus being able to adapt to this vaccination strategy has now replaced some of the vaccine strains with other strains, some of which are more virulent, and that effect may be that there is more severe pneumonia occurring in certain populations than was appearing before the vaccine was introduced.^[5] So if that turns out to be true and can be confirmed in other populations, it may negate some of that herd immunity benefit that has been seen in the nonvaccinated individuals.

Medscape: What preventive measures would you say are helpful in the hospital setting to reduce HAP?

Dr. Niederman: Well the big issue right now in the hospital is the focus on mechanically ventilated patients, and there a lot of efforts have revolved around something that has been referred to as a "ventilator bundle." It's a bundling of interventions that many hospitals do in an effort to reduce the frequency of pneumonia. The typical bundle most widely promoted and used involves 5 elements, two of which are part of the bundle but really are good patient care that can help reduce intensive care unit stay and may indirectly reduce pneumonia but don't directly interfere with pneumonia pathogenesis. Those are gastrointestinal bleeding prophylaxis and deep venous thrombosis prophylaxis.

The other 3 interventions in the bundle are much more pneumonia-specific. One is elevation of the head of the bed with the idea of minimizing gastric reflux into the oropharynx and then aspiration into the lung. Keeping the head of the bed elevated can reduce gastric transmission of bacteria to the lungs. The 2 others are a daily interruption of sedation -- you wake the patient up every day, and when you do that there is a daily effort of weaning. That is the fifth element. So the bundle is: daily interruption of sedation and daily weaning trials, head of the bed elevation, deep vein thrombosis and gastrointestinal bleeding prophylaxis.

Although these bundles are probably effective, their advent has led to some interesting discussions and controversies. Some individuals are reporting that with the use of ventilator bundles they have eliminated pneumonia from their hospital. Some hospitals have even said we have gone as long as 2 years without an episode of ventilator associated pneumonia because of how valuable these bundles are and how successful we've been in implementing them.

The problem with those reports has been that many studies report a lower frequency of pneumonia in ventilated patients, but don't seem to report secondary benefits, meaning overall reduction in use of antibiotics, reduction in mortality, reduction in length of stay -- the known consequences of VAP. The diagnosis of VAP can often be subjective, and it's an elusive, difficult diagnosis. The worry is that people are now saying they don't have pneumonia in their hospital, but it isn't as credible as you would like because the secondary consequences of pneumonia are not also disappearing.

All of this has become increasingly more controversial because Medicare has proposed, and it's unclear what the final decision will be, that VAP should be considered a potential medical error that should not be given additional reimbursement. If so, the concern is that many hospitals would report very low rates of pneumonia. However, it's not clear to me that they're really eliminating the problem. It seems like there are populations of patients who are at such high risk because of their underlying comorbidities, chronic illness, and acute illness that they can't possibly have a zero-risk for pneumonia, even in the best hands and in the best hospitals.

Medscape: That really leads us directly into the Hospital Compare Web site. What impact will public reporting have on practice, or how will it change how patients choose hospitals?

Dr. Niederman: The Hospital Compare Web site right now is looking at CAP, but it may become part of the Medicare database that they'll be publicly reporting on VAP rates, and I would make the distinction. I think that in general it is good that pneumonia has become a target of public reporting, that people are aware of the importance of pneumonia. It is the number one cause of death from infectious diseases in the United States, and we are doing everything we can to reduce the frequency of pneumonia.

But you have to wonder whether the public reporting can have some unintended consequences that are not positive. One worry in the VAP side is if we have public reporting of very low VAP rates, that sort of strains credibility. There are populations where it's impossible to get the rates as low as some people report; you wonder if they are simply redefining the illness and haven't really made progress. What I worry about personally is that if we say pneumonia is a medical error, VAP, and it really is not eliminated, it will really, I think, hamper future research in this area. It would be very difficult for people to want to investigate a disease that when it occurs, it is considered bad medical care. So I think we have to get very accurate and honest in defining how low we can reduce these rates.

The Hospital Compare Web site, which compares different hospitals and their compliance with CAP, in general has been helpful. The one area that I think it still controversial is the antibiotic timing measure that Medicare has instituted. Originally that was looking at the frequency with which antibiotics were given within 4 hours and that has now been changed to 6 hours. But the concern has been that if it becomes publicly reported that 4 hours is the standard, then hospitals will inevitably try to get that rate to 100%. I think that many experts believe that 100% compliance with the 4-hour rule isn't necessarily good medical care. There may be cases of medical uncertainty, and so as another modification they have introduced medical uncertainty as an exemption to this 4-hour rule.

Published reports have raised concern about the 4-hour antibiotic timing rule. There are now 2 retrospective studies that show that when hospitals try to comply with the 4-hour rule, in general they give antibiotics to more patients, but the frequency with which the antibiotics were used for a final discharge of CAP actually dropped. In other words, many more patients got antibiotics but some of them got antibiotics when they didn't really have pneumonia.

Another consequence is at least one report of a hospital with very bad episodes of infection with Clostridium difficile. The majority of the episodes occurred in patients who were treated with antibiotics for pneumonia, but half of those patients who were treated for pneumonia didn't, in retrospect, have pneumonia. This occurred at a time period when the hospital was trying to be more compliant with the antibiotic timing measure.

I think that the Hospital Compare Web site is generally a good idea, but the goals that are set in comparison have to be accurate and realistic. What I worry about is that when the data get published publicly, everyone is going to look for the hospital that has the highest number. You have to recognize that it might be possible for some of these measures, that the highest number may not necessarily equal the desired goal. The desired goal might be 85% rather than 100% for some of these measures. It might be that there is a bell-shaped curve where the best care occurs when the compliance rate for a hospital is 80% to 85%. People below that and above that might not be providing the best possible care.

Source : http://www.medscape.com/viewarticle/577190

Greater Soy Consumption Appears to Lower COPD Risk

2009-07-12T18:30:00.000+07:00

The results of a study conducted in Japan and published in Respiratory Research suggest there is an association between high soy consumption and low risk of COPD and breathlessness.

Cigarettes are known to be the principle risk factor for COPD, Dr. Andy H. Lee of the Curtin University of Technology, Perth, Australia, and colleagues point out. "Other factors such as dietary and environmental exposures may protect against, or contribute to, disease development."

In a case-control study, the investigators examined the association between soy consumption and the risk of COPD and respiratory symptoms in 278 COPD patients (244 men and 34 women) between the ages of 50 and 75 years who were diagnosed within the past 4 years. A total of 340 controls (272 men and 68 women) were recruited from the community.

The study participants underwent spirometric measurements of respiratory function and structured questionnaires were used to collect information on demographics, lifestyle characteristics, and habitual food consumption. Control subjects had significantly higher mean soy intake than COPD patients (59.98 g/day versus 44.84 g/day, respectively, (p <>

A positive correlation was found between total soy consumption and lung function measures. The risk of COPD was significantly reduced among those with the highest versus the lowest quartile of daily total intake of total soybean products (p for trend = 0.001).

Similar decreases in the risk of COPD were observed with higher intakes of tofu and bean sprouts. An inverse association was found between high consumption of soy foods and respiratory symptoms, especially breathlessness.

"Habitual intake of soy foods offer a new prevention which can have an important impact on the cost to health care systems associated with the morbidity and death from this disease," Dr. Lee said in an interview with Reuters Health. "Long-term follow-up studies are recommended to ascertain whether soy consumption can lengthen the survival of patients already diagnosed with COPD."

Respir Res 2009;10.

Source : http://www.medscape.com/viewarticle/705630?sssdmh=dm1.497700&src=nldne

Statin-Induced Myopathy Reflects Structural Muscle Damage, New Study Shows

2009-07-11T14:19:00.000+07:00

Persistent muscle pain in patients taking statins reflects structural muscle damage, and this microscopic damage can occur in the absence of elevated creatine phosphokinase levels, according to the results of a new study [1].

"It's clear that a patient with statin-induced myopathy can have microscopic muscle damage, but the damage is not sufficient to break the cell open, and that means that it doesn't release creatinine phosphokinase into the blood," said study investigator Dr Richard Karas (Tufts-New England Medical Center, Boston, MA). "So to say that the other way around, we have clear evidence that there is ongoing damage to the muscle at the microscopic level, but it's not revealed in the blood tests that we use to check for muscle damage."

Speaking with heartwire , Karas said that muscle-related adverse effects limit statin use, despite the drugs being part of the foundation of cardiovascular risk reduction. He added that although these muscular side effects are well documented, little is known about the mechanisms of myopathy.

In this study, which is published online July 7, 2009 in the Canadian Medical Association Journal, Karas, along with lead investigator Dr Marcus Mohaupt (University of Bern, Switzerland), obtained biopsy samples from the vastus lateralis muscle of 83 patients. Overall, 44 subjects had clinically diagnosed statin-associated myopathy, and of these, 29 were currently taking a statin, while 15 had discontinued statin therapy for at least three weeks. Among the 83 patients, 19 were currently taking a statin but had no myopathy and 20 patients served as healthy controls.

Among the 44 individuals with myopathy, 57% had muscle injury defined by structural abnormalities in the muscle fibers, as did one patient without clinically diagnosed myopathy. Interestingly, just one patient with structural muscle injury had circulating creatine phosphokinase levels that exceeded 10 times the upper limit of normal, or >1950 U/L.

"This is clinically relevant because when a patient is on a statin and they come in complaining that their muscles hurt, we check the blood test for creatinine phosphokinase," said Karas. "If it's normal we tell them not to worry about it, that it's not the statin. This study tells us that in this group of patients, that clinical assumption is not true."

Not Your Average Patient on a Statin

Karas stressed that the patients included in this study are not typical patients on statins, but rather individuals with clinically identified statin-related myopathy. This distinction is important because patients treated with statins who feel fine and who have normal creatine phosphokinase levels should not worry they are damaging their muscles with the LDL-cholesterol-lowering medications.

The researchers point out, however, that patients with clinically diagnosed statin-induced myopathy who had stopped their statins for at least three weeks also had persistent microscopic evidence of muscle damage. Although he is cautious in interpreting results, saying it needs further study, Karas said that muscle problems might not go away among individuals with persistent muscle pain.

The researchers also performed a gene-expression analysis in 57 patients to look for association between muscle damage and genes that encode proteins located in T-tubule membrane or the adjacent sarcoplasmic reticulum and that are involved in the release of intracellular calcium. One of those proteins, ryanodine receptor 3, was significantly upregulated among patients with structural muscle damage when compared with individuals without muscle damage.

"The problem is that we don't know if this was elevated in the first place, and then this makes people susceptible to statin-induced myopathy, or whether it is elevated as a result of them having statin-induced myopathy," Karas explained to heartwire . "This is the first step, as it tells us that it's a gene that should be focused on in studies going forward. What we'd like to do is take a huge group of people and get their levels of expression and see if it predicts them getting myopathy."

Source : http://www.medscape.com/viewarticle/705429?src=mpnews&spon=34&uac=133298AG

Gluten and Glucose Management in Type 1 Diabetes

2009-07-08T23:31:00.002+07:00

Abstract

The prevalence of coeliac disease in patients with type 1 diabetes is significantly increased when compared to the general population. An explanation of the association between the development of both diseases may be explained by the inheritance of common major histocompatibility complex immunogenotypes that influence the presentation of auto antigens to CD4+ T-Cells. The subsequent loss of self tolerance results in destruction of the small bowel villi and pancreatic β-cells in coeliac and type 1 diabetes respectively. The diagnosis of coeliac disease in type 1 diabetic patients occurs commonly as a result of screening of individuals with subclinical coeliac disease. Recent studies have demonstrated the clinical benefit of treating subclinical coeliac disease in children with improvement in growth parameters, resolution of anaemia and fewer hypoglycaemic episodes. There is no current clinical evidence supporting routine screening of adult type 1 diabetic patients for coeliac disease. After the diagnosis of coeliac disease, type 1 diabetic patients should be commenced on a gluten-free diet with care co-ordinated between a dietician, gastroenterologist and diabetologist.

Introduction

Coeliac disease is a complex multifactorial autoimmune disease that is influenced by both genetic and environmental factors. Environmental exposure to gluten present in wheat, barley protein and rye results in immune mediated injury of the mucosa of the small intestine. Coeliac disease may be classified as symptomatic (diarrhoea with or without malabsorption) or subclinical (without gastrointestinal symptoms but may have extra-intestinal symptoms). Symptomatic coeliac disease is relatively rare occurring with a clinical frequency of one in 3,345 people worldwide, while asymptomatic coeliac disease detected on serological screening affects one of every 120–300 persons worldwide.^[1,2]

Type 1 diabetes is a relatively common disease accounting for 5–10% of all diabetes and is increasing in prevalence. It is a complex multifactorial autoimmune mediated disease characterised by the destruction of pancreatic β-cells leading to absolute insulin deficiency and subsequent ketoacidosis. The environmental antigen(s) has not been conclusively identified in type 1 diabetes though recent reports suggest that insulin may be the causative agent.^[3,4]

The association between coeliac disease and type 1 diabetes is estimated at 2–10% in European populations.^[5,6] In addition, both diseases are known to cluster with other organ specific autoimmune disorders such as autoimmune thyroid disorder and Addison's disease giving rise to Autoimmune Polyendocrine Syndrome type II.^[7.8] In this review we explore the common immune pathology between coeliac disease and type 1 diabetes, the role of screening for coeliac disease in individuals with type 1 diabetes and finally the clinical management of patients affected by both diseases.

Immunogenetics

A partial explanation for the association between type 1 diabetes and coeliac disease is their similarities in immunogenotype, with both diseases being associated with inheritance of the MHC genes located on the short arm of Chromosome 6 (6p21.31). The MHC class II genes encode for a cell surface HLA class II molecule (MHC class II molecule) that is expressed on APC. The HLA class II molecule is a heterodimer composed of an alpha and a beta subunit and the latter may be encoded by the alleles of the DP, DQ or DR genes.^[9,10]

Type 1 Diabetes

Type 1 diabetes has a concordance rate of 30–50% in monozygotic twins indicating a significant environmental contribution to the development of the disease phenotype. The average risk to siblings of an affected individual is estimated at 6%. Inheritance of one of the MHC class II haplotypes DR4 DQA1*0301/DQB1*0302 or DR3 DQA1*0502/DQB1*0201 increases the risk of type 1 diabetes. One of these haplotypes is found in 90% of children affected. The DR4 DQA1*0301/DQB1*0302 and DR3 DQA1*0502/DQB1*0201 haplotypes encode genes to form HLA-DQ8 and HLA-DQ2 class II molecules respectively. The combination heterozygous genotype DR4 DQA1*0301-DQB1*0302/DR3 DQA1*0502- DQB1*0201 confers the greatest susceptibility to the development of type 1 diabetes which commonly presents as diabetic ketosis in infancy. The MHC class II locus is estimated to confer 50% of the genetic susceptibility to type 1 diabetes with the remainder from genes outside the MHC.^[11,12]

Coeliac Disease

The total genetic contribution to development of coeliac disease has been estimated from monogenetic twin concordance data as 70% compared with 30% in HLA-identical siblings, indicating a contribution from loci outside the MHC genes such as 5q31-33. The most common MHC class II haplotypes inherited in coeliac disease are the HLA DR3 DQA1* 0502/DQB1*0201 encoding the HLA DQ2 class II molecule. The HLA DQ2 cell surface receptor is expressed in 90% of coeliac patients. The DR4 DQA1*0301/DQB1*0302 haplotype encoding the HLA-DQ8 class II molecule is also found in individuals with coeliac disease but more rarely. It is important to note that inheritance of these haplotypes confers susceptibility to coeliac disease but additional environmental triggers are necessary for disease development.^[13,14]

The HLA DR4 and DR3 loci occur frequently in type 1 diabetes and coeliac disease ( Table 1 ). The similar genetic background is the likely explanation for the common clinical concurrence of both conditions.^[15,16]

Pathogenesis

Coeliac Disease

The key event in the development of coeliac disease in genetically susceptible individuals is the ingestion of gluten – the storage protein of wheat. Gliadin is the alcohol soluble fraction of gluten and this has been investigated extensively. The current disease model for coeliac disease involves the deamidation of gliadin by tissue transglutaminase to glutamic acid peptides (Figure 1). Specifically a 33-amino-acid (33-mer) peptide that resists digestion by gastric and intestinal proteolytic enzymes, in vitro and in vivo, is immunogenic in coeliac patients. The 33-mer peptide is deaminated by transglutaminase on the subepithelial layer of the intestine. The deaminated peptide residues are then processed by APC to three epitopes that bind to the HLA DQ2 or DQ8. The T-cell receptor on intestinal CD4+ T-cells in the lamina propria recognise the epitopes displayed on the HLA DQ2/DQ8 as foreign and initiates the production of proinflammatory cytokines. This inflammatory environment results in immune deregulation and loss of tolerance with activation of CD8+ T-cells and B-cells in the intestinal epithelium. The pathophysiological result is intraepithelial lymphocytosis, villous atrophy and the production of transglutaminase antibodies.^[13,17]

Figure 1.

Activation of the immune system by gluten in coeliac disease. Gluten is degraded by gastrointestinal enzymes to a 33 amino acid (33-mer) peptide. The 33-mer peptide is absorbed across the small bowel epithelium to the subepithelial layer in the lamina propria. Tissue transglutaminase deaminates the 33-mer peptide. The deaminated peptides are processed by APC to three epitopes that bind to the HLA-DQ2 or DQ8 molecules. The T-cell receptor on T-cells then cross-react with the HLA molecule leading to the initiation of an autoreactive immune response with subsequent activation of B-cells, CD4+ Th1 cells and NK cells. The resultant proinflammatory environment results in further immune activation and migration of lymphocytes resulting in the characteristic pathological finding of increased intraepithelial lymphocytes and villous atrophy. APC = antigen presenting cells; HLA = human leukocyte antigen; NK = natural killer cells.

Figure 1.

Type 1 Diabetes

Overt symptoms of diabetes do not occur until approximately 80% of the β-cells have been destroyed, making it difficult to identify the precipitating environmental event.^[18] It has recently been suggested that insulin may be the primary auto antigen.^[19,20] In vivo, this auto antigen may be displayed on APC activating CD4+ T cells to initiate an immune response (Figure 2). Evidence to support this disease model of type 1 diabetes mainly originates from clinical trials involving administration of cyclosporin to achieve T-cell suppression. This treatment induced remission with enhanced insulin secretion. However the significant side effects of cyclosporin prevented the widespread use of this therapeutic strategy. Of late more targeted therapy with an anti T-cell monoclonal antibody (hOKT3gamma)Ab improved C-peptide responses with a single treatment lasting up to one year.^[21] The anti T-cell monoclonal antibody (ChAglyCD3) has been shown to maintain β-cell function for at least 18 months.^[22] These clinical trials demonstrate the pivotal role of T-cells in the development of symptomatic disease.

Figure 2.

Proposed autoimmune mechanism of the development of type 1 diabetes. An auto-antigen, proposed to be insulin, is presented to an APC. The antigen is processed to epitopes which are bound and displayed on HLA DQ2/DQ8. Cross-reaction occurs between CD4+ T-cell and APC to initiate autoimmune reaction directed at the β-cells of the pancreatic islets. A component of the T-cell mediated immune response involves the activation of B-cells to produce autoreactive antibodies. The ultimate result is immune mediated destruction of pancreatic β-cells with concomitant insulin deficiency and subsequent ketoacidosis. APC = antigen presenting cells; HLA = human leukocyte antigen

Figure 2.

In summary the development of both coeliac disease and type 1 diabetes share a similar immunopathogenesis requiring the activation of auto reactive T-cells in genetically susceptible individuals. Coeliac disease however differs from type 1 diabetes in that the environmental antigenic trigger gliadin (a component of gluten) has been identified and avoidance leads to remission of the disease.

Screening

The diagnosis of coeliac disease in individuals with type 1 diabetes is most commonly due to screening since most affected patients have subclinical disease. A minority will present with overt classical coeliac disease characterised by growth failure, muscle wasting, pallor, oedema and rickets. Screening for coeliac disease involves testing for circulating endomysial or transglutaminase antibodies, with diagnosis being confirmed by small bowel biopsy demonstrating infiltration of the intestinal mucosa by lymphocytes and the development of crypt hyperplasia and villous atrophy.^[2]

Many clinicians have suggested that all children with type 1 diabetes should be screened for coeliac disease and treated. However, others have questioned the potential benefits of treatment and the risks of screening. Support for the effectiveness of screening is provided by the facts that coeliac disease is known to be more common in type 1 diabetic patients (mean 4.1%, range 0–10.4%) than the general population (0.3–0.5%) and is usually subclinical. A highly effective treatment is available, withdrawal of gluten from the diet. Studies of non-diabetic coeliac children suggest that treatment may avoid the complications of growth failure, low bone density and potential neurological abnormalities. Glycaemic control may also be improved by a reduction in hypoglycaemic episodes caused by erratic absorption of glucose. Finally it is speculated that treatment of coeliac disease in type 1 diabetes could reduce the likelihood of the development of other autoimmune diseases such as Grave's or Addison's disease or non-Hodgkin's lymphoma of the small bowel.^[23]

Screening for coeliac disease was deemed inappropriate in children with type 1 diabetes by some clinicians since classical coeliac disease is easy to recognise. Screening therefore would only identify subclinical disease. The long-term outcome of subclinical coeliac disease in type 1 diabetes was unknown, as were the benefits of treatment. The definitive diagnosis of subclinical coeliac disease also requires invasive investigation with associated risk and treatment of coeliac disease in type 1 diabetes possibly leading to further complexity and psychological burden in patients. Screening of children with increased hypoglycaemic episodes for coeliac disease would be justified however.^[23,24]

Recent investigations have clarified many of the issues regarding the screening of children with type 1 diabetes for coeliac disease. An Italian multicentre study found the prevalence of biopsy proven coeliac disease in children with diabetes to be high (6.8%). Diabetes is usually diagnosed prior to the development of coeliac disease. The risk of the development of coeliac disease is correlated with earlier onset of type 1 diabetes, with three times the risk of onset at age less than four, than in children older than nine. The study also detected a trend of decreased prevalence of coeliac disease detection after 10 years duration of diabetes.^[25]

One group has shown that at diagnosis of type 1 diabetes raised EMA were predictive for the development of coeliac disease. In children who were negative for EMA antibodies at diagnosis seroconversion took place in the next 2.8–10.8 years in those who subsequently developed coeliac disease. All patients were asymptomatic at diagnosis. A recommendation of screening at two-year intervals for asymptomatic patients was suggested as a safe and cost-effective strategy.^[26]

A Danish study found the highest prevalence (10%) of coeliac disease in children (<16>1C remained unchanged in patients on a GFD though two patients experienced fewer hypoglycaemic episodes. Compliance with diet was good with 24 of the 31 patients having disappearance of the coeliac antibodies.^[27]

Clinical Management

The cornerstone of the treatment of coeliac disease is the initiation and maintenance of a GFD.^[28] However, commencement of a GFD in patients initially diagnosed with coeliac disease does not offer protection from the development of type 1 diabetes.^[27] Similarly, removal of gluten from the diet of individuals at high risk of the development of type 1 diabetes does reduce the incidence of coelic disease.^[29,30]

Care of type 1 diabetic patients with coeliac disease should be co-ordinated between a dietician, gastroenterologist and diabetologist. Patient compliance with treatment is highest in coeliac patients when the GFD is commenced as young children rather than as adolescents.^[31] Patient compliance with GFD may be monitored by self-reported diet, growth charts and/or transglutaminase antibody titres.^[32] Studies of GFD in type 1 diabetic patients with coeliac disease have demonstrated good compliance rates.^[33-36] However, it remains to be determined if these compliance rates can be achieved in a normal clinical setting.

The effect of GFD on glycaemic control in type 1 diabetic patients has been examined by a number of studies. Prior to treatment with GFD type 1 diabetic patients with coeliac disease have lower insulin requirements and BMI than type 1 diabetic (non coeliac) control patients. With treatment their insulin requirements increase as BMI increases. The overall effect on metabolic control remains unclear, one study has reported improvement in HbA_1C ^[35] while two others have reported that HbA_1C remains unchanged,^[27,33] and a reduction in microvascular complications or diabetic nephropathy has not been observed in type 1 diabetic patients affected with coeliac disease treated with GFD as when compared to diabetic patient controls.^[26,37] Standard glycaemic targets referenced to the patient's age should be pursued.^[38] As previously discussed there may be a reduction in hypoglycaemic episodes thereby allowing for tighter glycaemic control to be achieved.^[39]

Conclusions

Coeliac disease and type 1 diabetes may occur in patients as a result of their common immunogenotypes. Though both diseases differ in organ specificity they appear to share a similar pathogenic mechanism involving the deregulation of T-cell responses and the loss of self tolerance with resultant tissue damage to the small bowel (coeliac) and β-cells of the pancreatic islets (type 1 diabetes). Treatment of children, diagnosed first with coeliac disease with GFD does not provide subsequent protection from the development of type 1 diabetes.

Recent evidence has provided support for the screening of type 1 diabetic patients under the age of sixteen for subclinical coeliac disease given the resolution of gastrointestinal symptoms and improvement in growth parameters. Serological screening (EMA and tTGA with concurrent serum IgA) should be carried out every two years for a ten-year duration post diagnosis of type 1 diabetes. Positive serology should lead to formal small bowel biopsy to examine for partial or total villous atrophy ( Table 2 ). Treatment with a GFD may also reduce the number of hypoglycaemic episodes in patients, though overall glycaemic control remains unchanged.

Widespread screening for coeliac disease in adults with type 1 diabetes is not recommended since the clinical benefit is unknown. However, adult patients with type 1 diabetes with symptoms of coeliac disease or recurrent hypoglycaemic episodes or multiple endocrine diseases should be investigated for coeliac disease. Future screening studies of adult type 1 diabetic patients with subclinical coeliac disease should aim to demonstrate clinical benefit of initiation of GFD by improvement in metabolic control or possibly reduction in prevalence of non-Hodgkin's lymphoma of the small bowel.

References

Farrell RJ, Kelly CP. Coeliac Sprue. N Engl J Med 2002;346:180-8.
Green PHR, Jabri B. Coeliac disease. Lancet 2003;362:383-91.
Daneman D. Type 1 Diabetes. Lancet 2006;367:847-58.
American Diabetes Association. Standards of Medical Care in Diabetes 2007. Diabetes Care 2007;30:S4-S41.
Collin P, Kaukinen K, Valimaki M et al. Endocrinological disorders and coeliac disease. Endocr Rev 2002;23:464-83.
Hansen D, Brennedbaek FN, Hansen LK et al. High prevalence of coeliac disease in Danish children with type 1 diabetes mellitus. Acta Paediatr 2001;90:1238-43.
Eisenbarth GS, Gottlieb PA. Autoimmune Polyendocrine Syndromes. N Engl J Med 2004;350:2068-79.
Cronin CC, Shanahan F. Insulin-dependant diabetes mellitus and coeliac disease. Lancet 1997;349:1096-7.
McDevitt HO. Discovering the role of the Major histocompatibility complex in the immune response. Ann Rev Immunol 2000;18:1-17.
Kumanovics A, Takada T, Lindahl KF. Genomic organisation of the mammalian MHC. Ann Rev Immunol 2003;21:629-57.
Jahromi MN, Eisenbarth GS. Genetic determinants of type 1 diabetes across populations. Ann N Y Acad Sci 2006;1079:289-99.
Lambert AP, Gillespie KM, Thomson G et al. Absolute risk of childhoodonset type 1 diabetes defined by human leukocyte antigen class II genotype: A Population-Based Study in the United Kingdom. J Clin Endocrinol Metab 2004;89:4037-43.
McManus R, Kelleher D. Celiac disease the villian unmasked? N Engl J Med 2003;348:2573-4.
Sollid LM. Coeliac disease: dissecting a complex inflammatory disorder. Nat Rev Immunol 2002;2:647-55.
Bao F, Yu L, Wang T et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express coeliac disease-associated transglutminase autoantibiodies. J Autoimmun 1999;13:143-8.
Saukkonen T, Ilonen J, Akerblom HK, Savilahti E. Prevalence of coeliac disease in siblings of patients with Type 1 diabetes is related to the prevalence of DQB1*02 allele. Diabetologia 2001;44:1051-3.
Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterology 2005;128:S10-S18.
Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ 2006;175:165-70.
Kent SC, Chen Y, Bregoli L et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognise an insulin epitope. Nature 2005;435:224-8.
Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005;535:220-3.
Herold KC. Treatment of type 1 diabetes mellitus to preserve insulin secretion. Endocrinol Metab Clin North Am 2004;33:93-111.
Keymeulen B, Vandemeulebroucke E, Zieger AG et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 2005;353:2598-608.
Freemark M and Levitsk LL. Screening for coeliac disease in children with type 1 diabetes. Diabetes Care 2003;26:1932-39.
Murray JA. Celiac disease in patients with an affected member, type 1 diabetes, iron deficiency, or osteoporosis. Gastroenterology 2005;128:S52-S56.
Ceritti F, Beuno G, Chiarelli F et al. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes. Diabetes Care 2004;27:1294-8.
Glastras SJ, Craig ME, Verge CF et al. The Role of autoimmunity at diagnosis of type 1 diabetes in the development of thyroid and celiac disease and microvascular complications. Diabetes Care 2005; 28:2170-5.
Ludvigsson JF, J Ludvisson J, Ekbom A et al. Coeliac Disease and Risk of Subsequent Type 1 Diabetes. Diabetes Care 2006;29:2483-8.
Rewer M, Liu Edwin, Simmons J et al. Coeliac disease associated with type 1 diabetes mellitus. Endocrinol Metab Clin N Am 2004;33:197-214.
Hummel M, Bonifacio E, Naserke HE, Ziegler AG. Elimination of dietary gluten does not reduce titres of Type 1 diabetes-associated autoantibiodies in high risk subjects. Diabetes Care 2002; 25:1111-16.
Pastrone MR, Bazzigaluppi E, Belloni C et al. Six months of gluten-free diet do not influence autoantobody titres but improve insulin secretion in subjects at high risk for type 1 diabetes. J Clinical Endocrinology Metab 2003;88:162-5.
Cranney A, Rostom A, Sy R et al. Consequences of testing for celiac disease. Gastroenterology 2005;128:S109-S20.
Pieta MM. Follow-up of patients with coeliac disease: achieving compliance with treatment. Gastroenterology 2005;128:S135-S141.
Amin R, Murphy N, Edge J et al. Longitudinal study of the effects of a gluten-free diet on glycemic control and weight gain in subjects with type 1 diabetes and coeliac disease. Diabetes Care 2006; 25:1117-22.
Hansen D, Brock-Jacobben B, Lund E et al. Clinical benefit of glutenfree diet in type 1 diabetic children with screening-detected coeliac disease. Diabetes Care 2006;29:2452-6.
Sanhchez-Albisua I, Wolf J, Neu A et al. Coeliac disease in children with Type 1 diabetes mellitus; the effect of the gluten-free diet. Diabetic Medicine 2005;22:1079-82.
Saadah OI, Zacharin M, O'Callaghan A et al. Effect of gluten-free diet and adherence on growth and diabetic control in diabetics and coeliac disease. Arch Dis Child 2004;89:871-6.
Skovbjery H, Tarnow L, Locht H, Parving HH. The prevalence of coeliac disease in adult Danish patients with type 1 diabetes with and without nephropathy. Diabetologia 2005;48:1416-17.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 2003;27(suppl 2):S84-S89.
Mohn A, Cerruto M, Lafusco D et al. Celiac disease in children and adolescents with type 1 diabetes: importance of hypoglycaemia. J Pediatr Gastroenterol Nutr 2001;32:37-40.

Source : http://www.medscape.com/viewarticle/574648

Anxiety, Depression Linked to Angina Frequency in Heart Patients

2009-07-07T03:12:00.000+07:00

New research shows that ischemic heart disease patients who suffer significant anxiety have close to a 5-fold increased risk of experiencing frequent angina and those with depression have more than a 3-fold increased risk for these episodes.

This observed link between psychiatric symptoms and angina underlines the importance of treating anxiety and depression in cardiac patients, according to study coauthor Mark D. Sullivan, MD, PhD, from the department of psychiatry and behavioral sciences at the University of Washington School of Medicine, in Seattle.

Current cardiology care focuses almost exclusively on management of ischemia with medications and revascularization, said Dr. Sullivan. "We're saying that there's a very significant contribution of depression and anxiety to these symptoms." This is among the first studies to measure depression and anxiety in ischemic heart patients, he added.

The research is published online June 29 in the journal Circulation.

Significant Comorbidities

The study included patients with suspected ischemic heart disease who were scheduled for an outpatient stress test with myocardial perfusion imaging at 2 medical centers in Washington State between April 2004 and April 2006. Researchers focused on 191 patients with clearly established inducible ischemia on stress testing. The mean age of these subjects was 63 years. Many participants were middle-aged male veterans.

A significant portion of the study group had cardiac-related comorbidities. For example, 82% had hypertension, 81% had hyperlipidemia, 34% were smokers, and 14% had diabetes mellitus

Prior to the stress testing, patients completed the Seattle Angina Questionnaire. Researchers focused on the portion of this questionnaire that quantifies the frequency and burden of angina. Angina frequency was categorized as none, monthly, weekly, or daily; the last 2 frequencies were combined for the purposes of this analysis.

Angina pectoris was defined as discomfort, usually around the chest, jaw, shoulder, back, or arm, associated with atherosclerotic obstruction. Of the 191 patients with inducible ischemia on stress perfusion imaging, 68 (36%) reported no angina over the previous 4 weeks, 66 (35%) reported monthly symptoms, and 57 (30%) had weekly or daily angina.

Patients with more frequent baseline angina were much more likely to report chest pain during stress tests: 63% of patients with weekly or daily angina compared with 20% of patients with monthly angina and 11% of patients with no angina.

Psychosocial Factors

The researchers examined 5 psychosocial factors that might affect angina frequency: anxiety; depression; neuroticism (tendency to experience negative emotions such as sadness, anger, or guilt); alexithymia (impaired ability to express inner feelings); and somatosensory amplification (tendency to experience a somatic sensation as intense, noxious, and disturbing).

There was more anxiety and depression among patients with frequent angina. For instance, 22% of patients with no angina had clinically significant anxiety, defined as a score of 16 or greater on the Beck Anxiety Inventory scale, compared with 38% for patients with monthly angina and 64% for those with weekly or daily angina.

Other psychosocial factors were also increased among patients with more frequent angina. For example, 38% of patients with weekly or daily angina had a high level of alexithymia compared with 17% of patients with monthly angina and 14% of those without angina.

However, after adjustment for degree of myocardial ischemia, greater anxiety score (odds ratio, 1.39 per half–standard deviation increase in anxiety score) and greater depression score (OR, 1.51 per half–standard deviation increase in depression score) were the only psychosocial factors significantly associated with more frequent angina. As expected, previous coronary revascularization was also significantly associated with frequent angina.

Patients with at least moderate anxiety symptoms experienced a 4.7-fold increased risk of having more frequent angina (95% CI, 1.91 – 11.66; P = .001). Patients with clinically relevant depressive symptoms (16 or greater on the Center for Epidemiologic Studies Depression scale) had a 3.2-fold increased risk of experiencing more frequent angina (95% CI, 1.45 – 6.69; P = .004.)

Biological Factors

Not every patient with coronary artery disease develops angina. Up to 45% of these patients have asymptomatic ischemia. Several biological factors might explain the discrepancy between coronary artery disease and angina severity, according to the authors. For example, metabolic neuropathy or ischemic regional nerve injury may influence pain levels.

"Just as with other pain syndromes — for example, chronic back pain — the relationship between the injury or the disease severity and the pain severity is very loose," said Dr. Sullivan, who has an interest in chronic pain. "There are all sorts of things that modify it, but these have not been studied very much in angina. That's why we wanted to do this study."

While the study showed a link between psychosocial symptoms and angina frequency, there is no evidence yet that treating these symptoms would reduce angina, said Dr. Sullivan.

"In cardiology, we thought we knew exactly why people were having pain — because they've got plugged plumbing, and unplugging the plumbing was going to solve the problem," said Dr. Sullivan. And while revascularization often does relieve the pain, there is growing evidence that for stable angina, revascularization is not superior to medication, he noted.

Dr. Sullivan stressed that the study sample included heart patients, not psychiatric patients, and that most people with heart disease do not develop a clinical level of anxiety or depression. It is those who are vulnerable to begin with who are more susceptible to these psychological symptoms, said Dr. Sullivan.

Talk to Patients

Asked for his opinion, Gerald Fletcher, MD, professor of medicine and cardiology at the Mayo Clinic in Jacksonville, Florida, commended the authors for their innovative work.

The research underlines the need for doctors to talk to their patients more often to determine underlying psychological issues. "You can't determine sometimes if someone has anxiety, depression, or whatever without facing them in an exam room and talking to them."

Pursuing a healthy lifestyle, including exercising and not smoking, could make patients less prone to these psychological problems, he said. He added that psychotherapy and other treatment approaches may help to reduce stresses of everyday life.

Source : http://www.medscape.com/viewarticle/705085

ASMBS 2009: Gastric Banding Achieves Sustained Weight Loss, Improvement of Diabetes

2009-07-05T00:24:00.000+07:00

Laparoscopic adjustable gastric banding has a sustained and substantial positive effect on metabolic parameters in morbidly obese patients with type 2 diabetes, according to data presented here at the annual meeting of the American Society of Metabolic and Bariatric Surgery.

Investigators assessed the 5-year outcomes of 95 morbidly obese patients with type 2 diabetes, recording age, sex, race, body mass index (BMI), diabetes history, fasting glucose level, hemoglobin A1c (HbA1c), and use of medications. The patients underwent laparoscopic adjustable gastric banding between January 2002 and June 2004.

Morbid obesity was defined as a BMI of 40 kg/m² or more or a BMI of 35 kg/m² with an obesity-related illness. The mean age of patients before surgery was 49.3 years, and mean duration of diabetes was 6.5 years. The mean preoperative BMI was 46.3 kg/m² (range, 35.1 – 71.9 kg/m²), which fell to 35.0 kg/m² (range, 21.1 – 53.7 kg/m²) at 5-year follow-up. Mean excess weight loss was 48.3%.

The mean fasting glucose level fell from 146 mg/dL to 118.5 mg/dL (P = .004). The mean HbA1c decreased from 7.53% to 6.58% at 5 years after banding (P < .0001).

Diabetes resolution was defined as the patient being medication-free with an HbA1c of less than 6% and/or a glucose level less than 100 mg/dL. Resolution occurred in 23 (39.7%) of 58 patients. Improvement, defined as fewer medications required and fasting glucose levels between 100 and 125 mg/dL, was seen in 41 (71.9%) of 57 patients.

The overall combined improvement/resolution rate was 80% (64 of 80 patients).

"Our study shows that for the vast majority of diabetic, morbidly obese patients, they will have improvement in their diabetes and often times a resolution of their diabetes, which extends out to 5 years," said Christine Ren, MD, FACS, an associate professor of surgery at New York University School of Medicine in New York City, and one of the study's senior authors.

"We saw [that] the only difference between those who had complete resolution of diabetes vs those who did not was their weight loss," said Dr. Ren.

"It appears that in gastric banding, the probability of a patient having improvement or resolution of diabetes depends on how much weight you lose and keep off."

Investigators did not find a statistically significant difference in remission of diabetes based on the duration of diagnosis prebanding. A total of 83 (88.3%) of 94 patients were on oral medications before gastric banding, and 14.9% were on insulin. Five years after gastric banding surgery, 33 (46.5%) of 71 patients were on oral medications and 8.5% were on insulin.

Evidence has been available on the efficacy of gastric bypass surgery on resolution of diabetes, but these results point to the efficacy of laparoscopic adjustable gastric banding in resolving diabetes and in controlling metabolic parameters in the morbidly obese patient with diabetes, said Alan Wittgrove, MD, FACS, a member of the executive council of the American Society of Metabolic and Bariatric Surgery and medical director of the Bariatric Surgical Program at Scripps Memorial Hospital in La Jolla, California.

"It's important because the study follows the patients for at least 5 years," said Dr. Wittgrove. "It shows the longevity of the procedure in resolving diabetes through weight loss and [its] impact on the metabolic syndrome."

Although the study did not reveal the duration of diagnosis to be a factor that influenced whether or not patients experienced improvement in their diabetes, duration of diagnosis may have emerged as a variable that affected outcomes in a larger study, according to Dr. Wittgrove.

"That is probably a function of the power of the study," he said, noting that several studies have found that the timing of surgery has an effect on resolving diabetes in this type of patient. Surgery performed earlier results in more durable resolution, he pointed out.

"Since [duration of disease] has been shown to be a factor in other studies, I would extrapolate that if [the researchers] get more numbers, it would reach [statistical] significance," Dr. Wittgrove said.

The study was independently conducted. Dr. Ren is a member of the Speaker's Bureau, sits on an advisory board, and receives research and educational grants from Allergan Inc. She receives research and educational grants from Ethicon Endo-Surgery Inc and is a consultant for Explora Med Development, LLC. Dr. Wittgrove is a consultant for Ethicon Endo-Surgery Inc and receives research funding from Stryker Corporation.

American Society of Metabolic and Bariatric Surgery 2009 Annual Meeting: Abstract PL-104. Presented June 24, 2009.

Source : http://www.medscape.com/viewarticle/705047?src=mpnews

The Art of Patient Care in Clinical Medicine

2009-07-04T12:07:00.000+07:00

"... the secret of the care of the patient is in caring for the patient."
-Frances Peabody, 1925

There was a time not long ago, when physicians and nurses didn’t have much else to offer patients other than personal attention, comfort, compassion and concern for their ailments. Medical professionals were revered and respected for that and for what little they could do in regard to symptomatic treatment for incurable conditions.

The Twenty-First Century has thrust health care into an era of modernization, precipitated by advances in medical technology and computerization of everything in sight. We have made fantastic strides in the diagnosis and treatment of many serious illnesses. Patients are living longer and more productive lives as a result of these wonderful advances.

However, concomitant with these changes, we have experienced the indisputable depersonalization of patient care. Patients are often treated as diseases or numbers. We often hear medical personnel referring to a patient as “the gallbladder in room 232” or “the COPDer in 476”. We order test after test instead of taking a history because if we don’t “prove” our diagnosis with a test, we may be subjected to a lawsuit later if something goes wrong.

Health care costs have spun out of control. Forty-three million people in the US can no longer afford health insurance. Access to care has deteriorated. Prenatal care and birth rates are suffering. Doctors’ salaries are restricted by insurance companies. Busy primary care physicians have to see 30-40 patients a day to make enough income to pay off their own expenses beginning with a $250,000 debt for medical training.

There is no time to spend 20 minutes with an 80 year-old patient with diabetes, arthritis, heart failure, and hypertension out of control who has just developed shortness of breath recently, and who needs 6 prescriptions rewritten. Other patients in the waiting room are feeling ignored.

These are very difficult challenges. Unfortunately, in the middle of it all, we often lose site of the fact that our patients are people – in many cases, very ill people - who are looking to us for support and guidance as well as medical care. There is an art to providing this support and to personalizing care for each and every patient in the midst of an imperfect environment.

Anyone who works in the health care profession knows there is a right way and a wrong way to approach patient care. They also know this is somewhat different for every patient they encounter due to multiple variables – type of illness, gender, age, background, etc. This is an art that we learn mostly by experience – both by our own personal experience and by observing the experiences of others. How well we assimilate the information from these experiences and how well we use that knowledge determines a very large part of how we interact with patients and how we are perceived as medical professionals.

The key word here is the art of patient care. For the purposes of this site, the reference is not so much on the science of medicine per se, but rather on how medical personnel can interact with patients to improve the healing process, rather than dismantle it.

This is not to say that science is unimportant; but rather that concern for the humanity of the patient should not be so overwhelmed by science as to be nonexistent at the bedside. Indeed, true clinical competence is a blend of knowledgeable application of medical science along with the recognition and understanding of the human condition. The art of this blend, the integration of these two disciplines, and how well it is done, is what determines the quality of patient care that we provide. One without the other is not sufficient.

This can be a science unto itself. One of the influences that this site will hopefully promote is more discussion and ultimately more research on how to practice this art in a more meaningful and fulfilling way for both ourselves and our patients alike. In addition, the more formal exploration and inclusion of these concepts into medical training programs would have a huge effect on the future of medicine in this country.

Some people say you have to be born with this talent. I don’t think so. I do think it comes easier to some than others; but, whatever the genetics and background of the individual, patient care is an art that can be learned and practiced and improved upon, just as drawing or painting a thoughtful picture can be learned and practiced to the point where it can be greatly appreciated by others.

So what kind of doctor or nurse or care partner do you want to be?

What is your approach to patient care?

How do patients perceive your approach to them and your overall competence?

If you long to be one of those caring, well-respected and revered medical professionals that patients (and even other professionals) admire and tell their friends and neighbors about, you’ve found the right place.

Read and study the pages on this site. You will become a much more people-oriented professional, knowledgeable about how to approach all kinds of patients and challenging situations, and who will at the very least be perceived as someone who cares and is concerned about his or her patients.

If you practice what you learn here, you may find yourself actually rediscovering virtues you didn’t know you had. If you already have the nurturing gene, these pages will help you hone that talent into something very special; and your patients will benefit from it in ways you never thought possible.

Source : http://www.art-of-patient-care.com/

EULAR 2009: New Diagnostic Recommendations for Knee Osteoarthritis

2009-07-02T00:51:00.000+07:00

New EULAR recommendations for the diagnosis of knee osteoarthritis unveiled here focus on simple measures — clinical examination and plain radiography.

"These recommendations should be especially helpful for primary care physicians in providing them a firm foundation of diagnostic criteria," said lead author Weiya Zhang, associate professor at the University of Nottingham in the United Kingdom.

The guidance was released here during EULAR 2009: The Annual European Congress of Rheumatology.

Dr. Zhang pointed out that these EULAR recommendations differ from American College of Rheumatology (ACR) criteria by focusing on clinical diagnosis rather than classification, and they are more generalizable to different populations because they were based on a thorough evidence-based review of studies from 1950 to 2008 as well as expert consensus from different countries.

The task force was made up of 17 osteoarthritis experts from 12 countries. The expert panel developed 10 key recommendations, and then tested the diagnostic accuracy of these recommendations on 2 separate study populations: one from the United Kingdom and one from the Netherlands.

Three Recommendations Presented

At EULAR, Dr. Zhang presented 3 of the new recommendations — one on risk factors, one on clinical diagnosis, and one on radiography. The full document that includes all 10 recommendations will be published soon.

Risk factors for knee osteoarthritis were identified as follows: female sex, aging, overweight, joint injury, malalignment, joint laxity, occupational and recreational use, family history, and Heberden's nodes (bone overgrowth) at the distal finger joints.

The recommendation for clinical diagnosis focused on 3 symptoms (pain on use, short-lived morning stiffness, and functional limitation) and 3 signs (crepitus, restricted movement, and bony enlargement). The panel found that the 3 signs and 3 symptoms could correctly identify 99% of patients with knee osteoarthritis.

A validation study in the UK sample using the 6 criteria identified a prevalence of knee osteoarthritis of 44%. The probability of making the diagnosis increased with increasing use of the 6 features.

"This performance test tells us that the clinical diagnosis of knee osteoarthritis can be made with confidence based on these factors," Dr. Zhang said. "These 6 criteria apply even if the radiographs appear normal."

The third recommendation called for plain radiography of the knees, with a weight bearing, semi-flexed view, plus a lateral and skyline view. Classical features of osteoarthritis on radiography are space narrowing, osteophytes, and subchondral bone sclerosis.

"There is no gold standard for knee osteoarthritis, as there is for gout, but using the 3 views increases the probability of a correct diagnosis," Dr. Zhang explained. "Other imaging modalities, such as MRI [magnetic resonance imaging], sonography, and scintigraphy, are seldom needed.

"We call radiography a reference standard, not a gold standard," he pointed out. "Some patients with radiographic damage may not have symptoms, and some patients with symptoms may not have evidence of radiographic damage."

This is the first formal EULAR recommendation for diagnostic imaging for knee osteoarthritis. Imaging may also be needed for management, Dr. Zhang noted.

Consider Recommendations Within Context

The new EULAR recommendations should be considered within the context of the many new treatments available for osteoarthritis and the need to have a consensus for training purposes, according to Andrew Cope, MD, from King's College in London, United Kingdom.

"These are recommendations, not fixed guidelines. The idea is to guide clinicians according to the evidence base. There is no question that some patients won't fit the parameters, which is always a weakness of population-based recommendations. The long-term, far-off goal for rheumatologists is patient-specific targeted management," Dr. Cope said.

The recommendations should be helpful for primary care physicians, he continued. "Keep it simple, keep it safe," he said.

Dr. Zhang, the other panel members, and Dr. Cope have disclosed no relevant financial relationships.

EULAR 2009: The Annual European Congress of Rheumatology: Abstract OP-0209. Presented June 12, 2009.

Clinical Implications

Risk factors for knee osteoarthritis include female sex, aging, overweight, joint injury, misalignment, joint laxity, occupational and recreational use, family history, and Heberden's nodes; plain radiography is recommended with a weight-bearing, semi-flexed view plus a lateral and skyline view.
Clinical diagnosis should focus on 3 clinical symptoms (pain on use, short-lived morning stiffness, and functional limitation), and 3 signs (crepitus, restricted movement, and bony enlargement) with a prevalence of 44% in a UK sample using all 6 criteria.

Source : http://cme.medscape.com/viewarticle/704387?src=cmenews

EMEA Issues Warning on Possible Clopidogrel-PPI Interaction, But Is There Really a Problem?

2009-06-25T12:00:00.001+07:00

The European Medicines Agency (EMEA) has now issued a public statement on a possible interaction between clopidogrel (Plavix, Sanofi-Aventis/Bristol-Myers Squibb) and proton-pump inhibitors (PPIs) and has recommended that the product information for all clopidogrel-containing medicines be amended to discourage concomitant use of PPIs unless absolutely necessary [1].

The UK medicines regulator, the Medicines and Healthcare Products Regulatory Agency (MHRA), has also issued advice to GPs that concomitant use of a PPI with clopidogrel is not recommended unless considered essential, urging a review of the prescribing of PPIs at the next appointment for patients taking clopidogrel.

This follows an "early communication" issued by the US FDA earlier this year, stating that PPIs might interfere with the effectiveness of clopidogrel and that clinicians should reevaluate starting or continuing treatment with a PPI in patients taking clopidogrel.

But several leading cardiologists have voiced concern that the studies on which these warnings are based have many limitations and that it is far from certain whether there really is an interaction between clopidogrel and PPIs.

The EMEA statement points out that, as heartburn and stomach ulcers can occur as side effects of clopidogrel, patients taking clopidogrel often take PPIs to prevent or ease these symptoms. Figures from the UK estimate that around 500 000 patients in that country are currently prescribed clopidogrel and around half are also prescribed PPIs. Many more may be buying omeprazole over the counter, as it is available without prescription. Other PPIs available on prescription include esomeprazole, lansoprazole, pantoprazole, and rabeprazole.

EMEA says the new concern "relates to several recently published studies examining clinical outcomes of clopidogrel users. Taken together, these studies suggest that a significant interaction might occur between clopidogrel and members of the PPI class of medicines, making clopidogrel less effective when given with these medicines." It adds: "One possible explanation for this observation is that some PPIs prevent the conversion of clopidogrel into its biologically active form in the body, reducing the effectiveness of clopidogrel and increasing the risk of heart attack or other conditions involving harmful clotting (eg, strokes). However, as different PPIs have different capacity to affect the metabolism of clopidogrel and as the outcome studies have not fully reflected the different effect of PPIs on activation of clopidogrel, there may be more than one explanation for the effect of this class of medicines on clopidogrel."

Is It Just Confounding?

But some cardiologists contacted by heartwire about this issue are concerned that the clopidogrel-PPI interaction has been given too high a profile, given that the clinical studies suggesting such problems are all observational.

Dr Peter Berger (Geisinger Health, Danville, PA) commented to heartwire : "There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve."

He noted that these studies have shown that patients on clopidogrel and a PPI do worse than those on clopidogrel alone, but that there are three explanations for why that might be the case:

PPIs may interfere with the production of the clopidogrel active metabolite.
PIs may directly cause harm.
The effect may be due to confounding in the reported studies.

Berger says: "Everyone is assuming that the first explanation--that PPIs interfere with the metabolism of clopidogrel--is the reason, but I believe the third explanation is most likely correct. There is enormous confounding in these studies. Patients taking clopidogrel plus a PPI were much older and sicker than those taking clopidogrel alone. No amount of statistical adjustment can eliminate confounding when there are such large differences. That is always the problem with observational studies."

There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve.

Berger also points out that there are two randomized databases that are not subject to confounding, and both suggest that there is no interaction between clopidogrel and PPIs. His group has performed an analysis of the CREDO trial, which was presented at the AHA 2008 meeting and showed the same reduction in risk with clopidogrel regardless of whether patients were or were not taking PPIs. And PPI use was independently associated with adverse cardiovascular events at 28 days and one year in the overall population.

The second randomized trial database is the TRITON trial, where, Berger notes, prasugrel showed the same relative benefit over clopidogrel in patients taking a PPI and those not taking a PPI. "Prasugrel is not believed to be affected by a PPI interaction, and if there were an interaction with clopidogrel and PPIs, you would expect to see a larger relative benefit of prasugrel over clopidogrel in patients taking PPIs than those not taking PPIs, but that was not seen," he added.

"In all randomized data so far, patients taking PPIs have more events--that is because they are older, with more comorbidities, and taking more medications. Patients on H2 blockers do worse as well. This tells us that patients who have stomach problems are older and sicker," Berger stated.

He notes that concerns about other drugs that were thought to interact with clopidogrel have been raised before but were subsequently dropped. "This happened with atorvastatin and calcium blockers, but these concerns were refuted in both cases when randomized studies were analyzed," he noted. "While no one knows for sure whether there is an interaction with PPIs or not, I believe that the burden of evidence at the moment supports the view that PPIs do not interact with clopidogrel. I believe the FDA and EMEA statements are premature," he added.

Issue Overpublicized?

Dr Shamir Mehta (McMaster University, Hamilton, ON) is another who believes the evidence for the interaction is shaky. He raised very similar points to Berger's. "The cohort studies suggesting an interaction are very interesting, but they are observational, and patients taking PPIs are fundamentally different from those not taking PPIs. There are probably many unmeasured variables that could account for the difference in events seen. And data from the randomized trials (CREDO and TRITON) do not support an interaction. The fact is that we simply don't know."

Mehta is not critical of the regulatory authorities' statements on the possible interaction, saying, "They are just being cautious." But he expressed surprise about the amount of publicity that this issue has attracted. "There are observational analyses published all the time suggesting different things, but this PPI-clopidogrel interaction has sparked a huge amount of interest. Why this has been singled out I don't know."

There are lots of heavily confounded registry data circulating that have been widely reported and given more weight than they deserve.

The fact is that we simply don't know.

Another to voice a similar view is Dr Gabriel Steg (Centre Hospitalier Bichat-Claude Bernard, Paris, France). He commented to heartwire : "I think the recommendation that clopidogrel and PPIs should not be used together is too strong. Yes, there are good pharmacokinetic data showing an interaction between clopidogrel and omeprazole, but there are other studies suggesting that the clinical impact of the pharmacokinetic interaction may be limited." Steg also points out the hazards of observational studies: "We just need to remember the many observational studies that pointed to the major cardiovascular benefit of HRT in postmenopausal women." He adds: "More important, patients receiving clopidogrel often receive aspirin and other antithrombotics, and the potential for GI bleeds in this population is also real. So it is important to look at the big picture of overall clinical benefit of prevention of GI bleed vis-a-vis the potential for reduced effectiveness. In my view, the data are not definitive yet."

Other experts were more cautious. Dr Shaun Goodman (St Michael's Hospital, Toronto, ON) said: "We’ve been 'fooled' by observational studies before. But there is some biological plausibility based on the genetic-polymorphism data and some platelet-inhibition studies that warrant caution." Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) pointed out that in some of the observational data sets there was inadequate/incomplete information on concurrent aspirin use and that the higher event rate in the PPI patients may have been simply due to lack of aspirin in patients at risk for GI bleeding. But he added, "Nonetheless, there is a consistency across the observational data that should cause us to take pause."

Is There a Difference Between PPIs?

Another point of uncertainty is whether there may be a difference between individual PPIs, with some pharmacodynamic studies suggesting an interaction with omeprazole but not with pantoprazole. Dr Dirk Sibbing (Deutsches Herzzentrum, Munich, Germany), who conducted one such study, says he believes there is a difference between the various PPIs. "From my point of view, pantoprazole is safe to use with clopidogrel. The clinical evidence, however, is conflicting. But there has been one clinical trial from Canada suggesting an interaction with omeprazole but not with pantoprazole, which fits with our results," he said. He added that from a mechanistic view it is known that omeprazole is metabolized by the CYP219 enzyme, which converts clopidogrel into its active metabolite. And while pantoprazole can also be metabolized by this enzyme, it also uses other routes.

So What Are Doctors Supposed to Do?

All the experts contacted by heartwire agreed that although the data are not definitive, doctors should still be cautious, and PPIs should be prescribed to patients taking clopidogrel only if they are having stomach problems that are not controlled with H2 antagonists. There has been a recommendation that PPIs be given as blanket gastric protection to patients at risk of gastric problems taking dual antiplatelet therapy, but everyone heartwire spoke to said this was no longer advisable, given the possibility of an interaction. Goodman said he didn’t think the data were strong enough to support routine use of a PPI with dual antiplatelet therapy even before this whole interaction issue came to the forefront.

Remember the many observational studies that pointed to the major cardiovascular benefit of HRT in postmenopausal women.

Berger said: "Obviously, given the uncertainty, caution is appropriate, but in patients who we know need a PPI, I would not change or stop therapy at this point just because they are taking clopidogrel."

Sibbing commented: "In our clinic, we try not to use PPIs in patients taking clopidogrel, but if they really need one, we would give pantoprazole." But Berger says he would not differentiate between any of the PPIs or switch a patient off omeprazole and onto a different PPI. "Okay, some pharmacodynamic studies may have suggested a problem with omeprazole but not with the others, but I do not believe it is appropriate to guide therapy based on ex vivo studies of platelet function quite yet," he argued.

Harrington believes that the decision whether to prescribe a PPI to a patient on clopidogrel must be made on an individual patient basis. "A blanket statement to use or not use these drugs in combination seems to be overstepping the available evidence. Caution should be used regarding combining the drugs, selecting types of stents (ie, drug-eluting) that necessitate more prolonged antiplatelet therapies in patients with an increased risk for GI bleeding, etc," he commented. Dr Deepak Bhatt (VA Boston Healthcare System, MA) said: "There is a great deal of confusion. For the time being, it seems reasonable to make sure that patients who are prescribed PPIs really have a good indication for them. Beyond that, it seems premature to change clinical practice, unless new, more compelling data become available."

More Data on the Horizon

All the experts called for a randomized trial to investigate this question. But the only one that was under way--COGENT-1--was stopped prematurely by the sponsor due to financial issues. But other ongoing trials of clopidogrel have been tracking PPI use, including two large studies being reported at the forthcoming European Society of Cardiology meeting--OASIS 7/CURRENT and PLATO--and Berger has also requested permission from Bristol-Myers Squibb/Sanofi-Aventis to analyze the CAPRIE database regarding PPI usage. So more data should be available soon.

References

European Medicines Agency. Public statement on possible interaction between clopidogrel and proton-pump inhibitors. May 29, 2009. Available here.

Source : http://www.medscape.com/viewarticle/704651?sssdmh=dm1.488649&src=nldne

The Basic Geriatric Respiratory Examination

2009-06-24T13:02:00.001+07:00

The objective of the pulmonary assessment of a geriatric patient is to check for the following:

Quality of respiratory efficiency;
Gas exchange; and
Presence of disease.

Assessing Respiration Efficiency

Of note, if the patient is bedfast, complete evaluation of respiratory efficiency is often less than optimal because chest expansion is not always symmetric and percussion notes may be less resonant.

Respiratory Rate

Although a patient's respiratory rate is often recorded in his or her chart (most often as 20 breaths per minute), cultivate the discipline to obtain it yourself. Count the respirations for a minute and observe the pattern and degree of respiratory effort. Note that moving the diaphragm without moving any air does not count as a breath. Normal respiratory rates for older patients are12 to 18 breaths per minute for those living independently and 16 to 25 breaths per minute for those in long term-care.

Tachypnea. A respiratory rate of 20 breaths per minute (or more than 25 breaths per minute for someone in a nursing home) indicates tachypnea. In such cases, look for the following:

Infection (especially pneumonia);
Reactive airways disease (eg, in acute exacerbations of chronic obstructive pulmonary disease [COPD], the patient has air trapping and cannot empty the lungs);
Congestive heart failure (patient pants in midrespiration);
Pulmonary embolus (very few elderly patients with pulmonary embolus have respiratory rates less than 16); and
Metabolic acidosis.

A respiratory rate of more than 30 breaths per minute in a patient with suspected abdominal disease suggests primary chest disease with referred symptoms to the abdomen.

Bradypnea. Bradypnea is a form of hypoventilation, in which the patient has a respiratory rate of less than 10 breaths per minute. In such cases, you might suspect severe myxedema, ingestion of central nervous system (CNS) depressants (eg, narcotics, benzodiazepines), or CNS disease (pontine hemorrhage, hypoglycemia, meningitis).

Respiratory Effort

Normal breathing is quiet and unlabored. If it is labored, it is important to note respiratory effort. In patients with pneumonia or acute abdomen, labored breathing prevents airway closure. Patients who have air hunger will often breathe with an open mouth. Pursed lip breathing mainly in expiration is seen in end-stage emphysema and suggests small-airway disease with terminal bronchiole collapse. Expiring with pursed lips increases the end-expiratory pressure, keeping the airways open and reducing the work of breathing. (It takes more work to put the first breath into a balloon than to add a breath to an already half-filled balloon.)

Audible Breath Sounds

Pay attention to the breath sounds. Wheezing, a musical sound, is an important clue to reactive airways or local obstruction. Coughing indicates lower airway irritation. Stridor (a high-pitched shrieking sound) implies partial airway obstruction. Expiratory stridor without inspiratory stridor suggests lower airway obstruction. Stridor on inspiration and expiration implies airway obstruction at the glottis. Of note, inspiratory stridor suggests obstruction in the oral airway or epiglottis and is a medical emergency.

Respiratory Patterns

Check for respiratory patterns and signs that indicate specific conditions. For example, inspiration interrupted by cough suggests pleuritic pain or inflammation. The following are other patterns and signs to look for.

Kussmaul's Respiration. Kussmaul's respiration is deep rapid respiration (an exaggeration of normal) in metabolic acidosis and is classically associated with diabetic ketoacidosis. Patients with Kussmaul's respiration may have an increase in tidal volume. While talking, they need to breathe between phrases, so their speech pattern can seem choppy.

Cheyne-Stokes Respiration. The pattern of Cheyne-Stokes respiration is one of increasingly deep respirations followed by a steady diminution of breathing until an apneic episode occurs, which can signify prolonged circulatory time or primary neurologic disease. Among the differential diagnoses are the following:

Primary CNS disease;
Chronic heart failure, meningitis;
Pneumonia;
Carbon monoxide poisoning; and
Medications (eg, morphine).

Obesity may be present. Some patients will show pupillary dilation with rapid breathing and pupillary contraction with apnea.

Biot's Breathing. Biot's breathing is characterized by irregular breathing (the "atrial fibrillation" of respiration) with sudden apneas. It suggests CNS disease and can be a sign of increased intracranial pressure or meningitis.

Apneustic Breathing. Apneustic breathing is seen in severely ill patients with coma. The patient holds his or her breath at the end of inspiration until the Hering-Breuer (carotid body) reflex initiates exhalation. This breathing pattern suggests pontine disease.

Chest Movement During Respiration

The next part of the chest inspection is to observe the patient's chest movement during respiration.

Use of Accessory Muscles

Using accessory muscles implies that the forced expiratory volume in 1 second (FEV1) is decreased to 30% of normal, which is usually between 1.0 and 1.5 liters per second. In such cases, a sitting patient may lean forward with hands propped on the knees. Sternocleidomastoid tension is often present, which is indicated by tense neck muscles, with the muscle being thicker than the patient's thumb.

Diaphragm Movement

Diaphragm movement can sometimes be seen with inspiration as a flickering along the lateral chest. A loss of this movement on one side indicates a paralyzed hemidiaphragm (Litten's sign). Diaphragmatic movement is usually not visible in overweight people.

Chest Symmetry

To check chest symmetry, observe the sides of the chest from the patient's back. Symmetric but decreased expansion suggests extreme old age or emphysema. Decreased chest expansion resulting from substernal goiter is Bryson's sign. Symmetric but increased expansion suggests paralysis of the diaphragm with compensatory intercostal contractions. Asymmetric expansion suggests pneumonia, a large pleural effusion, rib fracture, or pneumothorax. With hemiplegia, the affected side moves more than the unaffected side during quiet respiration but becomes more sluggish with forced respiration (Jackson's breathing sign).

Paradoxic Chest Movements

Paradoxic sternal movement suggests trauma or multiple rib fractures. Paradoxical abdominal movement, in which the abdomen moves out with expiration, can be a sign of a paralyzed diaphragm, respiratory failure, or fatigue during an exacerbation of COPD. Intermittent paradoxic abdominal movement may be caused by muscle fatigue from respiratory pump failure (respiratory alternans). Epigastric depression with inspiration suggests large pericardial effusion or a paralyzed diaphragm (Duchenne's sign).

Intercostal Retractions

Intercostal retractions suggest an imbalance between the negative pressure generated and the ability of the lung to expand. Generalized retractions are a sign of significant inspiratory obstruction. Focal retractions suggests bronchial obstruction, flail chest, or constrictive pericarditis (Broadbent's sign) if over the heart. With flail chest, the ribs themselves show paradoxic movement. Unilateral loss of normal retractions suggests pleural effusion, pneumothorax, or consolidation.

Bulging Interspaces and Apices

Bulging interspaces on inspiration suggests a tension pneumothorax, a large pleural effusion, emphysema, or reactive airways disease. Elevation of the supraclavicular space in an asynchronous manner suggests pleural effusion as the lung floats like a cork on the pleural fluid. The side with the fluid will elevate first.

The Costal Angle (Hoover's sign)

An especially useful observation is to watch the costal angle during respiration (Hoover's sign). Normally this angle should increase as the intercostal muscles open the chest as the diaphragm contracts. Hoover's sign is paradoxic closing of the costal angle with inspiration because of the loss of intercostal contribution secondary to air trapping. This sign indicates chronic obstruction and an FEV1 less than 1 liter per second. Restrictive lung disease by itself does not produce Hoover's sign.

Unilateral Movements

If there are unilateral movements, consider the source of the inequality. One side moving more laterally implies significant atelectasis if it is pulling up from above or subphrenic abscess if pushing up from below.

If one side moves more medially than the other, consider intercostal paralysis, pleural effusion, or tension pneumothorax. Unilateral narrowing of the intercostal spaces suggests pneumothorax or inflammation (Przewalski's sign). If you see decreased medial movement with normal lateral movement, consider cardiac enlargement, severe right heart failure, and pericardial effusion.

Palpation

Palpate the Lateral Chest Walls

Palpation over the lateral chest wall can provide helpful information on respiratory excursion. Make sure your hands are warm before beginning. Feeling an area of localized warmth in a febrile patient could represent an empyema. Appreciating a mass in the chest wall could represent a rib fracture (there may be an area of point tenderness and possibly ecchymosis), tuberculosis, nocardia, or actinomycosis. A mass felt in an interspace suggests abscess (possibly actinomycosis, tuberculosis, or empyema necessitans) or lymphadenopathy from lymphoma. Detecting crepitus suggests subcutaneous emphysema from a rib fracture, ruptured bleb with pneumothorax, esophageal rupture, or abdominal perforated viscus with retroperitoneal air tracking.

Palpate the Trachea

If you have not already done so, palpate the trachea. Check the lateral tracheal wall with the clavicular heads to determine whether it is midline. Deviation from the midline is significant.

Palpate Rib Expansion

Palpate the rib expansion segmentally. For examining the upper lobes, place your hands on each upper lobe with the thumbs under each clavicular head. Watch for symmetric thumb expansion with each inspiration. To check the middle and lingular segments, place your hands across the lower chest with each thumb at the fifth intercostal space on the sternum. Watch for symmetric thumb expansion with each inspiration. A lack of symmetric movement suggests bronchial stenosis on the side with the reduced movement.

To evaluate the lower lobes, place your hands across the lower chest anteriorly, with each thumb at the costal margin.

It is especially useful to check the costal angle during respiration. Normally the angle increases on inspiration as the intercostal muscles open the chest and the diaphragm contracts. Paradoxic movement with a decrease in the costal angle on inspiration that is caused by severe air trapping in COPD (FEV1 <>

Tactile Fremitus

Checking for tactile fremitus requires detecting palpable vibrations. Have the patient say "toy coin" each time you touch the chest with the ulnar side of your hand. The "oy" sound is the key to producing the vibration. (It is sometimes recommended to ask the patient to say "99." However, the origin of this came from the German words for "99," which in that language contains "oy" sounds.). Feeling increased vibration (fremitus) over an area of dullness to percussion suggests consolidation or direct communication between the bronchus and the chest wall. Appreciating decreased fremitus over an area of dullness suggests pleural effusion or pneumonectomy. Use both hands to compare each side simultaneously. Begin at the apices posteriorly and work down the back, then go anteriorly to the apices. Normally the right apex will have slightly more fremitus than the left because of the aortic position. Note the level of the diaphragm.

Pain on Palpation

Localized pain on palpation suggests early herpes zoster, rib fracture, or costochondritis (Tietze's syndrome). Sternal tenderness can be a sign of fracture, leukemia (classically the lower third of the sternum), other blood marrow abnormalities, metastatic prostate cancer, or xiphoidalgia. Pneumonia can produce tenderness and spasm of the insertion of the sternocleidomastoid muscle.

Percussion

General Points

As with palpation, make sure your hands are warm before you begin percussion. Start at the back and check each side to compare the quality of the sensation. It is key to keep the wrist loose and the hand floppy. As you percuss, consider the characteristic of the structure you are percussing. One trick is to practice over a table percussing from the center toward the legs. Notice how the percussion note feels firm when over the leg of the table. Close your eyes and practice until you can reliably stop over the leg. Sometimes an elderly patient is too ill to sit up and percussion must be accomplished with the patient in the lateral decubitus position. This position can add some artifacts of lung compression, producing dullness in the mid lung fields of both the dependent and upward lungs. Of note, the feel of the resonance may be more sensitive than the sound of the percussion note, especially in a noisy setting such as a crowded emergency room, where subtleties of sound are more difficult to appreciate.

Basic Percussion Techniques

There are 3 basic percussion techniques: the light pat (an excellent general technique for pulmonary examination), the direct percussion, and the indirect percussion (what students are generally taught as percussion).

Light pat. Gently pat the back on each side starting at the apices and moving down to the diaphragm.
Direct percussion. Place your dominant hand on the skin and raise your forefinger and tap on the skin directly.
Indirect percussion Place your non-dominant hand on the skin and with your dominant middle finger tap the middle finger of your nondominant hand at the sistal interphalangeal joint.

Some experts believe that the second and third techniques are best used to define an interface such the cardiac border or the upper border of the liver.

The Sequence of Percussion

The patient should be upright if at all possible. Percuss down the posterior midclavicular line on each side of the chest. Note the diaphragmatic excursion by checking its level during expiration and then during deep inspiration. Normally this excursion is about 4 centimeters. Compare each side.

After percussing the diaphragm, percuss down the midaxillary line on each side. An elevated left hemidiaphragm is clearly abnormal and implies volume loss, paralysis of the left hemidiaphragm, or a left upper quadrant abdominal mass. An elevated right hemidiaphragm is normal but can suggest volume loss, a right upper quadrant mass, and a paralyzed right hemidiaphragm.

Next, percuss across the trapezius from the shoulder to the base of the neck to check Krönig's isthmus (of resonance) on each side. This area is significantly more resonant than the shoulder or the base of the neck. Loss of normal resonance in this area suggests upper lobe disease.

Percuss the clavicles. Dullness on one side suggests upper lobe disease.

Finally, percuss over the right middle lobe in the right midchest and along the left anterior chest.

Dullness and Its Indications

Dullness to percussion implies consolidation, pleural fluid, or pleural scarring. Parenchymal consolidation suggests pneumonia or cancer. If you suspect pleural fluid, recheck your percussion with the patient in the lateral decubitus position with the dull side up. Look for any change in dullness caused by fluid shift. No change in dullness with a change in position implies either consolidation or loculated fluid. Dullness to percussion plus absent breath sounds caused by hydatid disease in the lungs is Bird's sign.

Dullness in the medial base of the lung (Grocco's triangle) near the spinous process is contralateral to a pleural effusion (or significant pneumonia) and is ipsilateral to a massive pleural effusion or pericardial effusion (obviously on the left side).

Dullness below the left scapula (Ewart's sign) or below the right scapula (Conner's sign) suggests a large pericardial effusion.

Pleural effusion may be suggested by the following:

Increased rib vibration in the anterior chest to percussion posteriorly (Kellock's sign);
Change in the percussible dullness with change in position (D'Amato's sign); or
Hyperresonance just above an area of dullness (skodaic hyper-resonance).

With small pleural effusion, dullness is in the T9 to T11 interspaces. In pneumothorax, the percussion note is more resonate (Biermer's sign). In this case, check for hyperresonance over the midclavicle. Confirm by appreciating decreased breath sounds over the hyperresonant side and with the coin test (see below).

Noting a band of hyperresonance near the diaphragm suggests subphrenic abscess or lower lobe pneumonia.

Auscultation

General Points

Make sure that the listening area is quiet, and importantly, do not listen through the patient's clothing. Warm your stethoscope either by carrying it in your pants pocket or by vigorously rubbing it. One strategy is to place a rubber membrane on the bell and have the patient breath deeply with the mouth open. Make sure that your stethoscope bell is securely placed flat on the chest and that you are not breathing on your tubing. In fact, breathe on the tubing beforehand to appreciate the low-pitched rustling sound your breath produces. Be sure that your earpieces are securely in your ears to exclude environmental noise.

Listen to at least 2 respiratory cycles at each location. All breath sounds should increase in pitch with inspiration and decrease with expiration. If patient has been intubated, listen for bilateral breath sounds and over the epigastric area to help determine the tube placement.

Begin at the bases and work up the back. Starting at the bases allows you to appreciate any basilar crackles secondary to atelectasis or early congestive heart failure. If you start at the apices and work down, such crackles might disappear by the time you get to the bases. If you hear additional noises make sure they are coming from the patient's chest and not from the skin, muscles, or other extraneous source. For example, body hair can produce a crackling sound that resembles dry cellophane crackles.

Quality of Breath Sounds

Alveolar (vesicular) breath sounds are normal but pathologic processes cause these sounds to disappear. Upper airway or bronchial (tubular) breath sounds are normal over an airway but hearing these sounds in the peripheral lung fields suggests consolidation or lymphadenopathy. They also may be heard at the top of a pleural effusion. Bronchial breath sounds are only heard at the top of the effusion. Pay attention to the inspiratory to expiratory ratio of breath sounds. Chronic obstructive lung disease increases the expiratory phase of respiration. Hearing equal inspiratory and expiratory sounds suggests respiratory obstruction (Grancher's sign). Localized prolongation of expiratory sounds is Jackson's sign, which can sometimes signify a localized obstruction such as an endobronchial mass.

Loudness of Breath Sounds

Increased breath sounds over an area of dullness suggests consolidation. If there is upper lobe consolidation, consider tuberculosis, Pancoast's tumor, or aspiration pneumonia. Signs of middle lobe consolidation suggest pneumonia, malignancy, or conditions producing lymphadenopathy (middle lobe syndrome). Lower lobe consolidation suggests pneumonia, aspiration, or pulmonary infarct. Decreased breath sounds over an area of consolidation suggest pleural effusion or pneumonectomy.

Adventitious Breath Sounds

If there is stridor (see above), listen over the trachea or at the base of the neck to see if loudness is greatest there. Stridor heard on inspiration is a red flag for a medical emergency and you should consider epiglottic obstruction, epiglottitis, vocal cord dysfunction, tracheal obstruction, whooping cough, neoplasm, foreign body, tracheal stenosis, or palatal obstruction. Stridor only in expiration suggests lower airway obstruction, such as from a foreign body.

Wheezes

Wheezes are musical sounds that indicate airway obstruction, which when it occurs during expiration, suggests a source within the chest. Wheezing that occurs on inspiration suggests obstruction in the trachea (outside the chest). Hearing both inspiratory and expiratory wheezes is more concerning than hearing either alone. Focal wheezes help to localize the site of obstruction. End-expiratory wheezes suggest reactive airways (asthma) and imply bronchiolar disease. Peak flow is reduced significantly. Hearing wheezes throughout expiration suggests asynchrony of one lung area with another, such as occurs with organophosphate poisoning. Hearing end-inspiratory wheezes implies a small airway opening in the deflated section of lung. This finding suggests chronic bronchitis, bronchiectasis, or organophosphate poisoning. Hearing wheezes throughout inspiration implies a fixed stenosis or obstruction of the upper tracheal bronchial tree, such as in interstitial fibrosis or hypersensitivity pneumonitis.

Crackles (Rales)

Inspiratory crackles are common in elderly people. Early inspiratory crackles, however, imply significantly decreased FEV1/forced vital capacity caused by broncho-obstructive disease as a result of chronic bronchitis, emphysema, or reactive airways disease. Midinspiratory crackles suggest bronchiectasis, whereas late inspiratory crackles suggest restrictive (alveolar) disease caused by congestive heart failure, idiopathic pulmonary fibrosis, sarcoidosis, or drug toxicity.

Localized midexpiratory crackles can be a sign of bronchiectasis or pneumonia. Note the location of expiratory crackles. If their location changes with the patient's position, consider congestive heart failure because this implies an increased pulmonary capillary wedge pressure (above 25 mm Hg). Fixed crackles suggest fibrosis or pneumonia.

Note the quality of the crackles. Peripheral lesions tend to increase the pitch (fineness) of the crackles. Fine crackles (like crackling cellophane) suggest interstitial fibrosis, sarcoidosis, or asbestosis. Coarse Velcro®-like crackles suggest chronic pulmonary fibrosis. Moist crackles (resembling the sound of the fizz of a carbonated drink) suggest congestive heart failure. Posttussive rales (crackles) suggest parenchymal disease or lung abscess.

Rhonchi

Rhonchi are coarse flapping sounds that suggest fluid or mucus in an airway.

Amphoric Breathing

Amphoric breathing is a low-pitched sound resembling blowing over a soft drink bottle (an amphora). To appreciate the nature of this sound, trying listening over the occiput while the patient whispers "wahoo." Amphoric breathing is never heard in the presence of alveoli so hearing it suggests alveolar destruction with air going into and out of a cavity and signifies a large bullae or lung abscess. Disappearance of amphoric breathing suggests that something has occupied the void (aspergillus fungus ball or fluid).

Pleural Friction Rubs

Pleural friction rubs are leathery, creaky sounds similar to the sound of slowly rubbing your palms together. They do not have a musical quality, like a wheeze does, but suggest 2 inflamed pleural surfaces (the parietal and visceral pleura) rubbing together. They can occur on both inspiration and expiration, but they usually occur with inspiration and tend to be localized. Hearing a pleural friction rub implies neoplasm, pulmonary infarction, pneumonia, tuberculosis, or systemic lupus erythematosus. A sternal friction rub heard when the patient raises and lowers the arms suggests aortic arch aneurysm or fibrotic mediastinal tumor (Perez's sign).

Special Sounds and Signs

d'Espine's Sign. During auscultation, when you reach the level of the midscapula (about T5), check for an important sign of a posterior mediastinal mass (d'Espine's sign). Listen on either side of the vertebral column and compare the quality and intensity of these sounds with those over the spinous process. Normally, the lateral sounds are louder and more distinct. With a positive d'Espine's sign, the vertebral breath sounds are loud and upper airway sounds are of greater intensity than the corresponding lateral lung sounds. This implies continuity between the main stem bronchus and the vertebrae and suggests malignancy, lymphoma, metastatic cancer, tuberculosis, sarcoidosis, and other causes of mediastinal lymphadenopathy. Listen for egophony, bronchophony, and whisper pectoriloquy. These may be more sensitive for posterior mediastinal lymphadenopathy than the change in breath sounds. If d'Espine's sign is present, try also percussing over the spinous processes of T1-T5. The appearance of red spots over the spinous processes of T1-T5 after percussing them suggests bronchial lymphadenopathy (Cattaneo's sign). False positives of d'Espine's sign can occur in severe kyphosis, which should be obvious.

Egophony (Goat Sound). Egophony (or goat sound) is an "e" to "a" change and is considered the most sensitive sign of pulmonary consolidation. Have the patient say "e." A compressed lung will produce a bleat like a goat, changing the "e" to an "a" sound. For practice, listen over the skull or the base of the neck where this "e" to "a" change is normal. Egophony may be present along the top of a pleural effusion. It may also be present over a massive pleural effusion caused by significant lung compression. Extensive pulmonary fibrosis can also produce egophony.

Whisper Pectoriloquy. Whisper pectoriloquy is the second best sign of consolidation. Have patient whisper "66 whiskeys please," which produces hissing sibilant "s" sounds. When bronchial breathing is abnormal, the sounds will be more distinct and you can more easily appreciate the words whispered.

Bronchophony. In bronchophony, spoken sounds seem more distinct when listening over a consolidated or compressed lung. Have the patient say a sentence like "UNC is number one," or repeat a word such as "99" several times. With consolidation or compressed lung, the words will be heard clearly over the involved area.

Expiratory Time. Have the patient take a deep breath and exhale as quickly as possible. Listen over the trachea. Hearing expiratory sounds for more than 6 seconds suggests airway obstruction Another but less accurate method is to listen over the upper posterior chest and use a 3-second threshold.

The Test for Pneumothorax. For this test, the patient must be sitting upright and asked to hold a large silver dollar, flat against the chest just below the midclavicle. Tap the silver dollar with another coin. (Note: A Susan B. Anthony dollar or coins such as quarters or nickels are too small and will not work. It must be a pre-1964 silver dollar.) A pneumothorax or a large bulla will produce a loud ringing bell-like sound rather than the usual metallic tap. Tuning forks can sometimes be used as an alternative.

Shephard's Sign of Sleep Apnea. In some patients with sleep apnea, a sonorous expiratory wheeze will develop at the base of the neck. Listen with the patient supine and breathing through his or her nose.

Identifying Specific Conditions

Differentiating Pleural Effusion From Consolidation

Because both pleural effusion and consolidation produce dullness, percuss just above the dullness, preferably using the light pat technique. The following clues each indicate that the presence of a pleural effusion is more likely:

Increased rib vibration in the anterior chest to percussion posteriorly (Kellock's sign);
Change in the percussible dullness with change in position (D'Amato's sign);
A rim of hyperresonance heard just above the dullness (skodaic hyperresonance);
Increased resonance of the thoracic spinous processes (Korányi's sign);
An "s"-shaped line of dullness on percussion of the chest (Damoiseau-Ellis line); and
Change in the tympanitic note above a pleural effusion when the patient opens and closes his or her mouth.

The following are additional techniques for differentiating between pleural effusion and consolidation:

Listen to the quality of breath sounds in the area of dullness. Hearing an increased intensity of sounds suggests consolidation; a decreased intensity suggests pleural effusion;
Listen for egophony (see discussion above). A change to a goat-like "a" sound after saying "e" in the area of dullness suggests consolidation (Shibley's sign). Egophony -- either "e" to "a" or "u" to "a" (Karplus' sign) -- just above an area of dullness suggests pleural effusion;
Hearing no sound at all over an area of dullness implies resection; and
Listen for whisper pectoriloquy by having the patient whisper "66 whiskeys please." Clearly hearing the phrase in an area of dullness suggests consolidation; hearing no sound suggests pleural effusion.

If the signs suggest pleural effusion, gently move the patient while listening over the effusion. Hearing a sloshing sound suggests hydropneumothorax. Note the location of the effusion. A right-sided pleural effusion suggests congestive heart failure. A left-sided effusion suggests pancreatitis, pulmonary infarct, pericarditis, ascites, or a ruptured thoracic duct.

Signs of Cavitary Lung Disease

Pulmonary cavities may be identified in several ways. In patients with pulmonary cavities, the percussion note may change when the patient opens and closes his or her mouth (Wintrich's sign). While listening over a pulmonary cavity, harsh inspiratory sounds that quickly diminish in intensity (Seitz's sign) may be heard. Forced inspiration can lower the pitch of the sound over a cavity (Friedreich's lung sign). Cough following apical percussion producing an area of apical tympany suggests cavitary disease (Ernis' sign).

Signs of Pleural Inflammation

Decreased rib expansion can be caused by an inflammatory process in the lungs (Bethea's sign). Palpable intercostal muscle rigidity suggests pleural inflammation (Pottenger's sign); disappearance of this sign can indicate empyema (Ramond's sign).

Pain offers a clue to possible pleuritic inflammation. With pleuritic inflammation, the patient will lie with the good side down (Andral's decubitus sign). Pleural inflammation can produce sensitivity of the upper back and shoulder muscles to palpation (Sternberg's sign). Pain from pleural irritation may also be referred to the shoulder (Capp's sign). Pain on palpation on the left upper abdominal quadrant (the mirror image of Murphy's point) suggests lower lung pleural inflammation (de Mussey's sign). Chest pain that increases with bending toward the pain suggests intercostal neuralgia; increase in pain bending away from the pain suggests pleuritic pain (Schepelmann's sign).

Examining the Patient With Respiratory Distress

Demeanor and Posture

Patients in respiratory distress may appear restless, agitated, or drowsy. The patient's eyes may be prominent. Patients in respiratory distress will often sit leaning forward using their accessory muscles. Hypertrophy of the sternocleidomastoid may be present and the patient may have calluses on the extensor surface of the forearm or distal thigh (Dahl's sign) as evidence of the chronicity of their lung disease. Patients who sit leaning forward with their legs dependent (Fowler's position) may have severe heart failure. Patients leaning forward with their head protruding forward as if sniffing flowers may have epiglottitis.

Breathing difficulty when sitting up and relieved when supine is platypnea and implies severe upper lobe disease. Patients lying on one side (lateral decubitus position) tend to place the good lung in the dependent position to maximize ventilation-perfusion matching. However, if a pleural effusion is present, it will tend to be on the dependent side.

Skin Color

Obviously the patient's skin color gives important clues to the level of oxygen saturation. Cyanosis suggests at least 5 grams of deoxyhemoglobin. If only the nail beds are cyanotic, the peripheral circulation is clamped down or slowed.

Clubbing of the Fingernails and Schamroth's Sign

One way to see whether the fingers are clubbed is check for Schamroth's sign. Have the patient place both forefinger nails together. If you can see a small diamond space between the nails, the nails are not clubbed. If the diamond is not visible, Schamroth's sign is positive and clubbing is present. Pulmonary causes of clubbing (not an exhaustive list) include the following:

Bronchogenic carcinoma;
Alveolar cell carcinoma;
Pulmonic abscess;
Interstitial pulmonary fibrosis;
Sarcoidosis;
Beryllium poisoning; and
Pulmonary arteriovenous fistula.

Some cardiac and gastrointestinal disorders can also cause clubbing.

Chest Shape and Symmetry

Chest wall deformities can have a significant impact on respiratory dynamics. For example, scoliosis and kyphosis are common in elderly people. The following conditions should also be looked for.

A barrel-shaped chest, indicated by increased anterior-posterior diameter, suggests air trapping caused by chronic lung disease. In some cases of emphysema, the AP diameter may not really be increased but is an optical illusion because of decreased abdominal diameter. Emphysema is also suggested in patients with a thin wiry habitus and distended arm veins.

Pectus excavatum (funnel chest) occurs when the sternum is depressed, creating a funnel-like shape. It is associated with Marfan's syndrome and congenital abnormalities in the respiratory tract and heart.

In pectus carinatum (pigeon chest), the sternum sticks out like a ridge on the chest. It is associated with acromegaly, Marfan's syndrome, and congenital problems of the diaphragm.

Tracheal Location

Normally the trachea is slightly to the right of the midline. Atelectasis and consolidation shifts the trachea toward the involved side. Pleural scarring will cause the trachea to deviate to the involved side during inspiration. Pneumothorax will pull the trachea to the opposite side, whereas massive pleural effusion or goiter will push the trachea to the opposite side

Venous Patterns

Note the venous pattern over the chest, which may indicate specific conditions. Unilateral venous distension suggests an underlying pulmonary neoplasm. Juicy collaterals can be seen in superior vena cava syndrome. Varicosities over the C7-T3 spinous processes is Lombardi's sign of tuberculosis. Fine telangiectasias along the border of the costal margin are commonly seen in elderly men.

Reading List

Maitre B, Similowski T, Derenne J-P. Physical examination of the adult patient with respiratory diseases: inspection and palpation. Eur Respir J. 1995;8:1584-1593. Available at: http://www.erj.ersjournals.com/cgi/reprint/8/9/1584.pdf Accessed May 21, 2009.

Bureau of Medicine and Surgery, Department of the Navy. Hospital Corpsman Sickcall Screener's Handbook. Thorax, Lungs, and Respiratory Disorders. BUMEDINST 6550:9A; 1999. Available at: http://www.brooksidepress.org/Products/OperationalMedicine/DATA/operationalmed/Manuals/
CorpsmanSickcall/ThoraxLungsResp.html Accessed May 21, 2009.

Source : http://cme.medscape.com/viewarticle/703696

Some Surprises in Update to European Hypertension Guidelines?

2009-06-20T21:58:00.001+07:00

The European Society of Hypertension (ESH) is set to stir up the field of BP guidelines later this year, when it publishes an update to its 2007 recommendations. During a special session at the European Meeting on Hypertension 2009 here yesterday, Dr Giuseppe Mancia (University of Milan Bicocca, Monza, Italy), outlined the main changes and said the complete new guidelines will be published in the October 2009 issue of the Journal of Hypertension.

Key among the changes will be the recommendation of a lower threshold level--around 120 mm Hg systolic and 70 mm Hg diastolic--below which it could be dangerous to reduce blood pressure in high-risk individuals, representing the so-called J-curve phenomenon, Mancia said. And rather than emphasizing which antihypertensives should be used first-line, second-line, etc, the new guidelines will instead advise tailoring therapy to individual patient circumstances, he explained.

Also new will be the first European guidelines on the management of high blood pressure in children and adolescents, which will be published in the September 2009 issue of the Journal of Hypertension, Dr Empar Lurbe (University of Valencia, Spain) told meeting attendees. Of key importance among these recommendations will be the indications for future research, she said. "Currently, in Europe, we don't have reference data on adolescents and children, we have to rely on data from the US," so it's imperative that baseline values based on the European pediatric population are established. Other important future endeavors include the development of accurate nonmercury sphygmomanometers for pediatric use and drug trials in this "therapeutic orphan" patient population, she said.

Doctors are also eagerly awaiting new American guidelines on hypertension--the eighth edition of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) is expected later this year--but many are unsure exactly what to expect.

J-Curve: A Narrow Window of Optimum BP for High-Risk Individuals

Mancia told the meeting that the decision to update the 2007 European hypertension guidelines was taken "because, since then, there have been a number of trials published that could change the recommendations, or in other instances, new data have reinforced the recommendations made."

There are also other situations where "difficult and controversial conclusions" have created confusion, he explained, adding that although the new guidelines document "is still under refinement, the committee agrees on the principles and the issues, which is why I can present it today."

In terms of hypertension treatment thresholds and goals, these will remain pretty much the same as in 2007, he said, with a treatment threshold of 140/90 mm Hg or greater for general hypertension, and a therapy goal of <140/90 mm Hg for this population. For high-risk individuals, the treatment threshold is 130/85 or greater and the treatment goal should be <130/80 mm Hg, although he acknowledged that "the more aggressive goal in high-risk individuals is not supported by outcomes trials, so further hard evidence is needed."

But with the decision to include a lower threshold below which BP should not be lowered in high-risk individuals, this means the window of optimum BP will be narrow in high-risk individuals.

Explaining the new decision, Mancia said: "In 2007, apart from HOT, all the trials were retrospective, but we knew there must be a BP below which perfusion of vital organs is compromised. Now, a number of studies--including INVEST, ONTARGET, VALUE and TNT--have been remarkably consistent" in showing that there is indeed a floor for high-risk individuals below which BP should not be lowered "in order to avoid harm," he noted. "If BP approaches 120/70 in high-risk individuals, a J-curve appears, and this should generate concern," he said.

Treat the Elderly; Tailor Treatment to Specific Patients

Another important change since 2007 will be the recommendation for the very elderly, those aged over 80, in whom the benefits of lowering blood pressure had previously been "inconclusive," Mancia explained.

"Now things have changed with the HYVET data, which showed major benefit, suggesting that we prolong the life of these very old people if we control their BP when BP is elevated," although the trial does have some limitations, he commented.

In terms of choice of drug therapy for hypertension, in 2007 there were five drug classes listed as suitable for initiation of therapy--diuretics, ACE inhibitors, calcium-channel blockers (CCBs), angiotensin receptor blockers (ARBs), and beta blockers.

"Since then, a number of important trials have added new evidence in favor of the protective effects of ACE inhibitors, ARBs, and CCBs and have reinforced the position of these drugs as options to treat hypertension and other conditions such as heart failure and renal disease."

One of the controversies with regard to drug choice has been the debate about the use of beta blockers, he said, with the UK NICE and the British Society of Hypertension removing them from first-, second-, and even third-line choice of treatment in 2006.

"In 2007, the [ESH] committee felt this was not an appropriate decision, as beta blockers were usually employed together with diuretics in virtually all trials, so it was difficult to discriminate what was the favorable or unfavorable role of one drug class or another," he noted. And although there have been negative trials with beta blockers--LIFE and ASCOT--there have also been positive ones, such as HAPPHY, IPPPSH, STOP, INVEST, and UKPDS, he noted.

The totality of evidence now shows different conclusions for different patient populations, he said. "For example, for stroke prevention, beta blockers are inferior to calcium antagonists, but for congestive heart failure prevention, beta blockers are superior to calcium antagonists and similar to other drugs," he noted.

In fact, reducing the emphasis on the step-by-step approach to treatment in general--not recommending particular antihypertensives as first-line, second-line therapy--is another central tenet of the new guidelines, Mancia noted.

"Classifying agents as first choice, second choice, third choice, etc, betrays reference to an average patient who hardly exists in clinical practice," he said, adding: "It is much better to indicate which drug might be preferred in which patient under which circumstance. All drugs have advantages and disadvantages, and we have to try to see in which conditions the advantages of a drug come out."

But Combination Therapy Remains Choice for High-Risk Individuals

But the new guidance will again stress the importance of using combination therapy first-line in high-risk individuals, as advised in 2007, he said, although new data in the intervening two years are helping to refine these recommendations, he noted.

"In 2007, we took a strong stance in favor of combination treatment. This has been shown again--trials such as ACCOMPLISH, ADVANCE, HYVET, ASCOT and ONTARGET are changing the picture. We have to lower BP rather quickly [in these patients] to try to prevent a catastrophe," and more recently, studies have shown there is less discontinuation of treatment in this patient population if treatment is started with combination therapy, Mancia said.

"The evidence is now in favor of giving such patients a blocker of the renin-angiotensin system (RAS)--such as an ACE inhibitor or ARB--with a calcium-channel blocker or diuretic." However, he stressed: "This does not mean that other combinations cannot be used or are not useful."

Another issue that was debated was whether the use of an ACE-inhibitor/ARB combination "should be banned," on the basis of the ONTARGET findings, he noted. But he indicated this would likely not be the case, "because this remains an effective treatment to lower proteinuria compared with single blockade of the RAS system, and this is regarded by nephrologists to be important whenever proteinuria is not reduced sufficiently by one agent.

"But, of course, the data from ONTARGET cannot be forgotten," he stressed, "which means dose titration must be cautious, with frequent monitoring of renal function and BP and close attention to environmental circumstances that might reduce bodily fluids."

Source : http://www.medscape.com/viewarticle/704457?src=mpnews&spon=34&uac=133298AG

Malaria

2009-06-19T20:56:00.002+07:00

Introduction

Background

Malaria is the most deadly vector-borne disease in the world. Although typically an illness of tropical regions of the world, more than 1500 cases (nearly all foreign-originating) are diagnosed in the US each year. In some parts of the world, malaria is known as paludism (paludismo). Blackwater fever refers to the dark urine sometimes seen as a result of severe red blood cell hemolysis from malaria.

At least 10 of the more than 200 parasitic protozoa species of the genus Plasmodium (Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum), and Plasmodium knowlesi, cause human malaria. P falciparum causes the most severe morbidity and mortality.

Malaria is primarily transmitted through the bite of an infected female Anopheles species mosquito. Malaria also can be transmitted via a blood transfusion or congenitally between mother and fetus, although these forms of infection are rare.

At risk for contraction of malaria are persons living in or traveling to areas of Central America, South America, Hispaniola, sub-Saharan Africa, the Indian subcontinent, Southeast Asia, the Middle East, and Oceania. Of these areas, sub-Saharan Africa has the highest occurrence of P falciparum transmission to travelers from the United States.

Pathophysiology

The vector, the Anopheles species mosquito, passes plasmodia, which are contained in its saliva, into its host while obtaining a blood meal. Plasmodia enter circulating erythrocytes (RBCs) and feed on the hemoglobin and other proteins within the cells. One brood of parasites becomes dominant and is responsible for the synchronous nature of the clinical symptoms of malaria. Malaria-carrying female Anopheles species mosquitoes tend to bite only between dusk and dawn.

Schema of the life cycle of malaria. Image courtesy of the Centers for Disease Control and Prevention.

This protozoan brood replicates inside the cell and induces RBC cytolysis, causing the release of toxic metabolic byproducts into the bloodstream that the host experiences as flulike symptoms. These symptoms include chills, headache, myalgias, and malaise, and they occur in a cyclic pattern. The parasite may also cause jaundice and anemia. P falciparum, the most malignant of the 5 species of Plasmodium, may induce kidney failure, coma, and death. Malaria-induced death is preventable if the proper treatment is sought and implemented.

P vivax and P ovale may produce a dormant form that persists in the liver of infected individuals and emerges at a later time. Therefore, infection by these species requires treatment to kill any dormant protozoan as well as the actively infecting organisms. This dormant infection is caused by the hypnozoite phase of the life cycle, which involves a quiescent liver phase, which is not typically eradicated by normal courses of antimalarials and requires treatment with primaquine to prevent further episodes of disease.

Malaria-causing Plasmodium species metabolize hemoglobin and other RBC proteins to create a toxic pigment termed hemozoin (see Media file 3).

An erythrocyte filled with merozoites, which soon will rupture the cell and attempt to infect other RBCs. Notice the darkened central portion of the cell; this is hemozoin, or malaria pigment, which is a paracrystalline precipitate formed when heme polymerase reacts with the potentially toxic heme stored within the erythrocyte. When treated with chloroquine, the enzyme heme polymerase is inhibited, leading to the heme-induced demise of non–chloroquine-resistant merozoites.

The parasites derive their energy solely from glucose, and they metabolize it 70 times faster than the RBCs they inhabit, thereby causing hypoglycemia and lactic acidosis. The plasmodia also cause lysis of infected and uninfected RBCs, suppression of hematopoiesis, and increased clearance of RBCs by the spleen, which leads to anemia as well as splenomegaly. Over time, malaria infection may also cause thrombocytopenia.

The morbidity and mortality caused by P falciparum are increased greatly over that caused by other Plasmodium species because of the increased parasitemia of P falciparum and its ability to cytoadhere. When an RBC becomes infected with P falciparum, it produces proteinaceous knobs that bind to endothelial cells. The adherence of these infected RBCs causes them to clump together in the blood vessels in many areas of the body, leading to much of the damage incurred by the parasite. Furthermore, P falciparum is able to infect RBCs of all ages, resulting in high levels of parasitemia (>5% RBCs infected). By contrast, P vivax and P ovale only infect young RBCs and thus have a relatively limited parasitemia (usually <2%).

Frequency

United States

Although cases of malaria occur in some areas of the United States in people who have not traveled outside the country and have no other known risk factors, malaria ceased to be an endemic disease to the country as of 1947. Most cases of malaria reported by those living in the United States are associated with recent travel to an endemic area. Malaria may also be transmitted at birth or trans-placentally. Rarely, malaria is transmitted through blood transfusion, needle-sharing, or organ transplant.

Travelers to forested areas of Southeast Asia and South America have become infected by Plasmodium knowlesi, a dangerous species normally found only in long-tailed and pigtail macaque monkeys (Macaca fascicularis , Macaca nemestrina). This species can cause severe illness and death in people, but, under the microscope, the parasite looks similar to the more benign P malariae and has sometimes been misdiagnosed. As P malariae infection is typically relatively mild, Plasmodium knowlesi infection should be suspected in persons residing or traveling in the above geographical areas with microscopic evidence of P malariae infection who are severely ill. Diagnosis may be confirmed via polymerase chain reaction (PCR) methods.

International

Malaria remains an enormous international medical issue, with an estimated 300-500 million cases occurring annually.¹ It is most prevalent in rural tropical areas below elevations of 1000 m (3282 ft) but is not limited to these climates. P falciparum is found mostly in the tropics and accounts for about 50% of cases and 95% of malarial deaths worldwide. P vivax is distributed more widely than P falciparum, but it causes less morbidity and mortality; however, both P vivax and P ovale can establish a hypnozoite phase in the liver, resulting in latent infection.

HIV and malaria co-infection is a significant problem across Asia and sub-Saharan Africa where both diseases may be relatively common. Evidence suggests that malaria and HIV co-infection can lead to worse clinical outcomes in both disease processes, with malarial infections being more severe in HIV-infected patients, and HIV replication increasing in malaria infection.

Mortality/Morbidity

Internationally, as many as 2 million deaths occur annually. Of these deaths, the overwhelming majority is among children aged 5 years or younger, and 80-90% of the deaths each year are in rural sub-Saharan Africa.¹ Malaria is the world’s fourth leading cause of death in children younger than 5 years, accounting for the majority of malaria-related deaths.
Malaria is preventable and treatable. However, the lack of prevention and treatment due to poverty, war, and other economic and social instabilities in endemic areas results in millions of deaths each year.

Race

The sickle cell trait (hemoglobin S), thalassemias, hemoglobin C, or glucose-6-phosphate dehydrogenase (G-6-PD) deficiency are protective against death from P falciparum malaria, with the former being relatively more protective than the latter three. Individuals with hemoglobin E may be protected against P vivax infection. Individuals heterozygotic for RBC band 3 ovalocytosis are at reduced risk of infection with P falciparum, Plasmodium knowlesi and, especially, P vivax malaria. West African populations lacking RBC Duffy antigen are completely refractory to infection by P vivax.

Persons living in areas of malaria endemicity may develop partial immunity to infection with time and repeated exposure. This limited immunity reduces the frequency of symptomatic malaria and also reduces the severity of infection. Immunity to malaria infection can be lost with long periods of time spent away from endemic areas with limited exposure. As a result, those individuals born in malaria-endemic regions who move abroad for work or study and then return home may be at increased risk for developing severe malaria and complications of infection.

Sex

Males and females are affected equally. However, malaria may be devastating in pregnancy to both the mother and the fetus. P falciparum is the primary species responsible for increased morbidity and mortality in pregnancy. The prevalence of malaria is higher in primigravidas than in nonpregnant women or multigravidas. Maternal complications are thought to be mediated by pregnancy associated decreases in immune function as well as placental sequestration of (P falciparum) parasites. Anemia from malaria can be more severe in pregnant women. Fetal complications include death, premature birth, anemia, and low birth weight.

Age

All ages are affected by malaria.
Mortality is very high in children younger than 5 years.

Clinical

History

Most patients live in or have recently traveled to an endemic area; however, a few cases are reported each year in which the patient had no history of such travel (eg, airport malaria, from imported mosquitoes). Malaria may present over 1 year after travel to an endemic area. Previously infected patients may develop relapsing malaria, a recurrence of the disease after it has been apparently cured; this form is caused by reactivation of hypnozoites (dormant liver-stage parasites) in P vivax and P ovale infections.

Determine the patient's immune status, age, allergies, other medical conditions, other medications, and pregnancy status.
The patient usually remains asymptomatic for a week or more after the infecting mosquito bite.
Clinical symptoms include the following:
- Cough
- Fatigue
- Malaise
- Shaking chills
- Arthralgia
- Myalgia
- Paroxysm of fever, shaking chills, and sweats (every 48 or 72 h, depending on species)
The classic paroxysm begins with a period of shivering and chills, which lasts for approximately 1-2 hours, and is followed by a high fever. Finally, the patient experiences excessive diaphoresis, and the body temperature of the patient drops to normal or below normal.
Many patients, particularly early in infection, do not present the classic paroxysm but may have several small fever spikes a day.
Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.

• Less common symptoms include the following:

Anorexia and lethargy
Nausea and vomiting
Diarrhea
Headache
Jaundice

Physical

Physical signs that may be noted with malaria include the following:
- Tachycardia
- Fever
- Hypotension
- Signs of anemia
- Splenomegaly
- Icterus

Causes

Malaria most often is caused by the bite of a female Anopheles species mosquito that is infected with species of the protozoan genus Plasmodium. The 5 most common species affecting humans are as follows:
- P vivax: If this kind of infection goes untreated, it usually lasts for 2-3 months with diminishing frequency and intensity of paroxysms. Of patients infected with P vivax, 50% experience a relapse in a few weeks to 5 years after the initial illness. Splenic rupture may be associated with P vivax infection secondary to splenomegaly resulting from RBC sequestration. P vivax infects only immature RBCs, leading to limited parasitemia.
- P ovale: These infections are similar to P vivax infections, although they are usually less severe. P ovale infection often resolves without treatment. Similar to P vivax, P ovale infects only immature RBCs and parasitemia is usually less than that seen in P falciparum.
- P malariae: Those infected with this species of Plasmodium remain asymptomatic for a much longer period of time than those infected with P vivax or P ovale. Recrudescence is common in those infected with P malariae. It often is associated with a nephrotic syndrome, possibly resulting from deposition of antibody-antigen complex upon the glomeruli.
- P knowlesi: Autochthonous cases have been documented in Malaysian Borneo, Thailand, Myanmar, Singapore, and in the Philippines, and other neighboring countries. It is thought that simian malaria cases probably also occur in Central America and South America. Patients infected with this, or other simian species, should be treated as seriously as those infected with falciparum malaria, as P knowlesi may cause fatal disease.²
- P falciparum: The most malignant form of malaria is caused by this species. Infection with P falciparum is not limited to RBCs of a particular age and, hence, represents the highest level of parasitemia among the 5 Plasmodium species. This species also causes vascular obstruction due to its ability to adhere to endothelial cell walls. This property leads to most complications of P falciparum infection. P falciparum can cause cerebral malaria, pulmonary edema, rapidly developing anemia, and renal problems. Blackwater fever, is the darkening of the urine seen with severe RBC hemolysis resulting from high parasitemia, and is often a sign of impending renal failure and clinical decline.
Other less common routes of infection are through blood transfusion and maternal-fetal transmission. When P vivax and P ovale are transmitted via blood, no latent hypnozoite phase occurs and treatment with primaquine is not necessary, as it is the sporozoites that form hypnozoites in infected hepatocytes.

Differential Diagnoses

Workup

Laboratory Studies

Helpful studies include a CBC, electrolyte panel, renal function tests, pregnancy test, urinalysis, free serum haptoglobin, urine and blood cultures, and thick and thin blood smears. For those patients who may receive quinine or primaquine, a G-6-PD test should be ordered. Lumbar puncture may be indicated in patients who have encephalopathy in which the diagnosis is not clear. Rapid HIV testing may also be indicated in select cases.
Laboratory diagnosis in the ED may be limited in hospitals that do not have personnel who are well acquainted with malaria or special tests for rapid detection of the disease.
The British Committee for Standards in Haematology has guidelines on the laboratory diagnosis of malaria.³

Imaging Studies

A chest radiography may be helpful if respiratory symptoms are present.
If CNS symptoms are present, a CT scan of the head may be obtained once the patient is stable to evaluate evidence of cerebral edema or hemorrhage.

Other Tests

Microhematocrit centrifugation
- Using this method with the CBC tube is a more sensitive method of detection of malaria infection.
- However, microhematocrit centrifugation does not allow the identification of the species of Plasmodium. To determine that species, a peripheral blood smear must be examined.
Giemsa-stained thick and thin peripheral blood smears
- These smears are the criterion standard for malaria detection and should be sent to the laboratory immediately, since malaria is a potentially life-threatening infection.
- When reading the smear, 200-300 oil-immersion fields should be examined (more if the patient recently has taken prophylactic medication, because this temporarily may decrease parasitemia).
- One negative smear does not exclude malaria as a diagnosis; several more smears should be examined over a 36-hour period.
Fluorescent dyes/ultraviolet indicator tests: Several different dyes allow laboratory results to be obtained more quickly. These methods require the use of a fluorescent microscope (QBC II System, Becton-Dickinson's Quantitative Buffy Coat [QBC] method). Fluorescent /ultraviolet tests may not yield speciation information.
Polymerase chain reaction
- Polymerase chain reaction (PCR) is a very specific and sensitive test for determining if the species of Plasmodium are present in the blood of an infected individual. PCR is not usually available in most clinical situations.
- PCR is also very effective at detecting the Plasmodium species present in patients with parasitemias as low as 10 parasites/mL of blood.
Rapid diagnostic tests (RDTs) examples include Para Sight-F test (Becton Dickinson Advanced Diagnostics), ICT Malaria P.f/P.v (Binax Inc), OptiMAL pLDH (DiaMed USA, LLC), Kat-Quick (Katmedical CC), and Rapimal MT Pf Dipstick (Cellabs Pty Ltd) (dipstick tests). Note: This list is not all-inclusive; research individual tests for comparative efficacy and cost.
- These tests are useful in detecting P falciparum infections, while some also may detect other plasmodia antigens. RDTs are based on antibody recognition of the histidine rich protein 2 (HRP-2) antigen of P falciparum and, in most cases, it has been found to be as specific as microscopy studies.⁴ A false-positive result may occur up to 2 weeks or more after treatment due to persistence of circulating antigens.
- Some RDTs may be able to detect P falciparum in parasitemias that are below the threshold of reliable microscopic species identification.
- RDTs are not as effective when parasite levels are below 100 parasites/mL of blood, and the test rarely is negative in those with high parasitemias. For these reasons, always confirm RDT test results with a second type of screening test when possible.
- RDTs may not be available in the United States due to lack of FDA approval. The World Health Organization's Regional Office for the Western Pacific (WHO/WPRO) provides technical information, including a list of commercially available malaria RDTs, at Malaria Rapid Diagnostic Tests.
- In one study, RDTs were found to perform better than microscopy under routine conditions. RDTs performed by the health facility staff were 91.7% (95% confidence interval [CI], 80.8-100%) sensitive and 96.7% (95% CI, 92.8-100%) specific. Microscopy was 52.5% (95% CI, 33.2-71.9%) sensitive and 77% (95% CI, 67.9-86.2%) specific.⁵

Treatment

Emergency Department Care

Assess airway, breathing, and circulation; intervene as necessary. Protective airway may be indicated in cases of severe central nervous system complications.
- If evidence of life-threatening hemolytic anemia is determined, establish large-bore intravenous (IV) lines, initiate fluid resuscitation, and administer transfusion of type-specific packed RBCs.
- Hyponatremia likely reflects continued oral hypotonic fluid intake in the setting of hypovolemia and requires no therapy beyond rehydration.6 Overly aggressive treatment of hyponatremia may lead to death.
Consider exchange transfusion for life-threatening complications.
Monitor and treat hypoglycemia, as needed.
Search for any signs of microvascular malarial complications.
Laboratory analysis is helpful, although it is not always readily available to determine Plasmodium species, level of drug resistance, and degree of parasitemia. Obtain complete history for the laboratory.
General hospital admission guidelines are as follows:
- Patients with suspected or confirmed P falciparum or P knowlesi infection
- Children
- Pregnant women
- Immunodeficient individuals
Intensive care unit admission guidelines are as follows:
- Immediate life-threatening complications present, such as coagulopathy or end-organ failure
- Presence of signs and symptoms consistent with cerebral malaria (eg, altered mental status, repeated seizures, coma)
- Patients who are nonimmune with a falciparum parasitemia greater than 2% or who are semi-immune with a P falciparum parasitemia greater than 5%
- Presence of any other severe malarial complications
A reliable, semi-immune, adult patient with a P vivax, P ovale, or P malariae infection may be treated on an outpatient basis. However, special care must be taken if P malariae is diagnosed solely on the basis of a blood smear, as it may be confused with the sometimes fatal P knowlesi, an infection that would require inpatient treatment. Those treated as outpatients should have adequate follow-up care, including daily blood smears to confirm that the treatment is effective in decreasing parasitemia.
If the infection is caused by an unidentified species or by mixed species, treat it as if it were caused by P falciparum. In the absence of known drug sensitivities, assume that the Plasmodium species in question is chloroquine resistant. If Southeast Asia is the origin of the infection, then assume mefloquine resistance.
If a patient is diagnosed with P falciparum malaria with a parasitemia greater than 10% or if the patient is experiencing life-threatening complications (ie, coma, respiratory failure, coagulopathy, fulminant kidney failure), then investigate exchange transfusion as a treatment option. If transfusion is undertaken, it should continue until the parasitemia falls below 5%, although the mortality benefit of this intervention has not been proven.
Administer parenteral quinidine, quinine, or artemisinin therapy in conjunction with exchange transfusion to eradicate the protozoa from the bloodstream.
The World Health Organization also has guidelines on treatment of malaria.⁷

Consultations

It is recommended that the emergency physician contact an infectious disease clinician or the pathologist when confronted with a possible case of malaria based upon history and physical examination to ensure proper identification and diagnosis. It is particularly recommended that the physician contact the CDC directly for any known or suspected case. Consider HIV testing if indicated.

To aid in identification of the species of Plasmodium, also notify the pathologist of the patient’s information, including the following:
- Determine where the patient has traveled and when the patient returned home.
- Determine if the patient has been diagnosed with malaria ever before. If so, find out which species of Plasmodium caused the previous infection.
- Determine what medication or prophylaxis the patient has taken, and find out when the last dose was administered.
- Determine if the patient has a history of blood transfusion or of nonsterile needle usage.
- Identify the date and time that the patient's blood sample was drawn and determine what condition the patient was in at that time (eg, patient was symptomatic, any periodicity of symptoms). Also provide an indication of the severity of illness.
The Centers for Disease Control and Prevention has guidelines on the investigations of locally acquired mosquito-transmitted malaria.⁸

Medication

Antimalarial drugs have a rich history, since malaria was possibly the first human infection to be treated pharmacologically. The Chinese use of an extract from the sweet wormwood tree has led to artesemial drugs that, although expensive, are very effective. South American indigenous people have used the bark and root of the cinchona tree. The active ingredient in these medications turned out to be artemisinin and quinine, respectively, which now comprise 2 of the 4 major drug classes currently used to treat malaria. The 4 classes include quinoline-related compounds, antifolates, artemisinin derivatives, and antimicrobials.

No one drug that can eradicate all forms of the parasite's life cycle has been discovered or manufactured yet. Therefore, one or more classes of drugs often are given at the same time to combat malarial infection synergistically.

Beware of counterfeit antimalarial drugs being taken by patients that may have been purchased overseas or via the Internet. They may not contain any active ingredients at all and may contain dangerous materials.

Malaria treatment is not always straightforward. Contacting the CDC for the latest treatment guidelines and drug regimens is advised.⁹ Not all recommended treatment regimens or drugs are included below. Treatment in pregnancy and complicated malaria requires specialized drug regimens. Consult the CDC for further guidance. For the most recent CDC recommendations concerning malaria treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician. The CDC table of guidelines for treatment of malaria in the United States can be downloaded as a pdf at Guidelines for Treatment of Malaria.

Treatment regimens are dependent on the geographic derivation of infection, the likely Plasmodium species, and the severity of disease presentation.

Antipyretics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), are indicated to reduce the level of discomfort caused by the infection and to reduce fever. NSAIDs should be used with caution if bleeding disorder or hemolysis is suspected.

Antimalarials can cause significant prolongation of the electrocardiograph QT interval, which can be associated with an increased risk of potentially lethal ventricular dysrhythmias. Patients receiving these drugs should be assessed for QT prolongation at baseline and carefully monitored if present. Those with normal QT intervals on ECG may not be at significant increased risk for drug-induced dysrhythmia, but caution is advised, particularly if the patient is taking multiple drug regimens, or if the patient is on other drugs affecting the QT interval.

Methemoglobinemia is a complication that may be associated with high-dose regimens of quinine the derivatives chloroquine and primaquine.10 A patient presenting with cyanosis and a normal PaO₂ on room air should be suspected of having methemoglobinemia.

Malaria vaccine production and distribution continues to be in the research and development stage.

Antiprotozoal

Chloroquine phosphate remains the DOC if the patient is infected with a nonresistant strain of Plasmodium species. For chloroquine-resistant strains, a form of quinine is the drug next in line.

Chloroquine Phosphate (Aralen)

Inhibits parasite growth by concentrating within acid vesicles of the parasite and increasing its internal pH. In addition, inhibits hemoglobin utilization and metabolism by the parasite.

Dosing

Adult

600 mg base (=1,000 mg salt) PO immediately, followed by
300 mg base (=500 mg salt) PO at 6, 24, and 48 h
Total dose: 1,500 mg base (=2,500 mg salt) 10 mg base/kg PO immediately, followed by 5 mg base/kg PO at 6-h, 24-h, and 48-h intervals
Species not identified

Pediatric

10 mg base/kg PO, not to exceed 600 mg; then 5 mg base/kg PO; not to exceed 300 mg at 6-h, 24-h, and 48-h intervals (total 25 mg base/kg)

Interactions

Cimetidine may increase serum levels of chloroquine (possibly other 4-aminoquinolones); magnesium trisilicate may decrease absorption of 4-aminoquinolones

Contraindications

Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones; hypotension when given IV; impairs intradermal rabies vaccine

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sodium channel blocking activity may increase toxicity of type Ia antidysrhythmic drugs or others with quinidinelike effects; ECG should be checked to monitor increased QRS interval effect
Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long-term use in children; perform periodic ophthalmologic examinations; test for muscle weakness; retinopathy, tinnitus, nerve deafness, skin eruption, headache, anorexia, nausea, vomiting, and diarrhea may occur

Clindamycin (Cleocin)

Three major drug metabolites have been shown to have strong inhibitory effects, possibly by targeting apicoplast, a chloroplast-like organelle of uncertain function.
Inhibition causes modest antimalarial effects initially but is much more potent against progeny of treated parasites. Progeny inherits nonfunctional apicoplasts, blocking production of apicoplast proteins causing a "delayed-death effect".

Dosing

Adult

20 mg base/kg/d PO divided tid for 7 d

Pediatric

Administer as in adults

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

Contraindications

Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis by allowing overgrowth of Clostridium difficile

Doxycycline (Vibramycin, Vibra-Tabs, Doryx)

May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.

Dosing

Adult

100 mg PO bid for 7d

Pediatric

<8 years: Not recommended unless treatment benefit outweighs risks (consult CDC)
>8 years: 4 mg/kg/d PO divided bid for 7d

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Interactions

Documented hypersensitivity; severe hepatic dysfunction

Contraindications

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Primaquine

If uncomplicated infection is caused by P vivax or P ovale, important to treat patient with primaquine to prevent relapse. If species is initially unknown, then identified as P vivax or P ovale, primaquine phosphate treatment should be initiated. Binds to DNA and may disrupt parasite's mitochondria, causing major disruption in metabolic process of the parasite. Exoerythrocytic forms of the parasite are inhibited.

Dosing

Adult

30 mg base PO qd for 14 d

Pediatric

0.5 mg base/kg PO qd for 14 d or 0.8 mg base/kg PO once/wk for 14 d

Interactions

Coadministration with quinacrine or other quinidinelike drugs may increase toxicity (see chloroquine)

Contraindications

Documented hypersensitivity; drugs that suppress bone marrow

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in G-6-PD deficiency and those with tendency to develop granulocytopenia

Quinine sulfate (Formula Q)

Used in chloroquine-resistant or unknown resistant infections. By increasing pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.

Dosing

Adult

542 mg base (=650 mg salt) PO tid for 3-7 d

Pediatric

8.3 mg base/kg (=10 mg salt/kg) PO tid for 3-7 d

Interactions

Aluminum-containing antacids may delay or decrease quinine bioavailability when administered concurrently; cimetidine increases quinine blood levels and creates potential for toxicity; rifamycins decrease quinine concentrations by increasing hepatic clearance of quinine (effect can persist for several days after discontinuing rifamycins); concurrent administration of acetazolamide or sodium bicarbonate may increase toxicity by increasing quinine blood levels; quinine may enhance action of warfarin and other oral anticoagulants by decreasing synthesis of vitamin K-dependent clotting factors; digoxin serum concentrations may increase when digoxin administered concurrently with quinine; important to monitor digoxin levels periodically; quinidine may decrease plasma cholinesterase activity, causing decrease in metabolism of succinylcholine

Contraindications

Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of blackwater fever

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in G-6-PD deficiency and tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and thus can cause cardiac dysrhythmias due to sodium channel blocking activity

Quinidine gluconate (Cardioquin, Quinalan, Quinidex, Quinora)

Indicated for severe or complicated malaria and used in conjunction with one of the following: doxycycline, tetracycline, or clindamycin. Increases pH within intracellular organelles and possibly by intercalating into DNA of parasites, may inhibit growth of parasite.

Dosing

Adult

6.25 mg base/kg (=10 mg salt/kg) loading dose IV over 1-2 h, then 0.0125 mg base/kg/min (=0.02 mg salt/kg/min) continuous infusion for at least 24 h
Length of treatment varies by geographic origin of infection (consult CDC)

Pediatric

Administer as in adults

Interactions

Delays absorption of digoxin; antagonizes effects of antimyasthenics; mefloquine increases risk of seizures

Contraindications

Documented hypersensitivity; those with optic neuritis, tinnitus, G-6-PD deficiency, or history of cardiac dysrhythmias

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in G-6-PD deficiency and in patients with a tendency to develop granulocytopenia; prolonged treatment or overdosing with quinine may cause cinchonism; quinine has quinidinelike activity and can cause cardiac dysrhythmias via sodium channel blocking activity

Tetracycline (Achromycin V, Sumycin)

May specifically impair progeny of apicoplast genes resulting in their abnormal cell division. Loss of apicoplast function in progeny treated parasites leads to slow but potent antimalarial effect.

Dosing

Adult

250 mg PO qid for 7 d

Pediatric

<8 years: Not recommended unless benefits outweigh risks (consult with CDC)
>8 years: 25 mg/kg/d PO divided qid for 7 d

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

Interactions

Documented hypersensitivity; severe hepatic dysfunction

Contraindications

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Antimalarials

These agents inhibit growth of malarial pathogens by interfering with their stages of growth. US Food and Drug Administration has approved Coartem tablets (artemether and lumefantrine) for the treatment of acute, uncomplicated malaria infections.¹¹

Artemether 20 mg/lumefantrine 120 mg (Coartem)

Indicated for treatment of acute, uncomplicated Plasmodium falciparum malaria, the most dangerous form of malaria. Contains fixed ratio of 20 mg artemether and 120 mg lumefantrine (1:6 parts). Both components inhibit nucleic acid and protein synthesis. Artemether is rapidly metabolized into the active metabolite dihydroartenisinin (DHA), producing an endoperoxide moiety. Lumefantrine may form a complex with hemin, which inhibits the formation of beta-hematin.

Dosing

Adult

<35 kg body weight: Use pediatric dosing
>35 kg body weight: One dose is 4 tab; take 6 doses over 3-d period as described below
Day 1: Take 1 dose, followed 8 h later by 1 dose
Day 2: Take 1 dose bid
Day 3: Take 1 dose bid

Pediatric

<5 kg: Do not administer
5 to <15 kg: 1 tab
15 to <25 kg: 2 tab
25 to <35 kg: 3 tab
>35 kg: Administer as in adults
Take 6 doses over 3-d period as described for adults

Interactions

CYP3A4 inhibitors (including antiretroviral drugs, macrolide antibiotics, antidepressants, and imidazole antifungal agents) or CYP2D6 inhibitors (eg, flecainide, tricyclic antidepressants) may increase toxicity of lumefantrine, increasing QT prolongation; halofantrine may increase toxicity of lumefantrine, increasing QT prolongation (not for concurrent administration; administer 1 mo apart); antimalarials quinine and quinidine may have additive effects on QT interval (use caution); not approved for severe or complicated P falciparum malaria; not approved for prevention of malaria

Contraindications

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

QT prolongation may occur; avoid use in patients with congenital prolongation of QT interval (family history) and known disturbances of electrolyte imbalance (including hypokalemia or hypomagnesemia); common adverse effects include headache, dizziness, loss of appetite, and fever

Mefloquine (Lariam)

Not used in complicated malaria. Acts as a blood schizonticide and may act by raising intravesicular pH within the parasite acid vesicles. Structurally similar to quinine.

Dosing

Adult

15 mg base/kg PO, then 10 mg base/kg PO 6-8 h later (not to exceed 1250 mg; usually 750 mg PO, then 500 mg PO at 6-8 h)
684 mg base (=750 mg salt) PO as initial dose, followed by 456 mg base (=500 mg salt) PO given 6-12 h after initial dose
Total dose = 1,250 mg salt 13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed
by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose

Pediatric

13.7 mg base/kg (=15 mg salt/kg) PO as initial dose, followed by 9.1 mg base/kg (=10 mg salt/kg) PO given 6-12 h after initial dose

Interactions

Mefloquine administered with beta-blockers, quinine, quinidine, antiarrhythmics, TCAs, or astemizole may cause ECG abnormalities or cardiac arrest; mefloquine and chloroquine administered concomitantly may increase risk of convulsions; concomitant administration with halofantrine may cause potentially fatal prolongation of QTc interval; valproic acid administered with mefloquine can increase risk of seizures by reducing valproic acid blood levels

Contraindications

Documented hypersensitivity; patients with seizure disorder, heart block, or psychiatric disorders

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use for >1 y not established; perform periodic evaluations, including LFTs, when using for prolonged periods; mefloquine may have cardiac depressant effects and antifibrillatory activity
Not recommended in infections originating in some Southeast Asian countries due to drug resistance

Artemether (Artenam)

Used only for severe or complicated malaria. Not FDA approved.

Dosing

Adult

3.2 mg/kg IM (anterior thigh), then 1.6 mg/kg IM q24h until PO therapy is possible (never IV)

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Brainstem neurotoxicity and death in nonhuman primates have been reported; drug fever may occur

Artesunate

Experimental drug.

Dosing

Adult

4 mg/kg PO qd for 3 d (total dose 12 mg/kg; 1 tab = 50 mg); for severe or complicated malaria, use 2.4 mg/kg IV load, then 1.2 mg/kg IV at 12 h and 24 h, then 1.2 mg/kg IV q24h until PO therapy is possible

Pediatric

Administer as in adults

Follow-up

Further Inpatient Care

Perform thick and thin blood smears every 6-12 hours until parasitemia falls below 1% to ensure that the therapy instituted is clearing the infection.
If parasitemia does not fall by 75% within 48 hours or if the blood is not cleared of parasites after 7 days, immediately initiate a different therapeutic regimen.
Consult the CDC in all cases. Malaria infection may also be reportable to the local public health authority.

Further Outpatient Care

Thick and thin blood smears should be obtained at least weekly for at least one month post treatment commencement to ensure clearance of parasitemia.

Deterrence/Prevention

Avoid endemic regions.
Take the proper prophylactic drugs at proper intervals if traveling to endemic regions.
Use topical insect repellent (30-35% diethyltoluamide [DEET]), especially from dusk to dawn.
Wear long-sleeved permethrin-coated clothing if not allergic to permethrin; spray under beds, chairs, tables, and along walls.
Sleep under fine-nylon netting impregnated with permethrin.
Avoid wearing perfumes and colognes.
Seek out medical attention immediately upon contracting any tropical fever or flulike illness.
Chemoprophylaxis is available in many different forms.
- The drug of choice is determined by the destination of the traveler and any medical conditions the traveler may have that contraindicate the use of a specific drug.
- Before traveling, people should consult their physician and consult the CDC's Malaria and Traveler's Web site to determine the most appropriate chemoprophylaxis.¹² Travel Medicine clinics are also a useful source of information and advice.

Complications

Most complications are caused by P falciparum, and they may include the following:
- Coma (cerebral malaria)
  - Defined as coma, altered mental status, or multiple seizures with P falciparum in the blood, cerebral malaria is the most common cause of death in patients with malaria. If untreated, this complication is lethal.
  - Even with treatment, 15% of children and 20% of adults who develop cerebral malaria die.
  - The symptoms of cerebral malaria are similar to those of toxic encephalopathy.
- Seizures (secondary either to hypoglycemia or cerebral malaria)
- Renal failure: As many as 30% of nonimmune adults infected with P falciparum suffer acute renal failure.
- Hypoglycemia
- Hemoglobinuria (blackwater fever)
  - Blackwater fever is the passage of dark urine, described as Madeira wine-colored.
  - Hemolysis, hemoglobinemia, and the subsequent hemoglobinuria and hemozoinuria cause this condition.
- Noncardiogenic pulmonary edema: This affliction is most common in pregnant women and results in death in 80% of patients.
- Profound hypoglycemia: Hypoglycemia often occurs in young children and pregnant women. It often is difficult to diagnose because adrenergic signs are not always present and because stupor already may have occurred in the patient.
- Lactic acidosis: This occurs when the microvasculature becomes clogged with P falciparum. If the venous lactate level reaches 45 mg/dL, a poor prognosis is very likely.
- Hemolysis resulting in severe anemia and jaundice
- Bleeding (coagulopathy)

Prognosis

Most patients with uncomplicated malaria exhibit marked improvement within 48 hours after the initiation of treatment and are fever free after 96 hours.
P falciparum infection carries a poor prognosis with a high mortality rate if untreated. However, if diagnosed early and treated appropriately, the prognosis is excellent.

Patient Education

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Malaria.

Miscellaneous

Medicolegal Pitfalls

The emergency physician should have a high index of suspicion if a history of fever is accompanied by suggestive symptoms in a patient with a history of travel to an endemic region.
- Failure to consider malaria in the differential of a febrile illness following such travel, even if seemingly temporally remote, can result in significant morbidity or mortality, especially in children and pregnant or immunocompromised patients.
- Mixed infections involving more than one species of Plasmodium may occur in areas of high endemicity and multiple circulating malarial species. In these cases, clinical differentiation and decision making will be important; however, the clinician should have a low threshold for including treatment for P falciparum to avoid potentially incompletely or inadequately treating this more dangerous species.
- Failure to recognize cases for which, due to their relatively high complication and fatality rate, inpatient treatment is highly recommended, particularly those caused by P falciparum and P knowlesi.
- Importantly, although rare, malaria infection should be considered in patients with no history of travel who have otherwise unexplained fever, anemia, CNS dysfunction, or sepsis.
- Individuals traveling to malarial regions must be provided with adequate information regarding prevention strategies, as well as tailored and effective antiprotozoal medications.

Special Concerns

Pregnancy
- Pregnant women, especially primigravid women, are up to 10 times more likely to contract malaria than nongravid women. Gravid women who contract malaria also have a greater tendency to develop severe malaria.
- Unlike malarial infection in nongravid individuals, pregnant women with P vivax are at high risk for severe malaria, and those with P falciparum have a greatly increased predisposition for severe malaria as well.
- For these reasons, it is important that nonimmune pregnant women in endemic areas use the proper pharmacologic and nonpharmacologic prophylaxis.
- If a pregnant woman becomes infected, she should know that many of the antimalarial and antiprotozoal drugs used to treat malaria are safe for use during pregnancy for both the mother and the fetus. Therefore, they should be used, since the benefits of these drugs much outweigh the risks associated with leaving the infection untreated.
- To obtain the latest CDC recommendations for malaria prophylaxis and treatment, call the CDC Malaria Hotline at (770) 488-7788 (M-F, 8 am-4:30 pm, Eastern Time). For emergency consultation after hours, call (770) 488-7100 and request to speak with a CDC Malaria Branch clinician.
Pediatrics
- In children, malaria has a shorter course, often rapidly progressing to severe malaria.
- Children are more likely to present with hypoglycemia, seizures, severe anemia, and sudden death, but they are much less likely to develop renal failure, pulmonary edema, or jaundice.
- Cerebral malaria results in neurologic sequelae in 9-26% of children, but of these sequelae, approximately one half completely resolve with time.
- Most antimalarial drugs are very effective and safe in children, provided that the proper dosage is administered. Children commonly recover from malaria, even severe malaria, much faster than adults.

Source : http://emedicine.medscape.com/article/784065

Sleep-Disordered Breathing and Cardiovascular Disease

2009-06-18T11:10:00.002+07:00

Abstract

In recent years, there has been increasing awareness of the high prevalence and clinical significance of sleep-disordered breathing (SDB) and its effects on a range of cardiovascular conditions, including hypertension, heart failure (HF), myocardial infarction (MI), atrial fibrillation (AF), and type 2 diabetes.

SDB describes a group of disorders characterized by abnormalities in the frequency and/or depth of breathing while asleep. These intermittent episodes cause partial or complete obstruction of the upper airway, disrupting normal ventilation and sleep architecture.^[1] It not only causes poor sleep quality and daytime sleepiness, but has clinical consequences too.

Obstructive sleep apnea (OSA) is the most extreme variant, but other forms of SDB are highly prevalent, too. An analysis of 154 original investigations and reviews of sleep-related breathing disorders estimated that one in five adults has at least mild OSA and one in 15 adults has at least moderate OSA.^[2] Central sleep apnea is the most common SDB in patients with HF, occurring in an estimated 40-63% of HF patients.^[3,4] However, it may be more difficult to identify individuals with central sleep apnea since it does not tend to be associated with the typical excessive daytime sleepiness of OSA.

Case-control and retrospective studies first suggested that SDB is associated with an increased prevalence of coronary heart disease (CHD) and CHD-related outcomes, and large-scale cohort studies subsequently confirmed these findings. In the Sleep Heart Health Study (SHHS), for example, several cardiovascular disease outcomes, including MI and stroke, were associated with SDB.^[5] Also, the Nurses Health Study prospectively observed that self-reported snoring, a cardinal symptom of SDB, may be an independent risk factor for the development of CHD.^[6]

Cardiovascular Effects

There are several physiologic disturbances that can lead to cardiovascular consequences. As for specific cardiovascular effects, OSA places a strain on cardiac output by virtue of hypoxemia, large negative intrathoracic pressures, and high swings in systemic blood pressure. Here are other ways that SDB clinically affects specific heart conditions:

Heart Failure. As noted, central sleep apnea is highly prevalent in patients with left ventricular (LV) dysfunction and it often occurs before the development of overt HF.^[7] The main clinical significance of central sleep apnea is its association with increased mortality independent of other known risk factors. Also, OSA has the potential to worsen ventricular dysfunction in patients with overt HF.^[8]

Myocardial Infarction. Recently, investigators analyzed 1,660 patients with a first acute MI and found a strong association in the first 28 days after infarction between snoring and mortality. Occasional and regular heavy snorers had a 2.04 (95% confidence interval [CI], 1.50 to 2.79) and 3.30 (95% CI, 2.37 to 4.58) hazard ratio for mortality respectively within the first 28 days after controlling for age, gender, obesity, history of diabetes and hypertension, physical activity, smoking, and education.

Atrial Fibrillation. In a cohort of 3,542 people who underwent complete polysomnography, obesity and OSA were independent risk factors for incident AF over an average of about 5 years of follow-up (Figure 2).^[10] Both obesity and OSA may contribute to the looming epidemic of AF and both conditions should be recognized as independent risk factors for incident AF.

Figure 2.

In another recent study, investigators prospectively evaluated SDB in a relatively young patient population (mean age 55 years) with paroxysmal or persistent AF and normal LV function.^[11] The control population was comprised of patients referred to the same tertiary arrhythmia center during the same 18-month period but without AF. Among the AF group, there was a high prevalence of SDB (Figure 3) and more patients with significant SDB than the controls. After adjusting for relevant covariates, the odds ratio for the association between AF and SDB was 3.04 (95% CI 1.24-7.46, p = 0.02). In general, the authors said, OSA should be considered in patients with arrhythmias (including bradyarrhythmias) and — like the large cohort study above — particularly those individuals who are obese or hypertensive, regardless of the presence or absence of LV dysfunction.

[ CLOSE WINDOW ]

Figure 3.

Type 2 Diabetes. SDB is associated with insulin resistance and glucose intolerance, plus it is frequently found in individuals with type 2 diabetes. In a paper published in July 2008, the International Diabetes Federation Task Force on Epidemiology and Prevention "strongly recommends" that health professionals working in both type 2 diabetes and SDB adopt clinical practices to ensure that a patient presenting with one condition is considered for the other.^[12]

Is Intervention Effective? The adverse effects of OSA on LV function can be at least partially reversed with continuous positive airway pressure (CPAP). In a 2007 issue of the Journal of the American College of Cardiology, Wang et al. reported a single-center prospective observational study comparing the mortality of patients with coexistent HF and OSA with that of patients with only HF.^[13] Nearly 25% of the patients had OSA and risk of death was nearly three times higher in those with OSA versus those with mild or no OSA (Figure 4). None of the patients with HF and treated OSA died during 39-month follow-up. An accompanying editorial noted that "early diagnosis of OSA and initiation of effective CPAP therapy are of paramount importance in patients with coexistent HF and OSA."^[14]

(Enlarge Image)

Figure 4.

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Figure 4.

Evidence also suggests that CPAP decreases health care costs in moderate-to-severe OSA^[15,16] and is associated with lower recurrence of AF.^[17] Importantly, in patients with OSA, CPAP reduces the risk of car accidents from an excess risk of two to seven times greater than the background population to a level comparable to the general population.^[18]

It should be noted that current data do not support routine use of CPAP in chronic stable congestive cardiac failure unless there is co-existent OSA. Bi-level pressure support using newer devices that may more effectively treat both OSA and central sleep apnea are being evaluated.

Recently, investigators reported that 6 months of aerobic exercise training increased exercise capacity and improved central sleep apnea in patients with chronic HF from systolic dysfunction.^[19] Whether reducing central sleep apnea in this manner reduces the independent risk for poor long-term prognosis associated with SDB in this setting is unknown.

Investigators also have compared blood pressure response to nasal CPAP in a group of middle-aged men with mild-to-moderate untreated hypertension.^[20] Nearly half of the study group had SDB and 3 weeks of nasal CPAP treatment caused a substantial lowering of nocturnal systolic (-7.8 mm Hg, p = 0.02 versus no SDB) and diastolic (-5.3 mm Hg, p = 0.03 versus no SDB) blood pressure values. The authors noted that a reduction in blood pressure similar to that obtained with CPAP has been associated with a substantial reduction in the incidence of cerebrovascular accidents and MI in previous studies.

Finally, in late 2007, investigators published a retrospective cohort study of patients with OSA who subsequently underwent percutaneous coronary intervention (PCI).^[21] Patients were stratified according to whether they were treated for OSA (n = 175) or not (n = 196). Patients treated for OSA had a statistically significant decreased number of cardiac deaths on follow-up compared to untreated OSA patients (3% [95% CI 0% to 6%] vs. 10% [95% CI 5% to 14%] after 5 years, p = 0.027) (Figure 5), as well as a trend toward decreased all-cause mortality (p = 0.058). The authors concluded that screening for and treating OSA in patients with CHD who may undergo PCI may result in decreased cardiac death.

(Enlarge Image)

Figure 5.

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Figure 5.

In this interview, Dr. Bernard J. Gersh, who participated in several of the studies summarized here, discusses the cardiovascular mechanisms of sleep-disordered breathing and the diagnosis and management of this large population of patients.

Transcript

Dr. Conti: I'm Richard Conti here in Snowmass, Colorado, and with me is Dr. Bernard Gersh. We're talking about "Sleep-Disordered Breathing and Cardiovascular Disease." Bernard, do most cardiovascular specialists think about sleep disorders?

Dr. Gersh: More are starting to, but most do not – including me not that long ago. Five or 6 years ago sleep-disordered breathing, particularly obstructive sleep apnea, really was not part of my decision-making process. I didn't think about it as a diagnosis nor about how it might complicate treatment; to me it just was something specialists in sleep disorders take care of.

Then, for reasons still unclear to me, I was asked to co-chair a National Heart, Lung, and Blood Institute panel of cardiologists and sleep doctors on sleep-disordered breathing and cardiovascular disease.^[1] It was absolutely fascinating and at the end of the 3 days I realized that sleep apnea or sleep-disordered breathing is a very important co-factor in cardiovascular disease and we, as clinical cardiologists, have to learn more about sleep-disordered breathing.

Dr. Conti: Let's start with the epidemiology of this condition.

Dr. Gersh: The statistics are compelling: Somewhere in the range of 40 million Americans have sleep-disordered breathing and some 20 million Americans probably have sleep apnea. Of those, 60-80% are undiagnosed. I might add: one of the great ways to start thinking about the possibility of sleep apnea is to ask the spouse whether the other has sleep apnea.

The Wisconsin Sleep Study, a prospective longitudinal follow-up study, demonstrated that about 9% of women and about 24% of men have at least mild sleep apnea.^[22] What is staggering is the cost to society, both direct and indirect, through accidents, litigation, and lack of productivity; it's somewhere in the range $50 billion to $100 billion dollars a year.

Dr. Conti: Please talk about the potential pathophysiologic mechanisms of this disorder.

Dr. Gersh: There are several plausible mechanisms and a lot of good circumstantial evidence. First, remember that many of these patients with sleep-disordered breathing have comorbidities. For example, sleep apnea coexists with hypertension, obesity, diabetes, cigarette smoking, and so on. Aside from that, there's a considerable body of evidence looking at the events that occur with obstructive sleep apnea, particularly the apneic phase followed by arousal. During the apneic phase, there are tremendously negative intrathoracic pressures, so the transmural pressure in the left ventricle is very high and one of the mechanisms is increased left ventricular afterload.

Also, during the cycles of sleep apnea, there's sympathetic overactivity, rebound hypertension, catecholamine surge, release of inflammatory markers, elevated levels of C-reactive protein and interleukin-6, and an increase in free-oxygen radicals. All these so-called bad actors appear to be released during these cycles of sleep apnea and arousal.

There is other interesting work suggesting metabolic dysregulation associated with sleep-disordered breathing. I don't know whether it's a result of leptin metabolism or leptin release; it's not clearly understood, but the effects are clearly there.

One interesting aspect of sleep apnea is that in the year before diagnosis the patient often admits to a recent marked weight gain. That may be related to some disorder of leptin, satiety, and appetite suppression, but it's fair to say there are hosts of plausible physiological mechanisms related to hypoxia, hypocarbia, negative intrathoracic pressures, the sympathetic activity associated with arousal, and possibly pulmonary vasoconstriction. It hasn't been completely sorted out yet, but the evidence is pretty strong.

Dr. Conti: What are the main diseases that are directly related to obstructive sleep apnea?

Dr. Gersh: We owe a lot to the Wisconsin Sleep Study, which showed unequivocally that obstructive sleep apnea causes hypertension. A very important long-term follow-up study strongly suggests that obstructive sleep apnea is associated with an increase in stroke.^[23] There clearly is a relationship with heart failure, particularly central sleep apnea.

Although the data are a little inconsistent, some studies suggest that the treatment of sleep apnea may improve left ventricular function in people with heart failure. Many of these patients who I would have once said had mild cardiomyopathy – an ejection fraction 40% – now I suspect many have sleep apnea.

The evidence for coronary artery disease is a little more speculative but I'm pretty sure there's a relationship. Then there is a very strong relationship between obstructive sleep apnea and arrhythmias and this has been an area of, great interest to us at the Mayo Clinic. I have no doubt that obstructive sleep apnea is strongly associated with the development of atrial fibrillation and recurrence after treatment. My colleague, Virend Somers at the Mayo Clinic, with Dr. Apoor Gami, one of our fellows, published a study in the New England Journal of Medicine, showing that the diurnal rhythm of sudden cardiac death is completely reversed in sleep apnea.^[24] In other words, among people with obstructive sleep apnea, the highest incidence of sudden cardiac death is at night, whereas the normal diurnal rhythm's in the day. In addition there is a clear increase in bradyarrhythmias. I'm not sure if it's "heart block" but bradycardias and pauses. This may be related to the diving reflex; that's a reflex we all have to prevent asphyxia. It may well be that people with obstructive sleep apnea are getting bradycardias at night, secondary to the initiation or triggering of this diving reflex.

Probably the final question before we get onto treatment is this: Does treatment of sleep apnea reduce cardiovascular events? Or is the association with cardiovascular events because sleep apnea is a surrogate for other risk factors? Data suggest that the treatment of sleep apnea with CPAP independently reduces cardiovascular events and closes that loop, so to speak.

Dr. Conti: What about treatment?

Dr. Gersh: The indications to treat a patient right now would be symptoms, such as daytime somnolence or motor vehicle accidents. A key part of treatment is lifestyle modification: even a small amount of weight loss may have a big effect; other suggestions include avoidance of alcohol at night and avoidance of sedatives. One of our sleep doctors gave me a useful tip. He said, "Tell them to lie on their side when sleeping."

As for CPAP, more and more patients will comply if they are sent to centers with expertise in the use of this technology. It's not an easy treatment, but there's a lot going on to modify current forms of CPAP. However, right now patients need referral to a sleep center; this is not for the cardiologist.

Dr. Conti: What about surgical intervention?

Dr. Gersh: The data for surgical approaches are not convincing. One area that is very dynamic at the moment relates to diagnosis. Our sleep centers have a huge waiting list for sleep studies and there's a lot of discussion about ambulatory polysomnography. This may be available soon.

Dr. Conti: Bernard, thank you for sharing this with our ACCEL audience. This information should heighten the level of awareness of all of us about the problem of obstructive sleep apnea and its relationship to cardiovascular disease and events.

Dr. Gersh: Thank you so much, Dick.

Guidelines

Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2008;51:e1-62.

Source : http://www.medscape.com/viewarticle/579521

New Test May Detect Early Alzheimer's Disease

2009-06-17T15:31:00.000+07:00

Researchers have developed a new cognitive test that is quick to use, examines 10 skills, and reportedly detects 93% of cases of Alzheimer's disease. Published online June 10 in BMJ, investigators suggest the new self-administered test is a powerful and valid screening tool.

"If a patient completes the test while in the waiting area supervised by the receptionist, it can be scored and analyzed by the doctor in 2 minutes," explain the researchers, led by Jeremy Brown, MD, from Addenbrooke's Hospital, in Cambridge, the United Kingdom. "If there is time during the consultation to observe the patients filling in the test, this can also be a useful aid to diagnosis."

Dr. Brown is a neurologist, but his team found that with 10 minutes' training and a scoring sheet, a nurse without experience working in memory clinics was able to evaluate the test as accurately as a specialist.

In an accompanying editorial, Claire Nicholl, MD, also at Addenbrooke’s Hospital, pointed out that the study showed that the new test was more sensitive than the Mini-Mental State Examination in this patient population (93% vs 52%).

More Sensitive Than Mini-Mental State Examination

"Longer scales are used in specialist settings," Dr. Nicholl notes, "but the test is not designed to replace these."

In this cross-sectional study, investigators evaluated subjects from 3 hospitals including a memory clinic. They looked at 540 control participants and 139 patients with dementia or amnesic mild cognitive impairment.

In the diagnosis of early Alzheimer's disease with a cut-off point of <42/50, the test had good sensitivity (93%), specificity (86%), and interrater reliability.

The test requires participants to write 10 answers on a double-sided card. The requested tasks evaluate a range of areas, including the patient's semantic knowledge, ability to calculate and name objects, and recall.

"If the memory test is to be adopted more widely, it must be validated in a range of settings and different populations," Dr. Nicholl writes. "Until then, the most important message is that clinicians should identify a test that suits their clinical setting, use it to screen or case find as appropriate, and develop experience in its use to improve the identification of patients with early dementia."

Must Be Validated

Dr. Nicholl points out that the authors do not comment on the ethnicity of the study participants, but the local population is mainly white and some of the items on the test likely show some cultural bias.

Elizabeth Gould, director of quality care programs at the Alzheimer's Association, echoed similar concerns to Medscape Neurology. Speaking during a recent interview, she emphasized the importance of taking cultural differences into account as much as possible. She also stressed the importance of early detection.

A Web site is being developed for clinicians to download the new test, scoring sheets, and further instructions. It will be available at www.tymtest.com.

Source : http://www.medscape.com/viewarticle/704393?sssdmh=dm1.486302&src=nldne

Neonatal Outcomes May Be Better With Vaginal Birth After Cesarean Delivery

2009-06-16T10:09:00.001+07:00

Neonates born after elective subsequent cesarean delivery have significantly higher rates of respiratory morbidity and neonatal intensive care unit (NICU) admission and longer length of hospital stay vs those with vaginal birth after cesarean (VBAC), according to the results of a retrospective cohort study reported in the June issue of Obstetrics & Gynecology.

"Controversy remains on whether a trial of labor or an elective repeat cesarean delivery is preferable for a woman with a history of cesarean delivery," write Beena D. Kamath, MD, MPH, from the University of Colorado School of Medicine in Denver, and colleagues. "Historically, concerns regarding the increased risk of uterine rupture and perinatal asphyxia in trial of labor after cesarean compared with planned repeat cesarean have swayed obstetricians away from recommending a trial of labor after cesarean delivery; however, the absolute risk of perinatal asphyxia remains small."

The goals of this study were to compare the outcomes of neonates born by elective subsequent cesarean delivery vs VBAC in women with 1 previous cesarean delivery and to compare the cost differences between these procedures. The study cohort consisted of 672 women with 1 previous cesarean delivery and a singleton pregnancy at or after 37 weeks of gestation. Participants were categorized based on their intention to have an elective subsequent cesarean delivery or a VBAC, whether successful or failed. The main endpoints of the study were NICU admission and measures of respiratory morbidity.

Compared with the VBAC group, neonates born by cesarean delivery had higher NICU admission rates (9.3% vs 4.9%; P = .025). Rates of oxygen supplementation were also higher in the subsequent cesarean group for delivery room resuscitation (41.5% vs 23.2%; P < .01) and after NICU admission (5.8% vs 2.4%; P < .028). The rates of delivery room resuscitation with oxygen were lowest in neonates born by VBAC and highest in neonates delivered after failed VBAC.

Although the costs of elective subsequent cesarean delivery were significantly higher vs VBAC, the highest costs for the total birth experience were for failed VBAC, considering both delivery and NICU use.

"In comparison with vaginal birth after cesarean, neonates born after elective repeat cesarean delivery have significantly higher rates of respiratory morbidity and NICU-admission and longer length of hospital stay," the study authors write.

Limitations of this study include relatively short postpartum follow-up of the mothers to determine the additional costs of postsurgical complications and insufficient data to allow estimation of costs other than those for hospital care.

"Given the increasing rates of primary cesarean delivery and the concomitant decrease in VBACs, once a woman has had a primary cesarean delivery, we must consider the risks that this places on her subsequent deliveries and subsequent neonates," the study authors conclude. "Indeed, this argues for greater selectivity in performing a cesarean delivery in the first place, and certainly a greater need for counseling before a primary elective cesarean delivery. As investigators continue to search for ways to make cesarean delivery safer, we may be better served by exploring other means for reducing overall cesarean delivery rates and recognizing our own preoccupation with the individual that will be our patient, whether it be mother or neonate."

The study authors have disclosed no relevant financial relationships.

Obstet Gynecol. 2009;113:1231-1238.

Clinical Context

The rate of cesarean delivery has reached an all-time high in the United States, and the current study provides an overview of the epidemiology of cesarean delivery. In 2006, 31.1% of all deliveries were via cesarean, and this rate was fueled by an increase in the rate of primary cesarean delivery by 60% between 1996 and 2005.

Women with a primary cesarean delivery have a greater than 90% chance of having another cesarean delivery. Overall, more than half of cesarean deliveries are performed electively, before the onset of labor.

The current study examines neonatal outcomes in women with a history of primary cesarean delivery, with the primary variable being VBAC vs subsequent elective cesarean delivery.

Study Highlights

The study was a retrospective review of cases at 1 Colorado hospital between 2005 and 2008.
Researchers focused on women with a history of 1 previous cesarean delivery who were pregnant with a singleton pregnancy at 37 weeks or more of gestation. 51% of these women had planned an elective subsequent cesarean delivery, and 49% had planned for VBAC.
The primary outcome of the study was admission to the NICU. Researchers conducted a multivariate regression analysis to account for the effects of maternal demographic and disease factors as well as birth factors on the study outcome. Other outcomes included the need for neonatal resuscitation and the cost of care.
672 women were included in the analysis. The mean maternal age was 29 years, and approximately half of women were of Hispanic origin.
35.6% of the study cohort had a planned elective cesarean delivery without labor, 15.5% had an elective cesarean delivery after the onset of labor, 36.3% of women had a successful VBAC, and 12.6% had a failed VBAC requiring cesarean delivery.
Older women and women with higher educational achievement were more likely to have an elective subsequent cesarean delivery.
9.3% of neonates delivered by elective subsequent cesarean delivery required admission to the NICU vs only 4.9% of neonates delivered by intended VBAC. The adjusted odds ratios for NICU admission in neonates delivered with elective subsequent cesarean delivery without and with labor vs successful VBAC delivery were 2.93 and 2.26, respectively.
Infants in the cesarean group were more likely to require blow-by oxygen and continuous positive airway pressure after delivery vs infants delivered by VBAC, and they also had higher rates of NICU admission for hypoglycemia.
Conversely, infants delivered by VBAC were more likely to require bag mask ventilation and endotracheal intubation after delivery.
Infants delivered via cesarean after a failed VBAC had rates of NICU admission similar to rates of admission in the elective subsequent cesarean delivery group. However, infants delivered after failed VBAC required the most resuscitation efforts after delivery.
Factors associated with failed VBAC included chorioamnionitis and induction of labor.
Neonates delivered at 37 weeks of gestation required more resuscitation efforts vs more mature neonates.
Successful VBAC was associated with the shortest hospital stay and the lowest overall cost of care. Although failed VBAC was associated with the highest cost of care from all groups, planned VBAC still cost less than planned elective subsequent cesarean delivery overall.

Clinical Implications

The rate of cesarean deliveries in the United States was 31.1% in 2006, and an increase in the rate of primary cesarean deliveries was primarily responsible for this high rate. In addition, women with a primary cesarean delivery have a greater than 90% chance of having another cesarean delivery, and more than half of all cesarean deliveries are performed electively, before the onset of labor.
The current study finds that the rate of NICU admission is higher in infants delivered via elective subsequent cesarean delivery vs VBAC. Overall, elective subsequent cesarean delivery was estimated to be a more costly strategy.

Source : http://cme.medscape.com/viewarticle/703772?src=cmemp

Naproxen Best NSAID for Heart-Disease Patients

2009-06-16T10:06:00.000+07:00

One of the first large studies to look at the safety of different nonsteroidal anti-inflammatory drugs (NSAIDs) specifically in patients with heart disease has found that naproxen appears to have better cardiovascular safety than diclofenac, ibuprofen, and higher doses of rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) [1].

The study, published in the May 2009 issue of Circulation: Cardiovascular Quality and Outcomes, was conducted by a group led by Dr Wayne Ray (Vanderbilt University School of Medicine, Nashville, TN).

They explain that the cardiovascular safety of NSAIDs is highly controversial, with several studies suggesting increased cardiovascular risk associated with the new COX-2 inhibitors and also some older traditional NSAIDs, and that this issue is particularly important for patients with existing serious coronary heart disease, whose baseline risk of adverse cardiovascular events is increased. In addition, many of these patients take low-dose aspirin, which may interact with the NSAID.

But they note that data on the cardiovascular safety of these drugs in heart-disease patients is limited. They therefore conducted the current retrospective cohort study in which they examined the cardiovascular safety of individual NSAIDs in 48,566 patients with a hospitalization for myocardial infarction (MI), revascularization, or unstable angina that had been recorded in one of three large databases--Tennessee's expanded Medicaid program, Saskatchewan Health databases in Canada, and the United Kingdom's General Practice Research Database--between 1999 and 2004. Medications given outside the hospital were identified from pharmacy and physician records. The primary study end point was serious coronary heart disease, defined as MI or out-of-hospital death from CHD [coronary heart disease]. A secondary end point was the composite of serious cardiovascular disease (MI or stroke) and death from any cause. Preplanned analyses were conducted for the most frequently prescribed NSAIDs, which were naproxen, ibuprofen diclofenac, celecoxib, and rofecoxib.

Results showed that cardiovascular safety was best for naproxen, which had a lower incidence rate ratio (IRR) for serious cardiovascular disease than non-NSAID users. In contrast, there was evidence that cardiovascular risk was increased for users of the other study NSAIDs.

Incidence Rate Ratios (IRRs) for Serious CV Disease or Serious CV Disease and Death for Users of Various NSAIDS vs Non-NSAID Users

Drug	IRR (serious CV disease)	IRR (serious CV disease/death)
Naproxen	0.88	0.91
Ibuprofen	1.18	1.14
Diclofenac	1.27	1.38
Celecoxib	1.03	0.99
Rofecoxib	1.19	1.07

Other results showed that individuals who took diclofenac had a 50% increased risk of MI, stroke, or death from any cause compared with naproxen users. The authors point out that diclofenac is widely used outside the US and has been the reference drug in several COX-2-inhibitor outcome trials, and this excess risk was present for low and moderate doses (<> 200 mg/day) and rofecoxib (> 25 mg/day) had increased risk of serious coronary heart disease.

Relative to NSAID nonusers, serious coronary heart disease risk increased with short-term (less than 90 days) use for ibuprofen, diclofenac, celecoxib, and rofecoxib, but not for naproxen. The authors note that this is in contrast to a widely publicized post hoc analysis of the APPROVE trial data, interpreted by some as suggesting no risk for use of less than 18 months. But they point out that observational studies of rofecoxib have reported increased risk within the first month of therapy, and in the VICTOR trial, rofecoxib patients had increased risk after a mean duration of 7.4 months. "Thus, our findings add to the evidence that at least one of the mechanisms for increased cardiovascular risk is acute," they say.

They comment that their current findings are generally consistent with previous studies, most of which were not restricted to patients with serious coronary heart disease. They caution that the follow-up in this study began 45 days after the qualifying hospitalization admission for coronary heart disease, so these results do not apply to the early postdischarge period, during which NSAID use may be particularly hazardous.

Breaking New Ground

In an accompanying editorial [2], Dr Daniel Solomon (Brigham and Women's Hospital, Boston, MA) says that this study breaks new ground in focusing on patients with known cardiovascular disease. As arthritis and cardiovascular disease commonly coexist, studying the cardiovascular safety of NSAIDs in this subgroup is of great public-health value, he comments.

Noting that the relative risks for rofecoxib were consistently lower when death from any cause was also included in the end point, Solomon suggests that this raises the possibility that death from gastrointestinal bleeds may have been reduced in persons using rofecoxib. He says this leads to questions about how to measure the overall safety of a drug. "Cardiovascular safety in patients with known cardiovascular disease is tremendously important, but clinicians and patients should focus on 'net' safety," he writes. But he adds that this is difficult concept to understand and even harder to measure.

Solomon continues that the use of NSAIDs in patients with cardiovascular disease is concerning because of the cardiovascular and gastrointestinal toxicities associated with these agents, but until newer analgesics are developed, these agents will continue to be used in this patient group.

While more information will come from the PRECISION trial, a large randomized comparison of celecoxib, naproxen, and ibuprofen in patients at moderate cardiovascular risk, these results will not be available until 2011 or later, and thus, until then, doctors will continue to rely on well-done pharmacoepidemiology to help answer questions about the relative safety of various analgesic strategies in important subgroups of patients, Solomon says.

He concludes that the current study "gives us new and useful information from an observational study focusing on an important subgroup with known cardiovascular disease" and that "diclofenac use should be limited in this group and naproxen appears relatively safe, but non-NSAID analgesic strategies might also be considered."

This study was funded by an unrestricted grant from Pfizer. Ray has consulted with plaintiff's attorneys and insurance companies regarding rofecoxib. Two other authors were employees of Pfizer when this research began, and other authors have received research support from Merck, AstraZeneca, Novartis, and Pfizer. Solomon receives salary support for research from Amgen and Abbott. He serves as an unpaid member of the executive committee of the Pfizer-sponsored PRECISION trial, and he serves as an unpaid member of the data safety monitoring board of a Pfizer-sponsored trial investigating a non-NSAID analgesic for osteoarthritis.

References

Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes 2009; 2:155-163.
Solomon D H. Searching for a safe analgesic in patients with cardiovascular disease. Circ Cardiovasc Qual Outcomes 2009; 2:146-147.

Clinical Context

There has been significant attention to the cardiovascular risks associated with NSAIDs and particularly the risk associated with COX-2 inhibitors. In a previous systematic review and meta-analysis by McGettigan and Henry, which was published in the October 4, 2006, issue of the Journal of the American Medical Association, the researchers found that rofecoxib significantly increased the risk for cardiovascular events, and this risk increased with higher doses of rofecoxib. Moreover, the risk for cardiovascular events with rofecoxib was evident in the first month of treatment. However, the researchers also found no significant association between celecoxib and the risk for cardiovascular events.

This systematic review also noted a higher risk for cardiovascular events in patients who received older, nonselective NSAIDs, particularly diclofenac. The current study examines this issue in patients at a high risk for events because of preexisting coronary heart disease.

Study Highlights

Researchers used 3 large patient databases in Canada, the United States, and the United Kingdom to examine disease and prescription data in adults between the ages of 40 and 89 years who had been hospitalized for acute MI, coronary heart revascularization, or unstable angina pectoris.
All participants were enrolled in a health plan, which provided full medication information to the study database, and all subjects had at least 1 prescription or outpatient visit record. Patients with a history of other potentially life-threatening illness were excluded from study analysis.
The primary outcome of the study was the relationship between the use of NSAIDs and incident MI or cardiac death. Participants were analyzed from day 45 after their initial cardiovascular event for this outcome, and researchers accounted for participants' comorbid conditions in the study analysis.
48,566 adults had data for analysis. The mean age was 65 years, and 58% of the cohort consisted of men. The qualifying hospitalization was for acute MI in 40% of subjects, and coronary revascularization and unstable angina pectoris accounted as reasons for the qualifying hospitalization in another 40% and 20% of subjects, respectively.
The baseline cardiovascular risk score was similar in adults who did and did not use NSAIDs.
There were 111,162 person-years of follow-up and 3600 coronary heart disease events during this period.
Compared with adults who did not use NSAIDs, the use of naproxen was associated with nonsignificant reductions in the rates of serious coronary heart disease events and cardiovascular disease/death.
Conversely, users of diclofenac experienced significantly higher rates of serious coronary heart disease events (IRR, 1.44) and cardiovascular disease/death (IRR, 1.52) vs adults who received naproxen.
Compared with the use of naproxen, the use of ibuprofen also increased the risk for cardiovascular disease/death (IRR, 1.25).
Even high-dose naproxen was not associated with a higher risk for cardiovascular disease. However, users of higher dose of high-dose celecoxib and rofecoxib had a higher risk for serious coronary heart disease vs subjects who received high-dose naproxen (IRR, 1.61 and 2.29, respectively).
The NSAIDs noted were associated with a higher risk for coronary heart disease events when the duration of use was less than 90 days but not with longer periods of use.
Subgroup analysis failed to alter the main outcome of the study.

Clinical Implications

In a previous meta-analysis, rofecoxib was found to increase the risk for cardiovascular events in a dose-dependent fashion, and this risk was apparent within 1 month of the initiation of therapy. However, celecoxib was not associated with a significantly increased risk for cardiovascular events.
In the current study, the use of naproxen was not associated with a higher risk for coronary heart disease events or cardiac death in patients with a history of coronary heart disease. However, ibuprofen; high-dose celecoxib; high-dose rofecoxib; and, most significantly, diclofenac, did increase this risk.

Source : http://cme.medscape.com/viewarticle/703986?src=cmemp

Legionnaires Disease

2009-06-13T08:33:00.002+07:00

Background

Legionella pneumophila is an important cause of both nosocomial and community-acquired pneumonia (CAP) and must be considered a possible causative pathogen in any patient who presents with pneumonia.

The Legionella bacterium was first identified in the summer of 1976 during the 58th annual convention of the American Legion, which was held at the Bellevue-Stratford Hotel in Philadelphia. Infection was presumed to be spread by contamination of the water in the hotel's air conditioning system. The presentation ranged from mild flulike symptoms to multisystem organ failure. Of the 182 people infected, 29 died. A bacterium that would later be named L pneumophila was isolated from different organ tissues of guinea pigs inoculated with lung tissue samples from 4 individuals who died. Although this pathogen was not identified until 1976, retrospective analysis suggests that L pneumophila may have been responsible for previous pneumonia epidemics in Philadelphia; Washington, DC; and Minnesota. L pneumophila was identified in a clinical specimen dating to 1943.

Legionellosis is the term that collectively describes infections caused by members of the Legionellaceae family. Legionnaires disease (LD) is the pneumonia caused by L pneumophila. LD also refers to a more benign, self-limited, acute febrile illness known as Pontiac fever, which has been linked serologically to L pneumophila, although it presents without pneumonia.

Pathophysiology

The Legionella bacterium is a small, aerobic, waterborne, gram-negative, unencapsulated bacillus that is nonmotile, catalase-positive, and weakly oxidase-positive. Legionella is a fastidious organism and does not grow anaerobically or on standard media. Buffered charcoal yeast extract (CYE) agar is the primary medium used for isolation of the bacterium.

The Legionellaceae family consists of more than 42 species constituting 64 serogroups. L pneumophila is the most common species, causing up to 90% of the cases of legionellosis, followed by Legionella micdadei (otherwise known as the Pittsburgh pneumonia agent), Legionella bozemanii, Legionella dumoffii, and Legionella longbeachae. Fifteen serogroups of L pneumophila have been identified, with serogroups 1, 4, and 6 being the primary causes of human disease. Serogroup 1 is thought to be responsible for 80% of the reported cases of legionellosis caused by L pneumophila.

Legionella species are obligate or facultative intracellular parasites. Water is the major environmental reservoir for Legionella. The bacterium can infect and replicate within protozoa such as Acanthamoeba and Hartmannella species, which are free-living amoebae found in both natural and manufactured water systems. The Legionella species within the amebic cells can avoid the endosomal-lysosomal pathway and can replicate within the phagosome. Legionella can survive and grow in the amebic cells, thereby enabling the organism to persist in nature.

Legionella species infect human macrophages and monocytes, and intracellular replication of the bacterium is observed within these cells in the alveoli. The intracellular infections of protozoa and macrophages have many similarities.

Transmission is thought to occur via inhalation of aerosolized mist from water sources (eg, whirlpools, showers, cooling towers¹) contaminated with either the bacterium or amebic cells infected with the bacterium. Direct inhalation is the most likely method of transmission, with aerosol-generating systems playing a crucial role.²Person-to-person transmission has not been documented. The highest incidence occurs during the warmer months, when air-conditioning systems are used more frequently. Nosocomial acquisition likely occurs via aspiration³, respiratory therapy equipment², or contaminated water. In addition, transmission has been linked to the use of humidifiers, nebulizers, and items that were rinsed with contaminated tap water.

The following features increase the likelihood of colonization and amplification of legionellae in man-made water environments: (1) temperature of 25-42°C, (2) stagnation, (3) scale and sediment, and (4) presence of certain free-living aquatic amoebae capable of supporting intracellular growth of legionellae. Legionellae can resist low levels of chlorine used in water distribution systems.

Activated T cells produce lymphokines that stimulate increased antimicrobial activity of macrophages. This cell-mediated activation is key to halting the intracellular growth of legionellae. The significant role of cellular immunity explains why legionellae are observed more frequently in immunocompromised patients. Humoral immunity is thought to play a secondary role in the host response to legionellae infection.

Frequency

United States

LD has a reported incidence of 8000-18,000 cases per year. In certain geographic areas, community-acquired LD is more common.

LD is reportable in all 50 states. Only 5-10% of cases are estimated to be reported. While most cases of LD are sporadic, 10-20% are linked to outbreaks. LD is among the top 3-4 microbial causes of CAP, constituting approximately 1-9% of patients with CAP who require hospitalization. LD is an even more common cause of severe pneumonia in patients who require admission to an intensive care unit (ICU). LD ranks second, after pneumococcal pneumonia, as the etiology of pneumonia severe enough to require ICU admission.

Some LD cases are acquired in the hospital; they usually occur as outbreaks. Legionellae in the hospital setting is usually due to its presence in water sources and on surfaces (eg, pipes, rubber, plastics). The organism is also found in water sediment, which may explain its ability to persist despite flushing of hospital water systems.

International

LD is thought to occur worldwide and to be the cause of 2-15% of all CAP cases that require hospitalization.

Mortality/Morbidity

The mortality rate may approach 100% in patients with underlying disease. In untreated patients, the mortality rate may be as high as 80%.

Sex

Men have a greater risk of acquiring L pneumophila infection.

Age

Elderly persons have a greater risk of acquiring infection with Legionella species.

Clinical

History

L pneumophila causes 2 distinct disease entities. Legionnaires disease (LD) is characterized by pneumonia. Pontiac fever is a milder illness than LD and is not characterized by pneumonia; Pontiac fever manifests as fever and myalgias that resolve without treatment.

Legionnaires disease
- The incubation period ranges from 2-10 days.
- Patients who develop legionellae infection and who have been hospitalized continuously for 10 or more days before the onset of illness are classified as having definite nosocomial LD. Patients with laboratory-confirmed infection that develops 2-9 days after hospitalization are classified as having possible nosocomial LD.
- Nosocomial LD occurs in clusters.
- Individuals with LD can present with a broad spectrum of symptoms.
Symptoms of legionnaires disease
- Fever greater than 40^ºC (>102 º F)
- Chills
- Cough - Dry or productive; hemoptysis rare
- Pleuritic or nonpleuritic chest pain
- Neurologic symptoms
  - Headache
  - Lethargy
  - Encephalopathy
  - Mental status changes - The most common neurologic symptom
- GI symptoms
  - Diarrhea - Watery, not bloody
  - Nausea, vomiting, and abdominal pain
- Myalgias

Physical

Manifestations of LD may include the following:
- Mental status changes
- Fever greater than 40°C (range, 38.8-40.5°C)
- Hypotension
- Relative bradycardia in all (excluding patients with pacemakers or arrhythmias or those receiving beta-blockers, diltiazem, or verapamil)
- Tachypnea
- Localized rales
- Depressed mental status or agitation
Extrapulmonary manifestations
- In addition to relative bradycardia, cardiac manifestations are common findings and include myocarditis, pericarditis, and prosthetic valve endocarditis.
- Pancreatitis
- Peritonitis
- Acute renal failure

Modified Winthrop-University Hospital Infection Disease Division's Point System for Diagnosing Legionnaires Disease in Adults

Table

Clinical Features	Qualifying Conditions	Point Score
Temperature >103°F*	With relative bradycardia	+5
Headache	Acute onset	+2
Mental confusion/lethargy*	Not drug induced	+4
Ear pain	Acute onset	-3
Nonexudative pharyngitis	Acute onset	-3
Hoarseness	Acute, not chronic	-3
Sputum (purulent)	Excluding chronic bronchitis	-3
Hemoptysis*	Mild/moderate	-3
Chest pain (pleuritic)	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome)	-3
Loose stools/watery diarrhea*	Not drug induced	+3
Abdominal pain*	With or without diarrhea	+5
Renal failure*	Acute, not chronic	+3
Shock/hypotension*	Not 2° to acute cardiac	-5
	/pulmonary causes	+5
Splenomegaly	Excluding non-CAP causes	-5
Lack of response to beta lactams	After 72 h (excluding viral pneumonias)	+5
Laboratory Features
Chest radiograph	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS)	+3
↓ PO2 with ↑ A-a gradient (>35)*	(Excluding severe influenza/SARS)	-5
↓ Na+	Acute onset	+1
↓ PO₄ =*	Acute onset	+5
↑ SGOT/SGPT (early mild/transient)*	Acute onset	+4
↑ Total bilirubin	Otherwise unexplained	+1
↑ LDH (>400 U/L)*	Excluding HIV/PCP	-5
↑ CPK/aldolase	Otherwise unexplained	+4
↑ CRP (>30 mg/L)	Acute onset	+5
↑ Cold agglutinins (≥1:64)	Acute onset	-5
↑ Creatinine	Acute onset	+2
Microscopic hematuria*	Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms	+2
	*Likelihood of Legionella* infection**
Total points	>15 Legionella infection very likely
	5-15 Legionella infection likely
	<5>Legionella infection unlikely

Clinical Features	Qualifying Conditions	Point Score
Temperature >103°F*	With relative bradycardia	+5
Headache	Acute onset	+2
Mental confusion/lethargy*	Not drug induced	+4
Ear pain	Acute onset	-3
Nonexudative pharyngitis	Acute onset	-3
Hoarseness	Acute, not chronic	-3
Sputum (purulent)	Excluding chronic bronchitis	-3
Hemoptysis*	Mild/moderate	-3
Chest pain (pleuritic)	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome)	-3
Loose stools/watery diarrhea*	Not drug induced	+3
Abdominal pain*	With or without diarrhea	+5
Renal failure*	Acute, not chronic	+3
Shock/hypotension*	Not 2° to acute cardiac	-5
	/pulmonary causes	+5
Splenomegaly	Excluding non-CAP causes	-5
Lack of response to beta lactams	After 72 h (excluding viral pneumonias)	+5
Laboratory Features
Chest radiograph	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS)	+3
↓ PO2 with ↑ A-a gradient (>35)*	(Excluding severe influenza/SARS)	-5
↓ Na+	Acute onset	+1
↓ PO₄ =*	Acute onset	+5
↑ SGOT/SGPT (early mild/transient)*	Acute onset	+4
↑ Total bilirubin	Otherwise unexplained	+1
↑ LDH (>400 U/L)*	Excluding HIV/PCP	-5
↑ CPK/aldolase	Otherwise unexplained	+4
↑ CRP (>30 mg/L)	Acute onset	+5
↑ Cold agglutinins (≥1:64)	Acute onset	-5
↑ Creatinine	Acute onset	+2
Microscopic hematuria*	Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms	+2
	*Likelihood of Legionella* infection**
Total points	>15 Legionella infection very likely
	5-15 Legionella infection likely
	<5>Legionella infection unlikely

*Otherwise unexplained (acute and associated with pneumonia)

Adapted from Cunha BA. Antibiotic Essentials. 5^th ed. Royal Oak, Mich: Physicians Press; 2006.

A clinical point score may be helpful in increasing probability of LD and prompting specific/definitive LD testing.

Causes

The risk of infection increases with the type and intensity of the exposure, as well as the health status of the exposed individual. Numerous factors increase the risk of acquiring legionellae infections.

Risk factors for infection
- Advanced age
- Smoking
- Chronic heart or lung disease
- Immunocompromised state or immunosuppressive medication use (especially corticosteroids)
- Recent exposure to water or soil
Pediatric cases of Legionella pneumonia are less common. Most of these cases occur in children who are immunosuppressed or in immunocompetent children who have undergone surgery or who are on a ventilator.

Differential Diagnoses

Workup

Laboratory Studies

While pneumonias caused by numerous pathogens share similar laboratory findings, hyponatremia (sodium <130>
Additional laboratory findings in LD and in pneumonias due to other causes include the following:
- Elevated liver enzyme levels
- Increased creatine phosphokinase levels
- Increased creatine phosphokinase (CPK) levels
- Increased C-reactive protein levels (>30 mg/L)
- Hypophosphatemia (specific to LD excluding other causes of hypophosphatemia)⁴
- Microscopic hematuria
- Proteinuria (40%)
Gram stain
- Typically, many leukocytes and a paucity of organisms are observed.
- If visible, the organisms are small, faintly staining, gram-negative bacilli.
Culture of respiratory secretions
- The definitive method for diagnosing Legionella is isolation of the organism in the respiratory secretions (ie, sputum, lung fluid, pleural fluid). However, Legionella species do not grow on standard microbiologic media.
- Legionella requires buffered CYE agar and cysteine for growth. Optimal growth occurs at 35-37°C.
- Legionella is a slow-growing organism and can take 3-5 days to produce visible colonies. The organisms typically have a ground-glass appearance.
- Routine sputum cultures have a sensitivity and specificity of 80% and 100%, respectively.
- Transtracheal aspiration of secretions or bronchoscopy specimen increases the sensitivity.
- Bronchoalveolar lavage (BAL) fluid provides a higher yield than bronchial wash specimens.
Blood cultures: Legionella can be isolated from blood, but it shows a much lower sensitivity.
Direct fluorescent antibody staining of sputum
- Direct fluorescent antibody staining (DFA) is a rapid test that yields results in 2-4 hours but has a lower sensitivity. The specificity of DFA is 96-99% using monoclonal antibody instead of polyclonal antibody.
- A positive result depends on finding large numbers of organisms in the specimen; therefore, the sensitivity is increased when samples from the lower respiratory tract are used.
- DFA results rapidly become negative (in 4-6 d).
Serology
- The most widely used tests include the immunofluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA). A single increased antibody titer confirms LD if the IFA titer is greater than or equal to 1:256.
- While LD serologic tests are the most readily available, they require a 4-fold increase in antibody titer to 1:128 or greater, which takes 4-8 weeks. Paired measurements from both the acute and convalescent periods should be obtained, since an antibody response may not be apparent for up to 3 months. Of note, antibody levels do not increase in approximately one third of patients with LD.
Urinary antigen test
- The Legionella lipopolysaccharide antigen is detected with ELISA, radioimmunoassay (RIA), and the latex agglutination test. The Legionella lipopolysaccharide antigen becomes detectable in 80% of patients on days 1-3 of clinical illness.
- The urinary antigen assay can be used to detect only L pneumophila (serogroup 1).⁵
- The advantages of this test include rapidity and simplicity. In addition, the relative ease of obtaining a urine sample compared with obtaining sputum specimens and the persistence of antigen secretion in patients who are on antibiotic therapy increase the usefulness of the urine antigen detection method.⁵
- The urinary antigen result can remain positive for months after the acute episode has resolved.⁵
Amplification with polymerase chain reaction
- Polymerase chain reaction (PCR) of urine, serum, and bronchiolar lavage fluid is very specific for the detection of legionellae, but the sensitivity is not greater than that of culture.
- The primary benefit of this procedure, like IFA titers, is that it can be used to detect infections caused by legionellae other than L pneumophila serogroup 1.⁶

Imaging Studies

No typical LD radiographic presentation exists.⁷
Rapidly progressive asymmetrical infiltrates are characteristic of LD.
Approximately one quarter of patients had infiltrates that were described as interstitial. Almost half of the patients had patchy alveolar infiltrates.
In general, the abnormalities are typically unilateral and are found in the lower lobes.
Pleural effusions are found in one third of patients.
Cavity and abscess formation are rare and can occur in immunocompromised hosts.
Improvement revealed on the chest radiograph can lag behind the clinical improvement by 5-7 days. The abnormalities on chest radiograph can take up to 3-4 months to resolve completely.

Procedures

Bronchoscopy: While the sensitivity of specimens retrieved via bronchoscopy is comparable to that of sputum, BAL fluid gives a higher yield than bronchial wash specimens.
Thoracentesis: If a pleural effusion is present, fluid can be evaluated using DFA or LD culture.

Histologic Findings

Typically, legionellae histopathological lesions are found in interstitial lining and alveoli with polymorphonuclear cells and macrophages.

Treatment

Medical Care

A delay in treatment significantly increases the risk of mortality. Therefore, include empiric anti-Legionella therapy in the regimen for severe CAP and in specific cases of nosocomial pneumonia.
Although Legionella pneumonia can present as a mild illness, most patients require hospitalization with parenteral antibiotics.
Historically, erythromycin was used for L pneumophila infection, but doxycycline, azithromycin, macrolides, and quinolones are more active against legionnaires disease (LD) than erythromycin.⁸
Fluoroquinolones, telithromycin, and azithromycin have greater in vitro activity and better intracellular penetration than erythromycin.⁸In addition, animal studies of L pneumophila infection have shown these agents to have superior activity.
The fluoroquinolones doxycycline, telithromycin, and azithromycin are superior because of their activity and pharmacokinetic properties (eg, better bioavailability, better penetration into macrophages, longer half-life).
For severe disease, a fluoroquinolone is recommended. Severe disease is defined by respiratory failure, bilateral pneumonia, rapidly worsening pulmonary infiltrates, or the presence of at least 2 of the following 3 characteristics:
- Blood urea nitrogen greater than or equal to 30 mg/dL
- Diastolic blood pressure lower than 60 mm Hg
- Respiratory rate greater than 30/min
With doxycycline or fluoroquinolones, rifampin does not need to be added in severely ill patients.
Most healthy hosts exhibit clinical response to treatment within 3-5 days.

Medication

Treat intravenously until clinically improved; then, consider changing to an oral with a 10- to 14-day course after patients begin to show signs of clinical improvement. A 21-day course is recommended in patients who are immunocompromised, who have severe underlying disease, or who develop severe Legionella pneumonia.

For immunosuppressed patients, fluoroquinolone therapy is recommended for several reasons. The fatality rate of Legionella pneumonia is high in this patient population.

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Levofloxacin (Levaquin)

Fluoroquinolone for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

Adult

500 mg PO/IV qd, adjust dose in renal disease

Pediatric

<18>18 years: Administer as in adults

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment

Azithromycin (Zithromax)

Macrolide antibiotic used to treat mild-to-moderate microbial infections.

Adult

Day 1: 500 mg PO
Days 2-7: 250-500 mg PO qd; may treat for 10 d
500 mg IV qd for 7-10 d

Pediatric

<6>6 months: 10 mg/kg PO on day 1, not to exceed 500 mg; 5-10 mg/kg/d PO qd on days 2-7, not to exceed 500 mg/d; may treat for 10 d

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Clarithromycin (Biaxin)

Macrolide antibiotic. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Adult

250 mg PO bid; may increase to 500 mg PO tid or 500 mg PO q12h

Pediatric

15 mg/kg/d PO divided bid; not to exceed 1 g qd

Toxicity increases with coadministration of fluconazole and pimozide; clarithromycin effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, HMG CoA-reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmia and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents

Documented hypersensitivity; coadministration of pimozide

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25>

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis, and, consequently, growth.

Adult

250-750 mg PO q12h; 200-400 mg IV q12h

Pediatric

15-30 mg/kg/d PO divided q12h; not to exceed 1.5 g/d

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sparfloxacin (Zagam)

No longer available in the United States. Inhibits bacterial DNA synthesis and, consequently, growth.

Adult

200 mg PO qd

Pediatric

<18>18 years: Administer as in adults

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Documented hypersensitivity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Telithromycin (Ketek)

First antibiotic in a new class called ketolides. Combats resistant bacteria by inhibiting the protein synthesis necessary for bacterial reproduction, binding 10 times tighter than macrolides at 2 different sites on bacterial ribosomes. Blocks protein synthesis by binding to 50S ribosomal subunit (23S rRNA at domain II and V). Binding at domain II retains activity against gram-positive cocci (eg, S pneumoniae) in the presence of resistance mediated by methylases (e rm genes) that alter the domain V binding site. May also inhibit the assembly of nascent ribosomal units.Resistance and cross-resistance have not been observed. Active against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis, as well as atypical bacteria (eg, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumoniae). Indicated to treat mild-to-moderate CAP, including infections caused by multidrug-resistant S pneumoniae.

Adult

800 mg PO qd for 7-10 d

Pediatric

Not established

CYP 3A4 inhibitor and substrate; coadministration with other CYP 3A4 inhibitors (eg, itraconazole, ketoconazole) decreases elimination and increases C_max and AUC; CYP 3A4 inducers (eg, rifampin) decreases telithromycin C_max and AUC by 79% and 86%, respectively; increases C_max and AUC of other CYP 3A4 substrates (eg, cisapride, pimozide, simvastatin, lovastatin, atorvastatin, midazolam, triazolam); HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin, lovastatin) should be temporarily discontinued owing to increased myopathy risk when coadministered; increases digoxin and theophylline serum levels; decreases sotalol C_max and AUC secondary to decreased absorption; caution with other drugs that increase QTc interval (eg, quinidine, procainamide, dofetilide)

Documented hypersensitivity; coadministration with cisapride or pimozide; myasthenia gravis; history of hepatitis and/or jaundice with use of macrolides

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in severe renal impairment (limited data exist); consider the diagnosis of pseudomembranous colitis if diarrhea occurs following antibiotic treatment; may prolong QTc interval (caution in heart conduction abnormalities); common adverse effects include diarrhea and nausea; may rarely cause visual disturbances; acute hepatic failure and severe liver injury (in some cases fatal) have been reported (if clinical hepatitis or liver enzyme elevations combined with other systemic symptoms occur, permanently discontinue)

Doxycycline (Vibramycin)

Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Adult

100 mg PO/IV q12h

Pediatric

<8>8 years: Not established

Documented hypersensitivity; severe hepatic dysfunction

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider measuring drug serum level in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines

Moxifloxacin (Avelox)

Inhibits bacterial DNA synthesis and growth. Activity is similar to that of ciprofloxacin and levofloxacin.

Adult

400 mg PO qd for 10 d

Pediatric

<18>18 years: Administer as in adults

Follow-up

Further Inpatient Care

Patients with mild-to-moderate pneumonia are admitted to the hospital for parenteral antibiotics and supportive measures. Patients deemed to have a severe pneumonia may require ICU admission for closer monitoring. Quickly initiate empiric antibiotic treatment and obtain a diagnostic workup.

Further Outpatient Care

In milder cases, patients can be treated in the outpatient setting with oral antibiotics.
For patients who are hospitalized and treated with intravenous antibiotics, start oral antibiotics while in the hospital and observe for continued response. Continue oral antibiotics on an outpatient basis for 14-21 days, depending on the severity of the presenting illness. Patients should receive close follow-up care to ensure complete resolution of their respiratory symptoms.

Inpatient & Outpatient Medications

Patients should complete the full course of their antibiotics, whether the treatment is initiated in the outpatient setting or in the hospital.

Deterrence/Prevention

Prevention and control of nosocomial legionellosis
- Legionellae should be sought in hospitalized patients with an increased risk for infection and subsequent death.
- If one definite case or 2 possible cases of nosocomial legionnaires disease (LD) occur among inpatients, initiate an investigation for a hospital source.
- Routinely maintain cooling towers and use only sterile water for filling and rinsing of nebulization devices.
- Improve the design and maintenance of cooling towers and plumbing systems.
Disinfection
- Superheating water to 70-80°C, with flushing of distal sites
- Installation of copper-silver ionization units, which produce metallic ions that disrupt the bacterial cell wall, thus resulting in lysis and cell death: This method provides sustained protection and is very effective at eradicating legionellae.
- Use of ultraviolet light, which kills legionellae by damaging cellular DNA: This system is effective when disinfecting localized areas; however, because it provides no sustained protection, adjunctive treatments must be used.
- Hyperchlorination of water is no longer recommended because legionellae are fairly chlorine resistant, and chlorine decomposes at higher water temperatures found in hot water systems being treated.

Complications

Decreased pulmonary function
Abscess formation (in the lungs or at extrapulmonary sites)
Pulmonary fibrosis or scarring
Fulminant respiratory failure
Death

Prognosis

Progressive respiratory failure is the most common cause of death in patients with Legionella pneumonia. The mortality rate depends on the comorbid conditions of the patient, as well as the choice and timeliness of antibiotics administration. The site of acquisition (eg, nosocomial, community-acquired) may also affect the outcome.

Patient Education

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

Miscellaneous

Medicolegal Pitfalls

Failure to recognize L pneumophila as an important cause of CAP could lead to suboptimal treatment with inappropriate antibacterial agents and could result in unnecessary patient morbidity and mortality.

Source : http//emedecine.medscape.com/artilce/220163

A 31-Year-Old Woman With a Painful Right Wrist

2009-06-12T15:47:00.002+07:00

A 31-year-old woman presents with a 5-month history of progressive right wrist pain following delivery of her baby girl. The patient claims that the pain has become so severe and disabling that it has significantly affected her ability to perform daily activities. The pain is particularly intense when she picks up her child. The patient is a software engineer by training, but she is currently on maternity leave and is staying at home to care for her newborn baby. She lives in a single-family house with her husband and their 2 dogs. She denies having any fever, chills, or any other associated systemic symptoms. She has no remarkable past medical history; her surgical history is only remarkable for appendicitis when she was 13 years old. She is not taking any medications, except for recent daily acetaminophen use to alleviate her wrist pain. The acetaminophen has provided only mild and inconsistent improvement of her pain. She denies smoking cigarettes but does admit to drinking a glass of wine on occasion. She does not use any illicit drugs.

On physical examination, the patient is not in any apparent discomfort. Her oral temperature was 96.3°F (35.7°C). Her pulse has a regular sinus rhythm, with a rate of 88 bpm. Her blood pressure is measured at 145/75 mm Hg. No skin rash or discoloration is noted. Her head and neck examination is unremarkable. Her lungs are clear to auscultation, with normal respiratory effort. Her abdomen is soft and nontender to deep palpation. There is no evidence of organomegaly. The patient's reflexes are normal and symmetrical. Close examination of her right wrist shows mild but definite soft-tissue swelling just proximal and posterior to the radial styloid. There is no associated erythema over the area of pain, and no pain is elicited on palpation. There is exquisite pain at the thumb with the Finkelstein maneuver (a specific maneuver in which the thumb is placed in the closed fist and the affected hand is tilted towards the little finger, into ulnar deviation).

Her laboratory workup includes a complete blood count, with normal red and white blood cell counts and no thrombocytopenia. The erythrocyte sedimentation rate (ESR) is mildly elevated. Her basic metabolic panel is normal. Her serum rheumatoid factor is within normal limits. The antinuclear antibodies (ANA) are within the normal range. Radiographs of the right wrist fail to reveal any bony abnormalities. A magnetic resonance imaging (MRI) scan of her affected wrist is performed (see Figure 1).

What is the diagnosis?

Hint: The condition is caused by overuse, classically among mothers of infants repetitively picking up their children.

a. Carpal tunnel syndrome

b. Stress fracture of the scaphoid
c. Bursitis

d. De Quervain tenosynovitis

Discussion

The coronal T2-weighted MRI image sequence showed abnormal segmental tendinous thickening involving the first dorsal extensor component of the wrist just proximal the radial styloid process, with a mild amount of fluid within the tendon sheath. There was no evidence of significant bony abnormality or soft-tissue masses or collections. These findings are consistent with a diagnosis of de Quervain tenosynovitis, an inflammatory process that typically involves the first dorsal extensor components of the wrist (namely, the abductor pollicis longus [APL] and the extensor pollicis brevis [EPB]) within the narrow fibro-osseous tunnel through which they normally pass. Although MRI is not typically necessary for the diagnosis of de Quervain tenosynovitis, the image here nicely shows the inflammatory changes characteristic of the condition.

De Quervain tenosynovitis was first described in 1895 by a swiss surgeon, Fritz de Quervain, who reported 5 cases of patients with a tender, thickened first dorsal wrist compartment. The condition has subsequently named after him. It is considered to be the second most common entrapment tendinitis of the hand and wrist (after trigger digit syndrome). In 1930, Finkelstein reviewed the literature and reported 24 additional cases. He felt that chronic trauma should be considered as the principal cause of de Quervain tenosynovitis. From his work, the author derived the well-known "Finkelstein sign", which is used to diagnose the disease. The Finkelstein sign classically occurs in mothers of infants 6-12 months of age. Interestingly, the cause is believed to be principally endocrine and related to fluid retention in breast-feeding mothers, not solely as a result of repetitive lifting motion. De Quervain tenosynovitis has also, however, been described in fathers. This suggests that the condition can occur in the absence of postpartum endocrine changes. Repetitive trauma in manual laborers is also a common cause. The pain itself may appear either gradually or suddenly.^[1,2,11]

In most cases, the patient will often complain of weeks to months of gradually worsening pain proximal and posterior to the radial styloid process, especially when using the thumb. The patient will experience difficulties with gripping and pinching and, in severe cases, the affected hand may be too painful to use. The pain may radiate into the thumb, or it may radiate proximally into the ipsilateral forearm or shoulder. In the vast majority of the cases, a discrete soft-tissue mass corresponding to the affected tendon sheath thickening of the first extensor compartment at the level of the distal dorsolateral aspect of the radial styloid process is encountered on clinical examination. The presence of multiple tendon slips and variable insertions of the abductor pollicis longus, and the presence of a separate compartment for the extensor pollicis brevis, have been noted in patients who have de Quervain tenosynovitis. Anatomical studies involving human cadavers have shown great variability in the incidence of separate compartments for the extensor pollicis brevis and abductor pollicis longus tendons. In a large series, there was a separate compartment for the extensor pollicis brevis in 120 (40%) of 300 dissected wrists. In addition, several reports have described the anatomical variations of the first dorsal wrist compartment, and suggested that normal variations of the tendons of this compartment could be related to a cause of de Quervain tenosynovitis. No associated skin changes or discoloration are typically present.^[3,4,5,11]

De Quervain tenosynovitis is diagnosed clinically and rarely requires laboratory testing or imaging for confirmation (such as occurred in this case); however, imaging abnormalities have been described, and MRI is currently the preferred imaging modality. It is most often ordered in atypical cases in which an alternative diagnosis is being entertained, or in cases that are recurrent or resistant to conventional treatment. An MRI typically shows thickening and edema of the involved segment of the tendon, which is best depicted on the long TR sequences (mainly T2-weighted images). There may be hyperintense fluid signal-intensity surrounding or within the affected tendon sheath. A normal caliber tendon does not exclude the diagnosis. Intravenous (IV) administration of gadolinium is not usually necessary; however, when administered, enhancement within the tendons and surrounding soft tissue consistent with tenosynovitis may be seen. Additionally, in atypical cases, an MRI scan is helpful in excluding other etiologies of wrist pain, such as ganglion cysts and nerve sheath tumors.^[6,11]

Several studies have shown that ultrasonography is also a reliable and noninvasive method for detecting tenosynovitis changes. Ultrasonography of the symptomatic tendon typically shows distention in the tendon sheath, with surrounding fluid that is hypoechoic or anechoic. An axial scan of the tendon will exhibit a so-called "double target" appearance. Ultrasonography is also used to guide the delivery of therapeutic agents into the affected tendon sheath (as injections into the tendon should be avoided) and to follow the response to treatment. It can also help to determine the segment with the most inflammatory changes, allowing for precise administration of the steroids. Studies have shown a significant decrease in the thickness of the affected tendon sheath at 1 week after a local corticosteroid injection, with complete relief of the clinical symptoms and signs observed at 6 and 12 weeks postinjection. Conventional radiography is typically of limited usefulness, but it may show the area of soft-tissue swelling proximal to the styloid process. Some clinical series have shown focal radial styloid process abnormality at the first dorsal wrist compartment that is significantly associated with de Quervain tenosynovitis. Moreover, in clinical conditions that may mimic de Quervain tenosynovitis, radiographs can be helpful in ruling out offending bony pathology, such as degenerative bony changes.^[9,10]

Histologic examinations may reveal myxoid degeneration, which is responsible for the thickening observed in the sheath, and intramural deposits of mucopolysaccharides predominantly within the subsynovial regions. Macroscopically, classic de Quervain tenosynovitis demonstrates chronic inflammation, with scar formation and stenosis of the approximately 1-cm section of the fibro-osseous tunnel of the first dorsal compartment.^[7]

The goal of treatment for de Quervain tenosynovitis is to relieve the pain caused by irritation and swelling. Treatment includes conservative measures such as splinting of the affected thumb and wrist, which is sometimes ineffective (pain may return as soon as the splint is discontinued). In most cases, however, the disease is largely self-limiting and usually resolves after cessation of breast feeding. Injection of corticosteroids into the tendon sheath usually results in pain relief in about 82-95% of the cases. Symptomatic improvement from corticosteroid injection is usually observed within a few days after injection. The prognosis is generally good. A patient will generally return to full function after the inflammation quiets down with treatment. If 4-6 months of conservative treatment fails to alleviate the symptoms, then surgical release of the first dorsal compartment may be considered. The procedure is usually done on an out-patient basis. The surgery typically involves identification and cutting of the diseased tendon sheath segment under local anesthesia. Patients commonly return to their normal activities within 2-3 weeks. The procedure has been reported to be successful in about 90% of the cases.^[4,8]

The patient in this case failed conservative treatment (approximately 4 weeks) with splinting; there was only very mild improvement of her symptoms. As a result, intralesional injection of steroid using a 25 gauge needle was performed. The patient regained function and experienced pain relief within 3-4 days following the injection. No symptom recurrence was reported.

Which of the following statements regarding de Quervain tenosynovitis is NOT true?

The process can be bilateral.

It is usually a self-limited process.

The diagnosis is typically made clinically and rarely requires confirmation with imaging studies.

The pain typically occurs with repetitive lifting and radial deviation at the wrist.

Which of the following symptoms is most commonly seen in cases of de Quervain tenosynovitis?

a. Skin discoloration on the hand

b. Pain with use of the thumb
c. Loss of sensation in the hand

d. Bony abnormalities noted on imaging

Source : http://cme.medscape.com/viewarticle/702329

A Young Man With Lower Back Pain and Low-Grade Fever

2009-06-12T15:27:00.004+07:00

A 19-year-old man presents to his primary care provider with a 2-month history of lower back pain and stiffness. The pain is intermittent, achy, and usually worse in the morning than it is later in the day or evening. He has also noticed a progressive inability to perform activities that require flexibility in the back, such as bending down to pull on his pants or tying his shoelaces. The pain sometimes awakens him at night. It is improved with exercise. He also reports a several-month history of low-grade fever, malaise, and anorexia, as well as an unintended weight loss of 10 lb (4.5 kg). He has not noted any masses on his testicles with self-examination. The patient has no history of rash. He does not have any known chronic medical conditions. He takes one multivitamin per day. He has never smoked, but he does drink an occasional glass of wine with dinner. There is no significant family history of disease.

On physical examination, the patient has a blood pressure of 125/67 mm Hg and a heart rate of 60 bpm. His respiratory rate is 8 breaths/min and his temperature is normal at 98.0°F (36.7°C). The cardiovascular and respiratory portions of the examination are normal; specifically, no murmurs or rubs are detected. The patient has no photophobia, eye redness, or decreased visual acuity. On examination of the back, flexion of the lumbar spine is clearly decreased when the patient attempts to bend down to touch his toes. He also has pain and limited range of motion with rotation and lateral flexion at the lumbar spine. His chest expansion is mildly diminished. The remainder of the physical examination is within normal limits.

As part of the initial workup of the findings on physical examination, routine laboratory investigations, including a complete blood cell (CBC) count and a basic electrolyte panel, as well as plain radiographs of the back, are performed. The chemistry panel is unremarkable, and the CBC reveals a white blood cell (WBC) count of 4.6 × 10³/μL (4.6 × 10⁹/L), a hemoglobin of 13.7 g/dL (137 g/L), a hematocrit of 43% (0.43), and a platelet count of 120 × 10³/μL (120 × 10⁹/L). The electrolytes are within normal limits. A rheumatoid factor test is negative, and the erythrocyte sedimentation rate is 64 mm/hr (normal range, <10>

Anteroposterior and lateral radiographs of the lumbar spine are obtained (see Figure 1).

What is the underlying disease process for the radiographic abnormalities?

a. Ankylosing spondylitis

b. Spinal stenosis
c. Psoriatic Artritis

d. Diffuse idiopathic skeletal hyperostosis

Discussion

Figure 1.

The anteroposterior and lateral radiographs of the spine demonstrated the classic "bamboo-spine" finding seen in cases of ankylosing spondylitis. The images showed sclerosis and ankylosis of the vertebral bodies, without loss of disc space. Bone formation extended across the anterior and lateral margins of the intervertebral disks of the lower thoracic and lumbar spine (syndesmophytosis). The sacroiliac joints showed extensive periarticular sclerosis and focal ankylosis.

Ankylosing spondylitis is a chronic inflammatory disorder of multiple articular and para-articular structures that principally involves the axial skeleton. It usually affects the sacroiliac joints and the spinal facet joints of the vertebrae. It sometimes involves the appendicular skeleton as well, such as the joints of the greater trochanter, patella, and calcaneum. Other extraspinal manifestations include iritis/uveitis and pulmonary involvement. The basic pathologic lesion of ankylosing spondylitis occurs at the entheses, which are sites at which ligaments, tendons, and joint capsules attach to bone. In the outer layers of the annulus fibrosis of the intervertebral disks, the condition manifests as a formation of new bone. The name of the disease is derived from Greek; "ankylos" means stiffening of a joint, and "spondylos" means vertebra. The disease is classified as a chronic and progressive form of seronegative arthritis. Ankylosing spondylitis affects men 4-10 times more frequently than women, and the symptoms generally appear in those aged 15-35 years. More than 90% of whites with ankylosing spondylitis have the HLA-B27 gene, but 6-8% of those with this gene do not develop the disease.^[2,3]

Symptoms of ankylosing spondylitis include back pain and stiffness, peripheral joint and chest pain, sciatica, anorexia, weight loss, and low-grade fever. The back pain associated with this condition is typically transient at first, but it eventually becomes persistent. It is usually worse in the mornings and resolves with exercise. A typical patient may also complain of waking up with back pain at night. The pain is usually centered over the sacrum, but it may radiate to the groin, buttocks, and down the legs. With time, the back pain usually progresses up the spine and affects the rib cage, resulting in a restriction of chest expansion and diaphragmatic breathing (observed as ballooning of the abdomen during inspiration) as the costovertebral joints become affected. The cervical spine is ankylosed late in the course of the disease, leading to restriction in neck movement and head rotation. Without treatment, the spine eventually becomes completely rigid, with loss of the normal curvatures and movement.^[2,3]

On physical examination, the loss of lateral flexion of the lumbar spine is the earliest objective sign of spinal involvement. The sacroiliitis may be detected by eliciting a tenderness response during percussion over the sacroiliac joints. Objective tests to quantify spinal restriction include touching the toes, the Schober test, and measurement of chest expansion. Additional physical findings include restriction of motion in the peripheral joints and tenderness over the enthuses. The physical exam should also include evaluation for signs of potentially serious cardiovascular and pulmonary complications, such as aortic incompetence secondary to aortitis, conduction defects of the heart, cardiomyopathy, pericarditis, apical fibrosis of the lungs, bronchiectasis, cavitation of the chest, and development of a restrictive ventilatory pattern. Other associated conditions include the development of inflammatory bowel disease, uveitis (in up to 20% of patients), radiculitis secondary to inflamed nerves, and, rarely, amyloidosis.^[2,3]

Specific criteria for the diagnosis of ankylosing spondylitis include the Rome criteria (developed in 1963) and the New York criteria (developed in 1968). Although these criteria have been generally accepted as useful, limitations are recognized and overlaps exist among the clinical and radiologic features of various seronegative spondyloarthropathies. Sacroiliitis is the hallmark of ankylosing spondylitis and is a requisite for the diagnosis under both sets of criteria. Other conditions, such as psoriasis, Reiter disease, enteropathic arthropathy, hyperparathyroidism, and osteitis condensans ilii, may also result in bilateral symmetric sacroiliac joint disease and should be considered in the differential diagnosis. Ankylosing spondylitis may also present with asymmetric sacroiliitis, which may be more characteristic of other conditions, such as psoriasis, Reiter disease, rheumatoid arthritis, and gouty arthritis. Radiographically, diffuse idiopathic skeletal hyperostosis (DISH) has a similar appearance to ankylosing spondylitis; however, DISH typically occurs at a later age and does not involve the sacroiliac joint.^[2,3]

The radiographic changes usually first appear in the sacroiliac joints, followed by the thoracolumbar and lumbosacral spine; this is in line with the natural progression of the disease. The disease then proceeds cephalad up the spine; however, the cervical spine may also be affected without involvement of the thoracic or lumbar spine. Radiographically evident peripheral-joint abnormalities are seen in more than 50% of patients. Abnormalities can also be seen in the symphysis pubis and in the manubriosternal, sternoclavicular, and temporomandibular joints. Spinal findings include osteitis, syndesmophytosis, diskovertebral erosions and destruction (Romanus lesions), and disk calcification. Radiographically, joint involvement appears as joint-space narrowing, periostitis, osseous erosion, and minimal periarticular osteoporosis (less than that seen with rheumatoid arthritis). Sacroiliac joint involvement is usually bilateral and symmetric.^[1,3]

Common laboratory findings are an elevated erythrocyte sedimentation rate (during the acute phase), a positive HLA-B27 histocompatibility antigen, mild leukocytosis, normochromic normocytic anemia (anemia of chronic disease), and negative results for rheumatoid factor.^[2,3]

The general principles of managing chronic arthritis also apply to ankylosing spondylitis. Among the various nonsteroidal anti-inflammatory drugs (NSAIDs) available to treat the disease, indomethacin may be the most effective. The lowest dose that provides pain relief should be used in order to avoid potentially serious complications, such as gastritis, peptic ulcer disease, and renal insufficiency. Sulfasalazine can be useful if peripheral arthritis is substantial, but it may be less effective when spinal and sacroiliac pain are the most prominent symptoms. In the majority of patients, the symptoms persist for life, although in some cases remission does occur.^[5]

Physical therapy and exercise can help prevent axial immobility. Specifically, spinal extension and deep-breathing exercises maintain spinal mobility, encourage erect posture, and promote chest expansion. Maintaining an erect posture and sleeping on a firm mattress with a thin pillow can help reduce thoracic kyphosis. Severe hip or spinal involvement may require surgical repair. Antitumor necrosis factor (anti-TNF) agents, such as infliximab and etanercept, are relatively new but often very effective therapeutic agents that may be considered for patients with pain refractory to other interventions.^[4,5]

The patient in this case was started by his primary care provider on a low dose of indomethacin to reduce pain and decrease inflammation. He was referred by the primary care provider to a rheumatologist for further evaluation and management and ongoing medical treatment. He was also referred to a physical therapist to begin a proper exercise and stretching program. Information regarding support groups to provide further education on the disease process and available treatment options were also given to the patient.

Which of the following statements is true?

Ankylosing spondylitis is a chronic inflammatory disorder that principally involves the appendicular skeleton.

The disease affects women more frequently than men.

Symptoms generally appear in individuals aged 5-10 years.

More than 90% of white patients with the disease are positive for the HLA-B27 gene.

Which of the following statements about therapeutic modalities and treatments is/are accurate?

Indomethacin may be the most effective NSAID for managing arthritic pain.

Vigorous physical therapy such as spinal extension and chest expansion as well as regular exercise may help to prevent disability resulting from axial immobility.

Thoracic kyphosis may be reduced by maintaining an erect posture and sleeping on a firm mattress.

Severe spinal or hip involvement may require surgical repair.

All of the above

Source : http://cme.medscape.com/viewarticle/703652

Three years of pulmonary rehabilitation: inhibit the decline in airflow obstruction, improves exercise endurance time, and body-mass index, in COPD

2009-06-09T21:45:00.003+07:00

Abstract

Background

Pulmonary rehabilitation is known to be a beneficial treatment for COPD patients. To date, however, there is no agreement for how long a rehabilitation program should be implemented. In addition, current views are that pulmonary rehabilitation does not improve FEV₁or even slow its decline in COPD patients. The aim of the study was to examine the efficacy of a 3 year outpatient pulmonary rehabilitation (PR) program for COPD patients on pulmonary function, exercise capability, and body mass index (BMI).

Methods

A matched controlled trial was performed with outcome assessments evaluated at 6, 12, 18, 24, 30, and 36 months. Eighty patients with moderate to severe COPD (age 63 ± 7 years; FEV₁48% ± 14) were recruited. The control group received standard care only, while in addition, the case study group received PR for duration of three years. These groups were matched for age, sex, BMI, FEV₁% and number of pack-years smoked.

Results

The decline in FEV₁after the three years was significantly lower in the PR group compared to control, 74 ml versus 149 ml, respectively (p <>

Conclusion

Three years of outpatient pulmonary rehabilitation resulted in modifying the disease progression of COPD, as well as improving physical performance in these patients.

Background

Chronic obstructive pulmonary disease (COPD) is a chronic progressive respiratory disorder causing disability with an increasing burden to the patient, his family and to the health services. Ppatients with COPD commonly experience reduced exercise capacity and activity limitation. Furthermore, exercise intolerance is a major determinant of impaired quality of life for COPD patients, and improvement in exercise capacity is a key goal of COPD disease management [1].

Drug treatment regimens provides only partial benefit, and many patients remain symptomatic with impaired exercise capacity and and a worsening quality of life. For example, prospective studies testing for the effects of inhaled short-acting anticholinergic drugs, inhaled corticosteroids, or N-acetylcysteine on the progression of chronic obstructive pulmonary disease (COPD) failed to demonstrate a change in the slope of the forced expiratory volume in 1 second (FEV₁) in these patients [2-4]. To date, only smoking cessation has prospectively been shown to alter the rate of decline of FEV₁in patients with COPD [5]. Pulmonary rehabilitation (PR) is used as a complementary treatment option for these patients, Recently, the American Thoracic Society (ATS) and the European Thoracic Society (ERS) published a statement, in which PR was recognized as an evidence-based, multidisciplinary, and comprehensive intervention for patients with chronic respiratory diseases who are symptomatic and often have decreased daily life activities. [6]. This statement was followed by a position paper by the ACCP/AACVPR that support and enhance the previously described statement [7]. One of the major unresolved issues is the duration of treatment. For example, outpatient exercise training with two or three weekly sessions for 4 weeks showed less benefit than similar training for 7 weeks [8-10].

In order to evaluate the efficacy of pulmonary rehabilitation to alter the course of disease in COPD, we carried out in an outpatient setting, a controlled trial comparing 36 months of PR along with standard care and to the effects of standard care without rehabilitation. The outcome measurements included changes in the rate of FEV₁decline, its effects on exercise endurance and the change of body mass index (BMI).

Methods

COPD patients who were on long acting beta agonist (LABA) or combined inhalers of corticosteroids and LABA, were matched for age, sex, BMI, FEV₁% and number of pack-years smoked into two groups, those receiving pulmonary rehabilitation in addition to standard care and a control group receiving inhaled drugs as described above [11]. Patients were eligible for inclusion if they were younger than 70 years of age, had a FEV₁that was less than 60% and higher than 30%, of predicted value and their improvement after bronchodilator inhalation (400 μg salbutamol) was less than 12%. In addition, their clinical condition had been stable for at least 2 months prior to enrollment. We excluded patients who were active smokers or had quit smoking less than 2 years prior to the onset of this study and those in whom there were other severe medical problems such as heart failure, myocardial infarction, cerebrovascular disease, cancer, or severe orthopedic disorders.

PR was carried out in groups of 6–8 patients, twice a week during the course of the study. Each session consisted of exercises of both upper and lower extremities as well as integrated physical activity. This program was directed by an exercise therapist. Patients were instructed to carry out exercises at home simulating what they did in the groups, on at least two additional days per week. In addition, meetings on an individual basis with a psychologist, sometimes with family members included, occurred as needed. The patients were seen initially by the supervising physician and at intervals of three months for routine follow up and for functional evaluations. In addition, physician encounters occurred as needed. The control group was similarly seen and assessed by a pulmonary physician at three months intervals, in addition to as needed.

Pulmonary function studies were carried out at enrollment and at intervals throughout the study period. Spirometry (Medical Graphics, Inc., St. Paul, Minnesota) including FEV₁and forced vital capacity, were measured according to American Thoracic Society guidelines [12]. The BMI was re-calculated at every spirometry.

Exercise Endurance

During the run-in period, exercise tolerance was evaluated with a constant-load cycle ergometer on two separate visits. The constant-load tests were performed at 75% of the maximal work rate achieved during the incremental exercise test at screening. The purpose of the run-in exercise tests was to familiarize the study subjects with the constant-load exercise test procedures and reduce possible learning effects [13]. Cycle endurance time was defined as the duration of loaded pedaling. For the incremental test, the initial work rate was 10 Watts (W) and the work rate was increased by 10 W every minute until symptom limitation. Pulse oximetry, ECG, and BP were monitored at rest, during exercise, and at recovery.

Statistical Analysis

Data are presented as mean ± SD. Analysis of variance (ANOVA) was used to compare between the groups for analysis of the entire 36 months period. For time point differences we used, a two-sample t test with a significance level of 0.05.

Study ethics

The study was approved by the Tel Aviv Lung Association, Institutional Review Board

http://www.clinicaltrial.gov – TLA1948

Results

Eighty consecutive eligible patients fulfilled inclusion criteria and were matched to either the training group (40) or the control group (40). Thirteen patients, 16% (6 in the rehabilitation group and 7 in the control group) did not complete the 3 years of follow up (Table 1). All patients had moderate-severe COPD with moderate peripheral and respiratory muscle weakness and impaired functional and maximal exercise capacity. There were no significant differences in the characteristics of the 80 patients who initially participated in the PR and control groups (Table 1).

Table 1. Base line characteristics of the study subjects

The rate of FEV₁decline was measured after administration of a 400 ug of salbutamol, a short acting bronchodilator. Figure 1 depicts the changes in FEV₁over time in the pulmonary rehabilitation and control groups, and demonstrates a significant difference (p <>1 in the PR group was significantly lower when comparing each individual time point (p <>1 was reduced by 74 ml during the 3 years study, whereas in the control group it was 149 ml. Table 2 demonstrates an immediate significant improvement (p <>

Table 2. Effect of pulmonary rehabilitation on cycle exercise performance and BMI

Figure 1. Evolution of FEV₁decline, rehabilitation group represented by line and black triangles, whereas control group by line and black squares. A significant difference in the rate of FEV₁over time is noted between these two groups (p <>

Discussion

Our study demonstrates that a prolonged rehabilitation program inhibits the progression of airflow obstruction in COPD patients. In addition, it increased endurance time and work, and improved BMI. FEV₁is used in COPD for disease staging and since it declines progressively, its value is a predictor of life expectancy. Various exercise tests, different physiological parameters, and BMI are used as surrogates for clinical status assessment. Our study did not show that PR improved FEV₁, which is in accordance to a previous report, but showed beneficial interference with its progressive decline.

Previous studies have shown some improvement in FVC which may have been due to improved respiratory muscle function and a reduction in small airways disease [3]. The improvement in FEV₁in those cases was small and not statistically significant. We noted a significant inhibtion of the progression of airways obstruction occurring after the three years of treatment, and thus we speculate that participating in the pulmonary rehabilitation program increased in incremental stages small airways function and/or recruitment. In addition, the exercise regimen likely improve secretions evacuation, which can reduce airways infections/inflammation and decrease COPD exacerbations. For example, it was recently shown that moderate to high levels of regular physical activity are associated with a reduced lung function decline and COPD risk among smokers [14]. Furthermore, in earlier reports regular exercise was noted to protect against diseases associated with chronic inflammation [15]. Inflammation is an important element in the pathogenesis of COPD. The contribution of PR for reduction of FEV₁decline adds an additional beneficial effect of pulmonary rehabilitation for COPD patients. FEV₁decline may serve as a predictor of risk death from COPD, and therefore PR should be considered as a disease modifier [16]. The improvement of endurance time and work noted in the trial is consistent with previous reports [17]. One possibility no significant differences were noted regarding exacerbation-related hospitalizations in these two groups, may relate to the higher accessibility to medical care in the patients enrolled in our study, relative to the regular COPD patient. A randomized study would be preferable, in

Match study the control subjects who are 'matched' with the treated subjects on background covariates that the investigator believes need to be controlled [11]. Finally, since this study included patients with severe disease, the duration of three years to complete the study may have contributed to the relatively high number of dropouts (including death), for which we could not identify a specific reason.

Conclusion

Three years of pulmonary rehabilitation has an important beneficial impact on the rate of FEV₁decline, in addition to previously reported advantages of this treatment modality, for COPD patients.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

DS design the study, was responsible to the rehabilitation group and data analysis, and manuscript writing. MR participated in its design, data acquisition, coordination and drafted the manuscript IS was responsible to the matched control group, data acquisition and analysis, and reviewing manuscript.

Acknowledgements

The research was funded by the Tel Aviv Lung Association.

References

Rabe KR, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi F, Jenkins C, Rodriguez-Roisin R, Weel CV, Zielinski J: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
Am J Respir Crit Care Med 2007, 176:532-55. PubMed Abstract | Publisher Full Text
Return to text
The Lung Health Study Research Group: Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.
N Engl J Med 2000, 343:1902-92. PubMed Abstract | Publisher Full Text
Return to text
Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK: Randomised, double blind placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.
BMJ 2000, 320:1297-303. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R, van Schayck C, Olivieri D, Del Donno M, De Backer W: Effects of N-acetyl-cysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.
Lancet 2005, 365:1552-60. PubMed Abstract | Publisher Full Text
Return to text
Fletcher C, Peto R: The natural history of chronic airflow obstruction.
Br Med J 1977, 1:1645-8. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J, Carone M, Celli B, Engelen M, Fahy B: American thoracic society/european respiratory society statement on pulmonary rehabilitation.
Am J Respir Crit Care Med 2006, 173(12):1390-1413. PubMed Abstract | Publisher Full Text
Return to text
Ries L, Bauldoff GS, Carlin BW, Casaburi R, Emery CF, Mahler DA, Make B, Rochester CL, ZuWallack R, Herrerias C: Pulmonary Rehabilitation, Joint ACCP/AACVPR Evidence-Based Clinical Practice Guidelines.
CHEST 2007, 131:4S-42S. PubMed Abstract | Publisher Full Text
Return to text
Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J: Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial.
Lancet 2000, 355:362-68. PubMed Abstract | Publisher Full Text
Return to text
Troosters T, Gosselink R, Decramer M: Short- and Long-term Effects of Outpatient Rehabilitation in Patients with Chronic Obstructive Pulmonary Disease: A Randomized Trial.
Am J Med 2000, 109:207-212. PubMed Abstract | Publisher Full Text
Return to text
Engstrom CP, Persson LO, Larsson S, Sullivan M: Long-term effects of a pulmonary rehabilitation programme in outpatients with chronic obstructive pulmonary disease: a randomized controlled study.
Scand J Rehab Med 1999, 31:207-213. Publisher Full Text
Return to text
D'Agostino RB: Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group.
Statist Med 1998, 17:2265-2281. Publisher Full Text
Return to text
American Thoracic Society: Standardization of spirometry: 1994 update.
Am J Respir Crit Care Med 1995, 152:1107-36. PubMed Abstract
Return to text
American Thoracic Society/American College of Chest Physicians: ATS/ACCP statement on cardiopulmonary exercise testing.
Am J Respir Crit Care Med 2003, 167:211-277. PubMed Abstract | Publisher Full Text
Return to text
Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM: Regular physical activity modifies smoking-related lung function decline and reduces risk of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2007, 175:458-463. PubMed Abstract | Publisher Full Text
Return to text
Petersen AM, Pedersen BK: The anti-inflammatory effect of exercise.
J Appl Physiol 2005, 98:1154-1162. PubMed Abstract | Publisher Full Text
Return to text
Sircar K, Hnizdo E, Petsonk E, Attfield M: Decline in lung function and mortality: implications for medical monitoring.
Occup Environ Med 2007, 64:461-466. PubMed Abstract | Publisher Full Text
Return to text
Laviolette L, Bourbeau J, Bernard S, Lacasse Y, Pepin V, Breton MJ, Baltzan M, Rouleau F, Maltais F: Assessing the impact of pulmonary rehabilitation on functional status in COPD.
Thorax 2008, 63:115-121. PubMed Abstract | Publisher Full Text

Source : http://www.biomedcentral.com/1471-2466/9/26

COPD exacerbation: Lost in translation

2009-06-09T20:58:00.001+07:00

Abstract

The introduction and acceptance of a standard definition for exacerbations of COPD can be helpful in prompt diagnosis and management of these events. The latest GOLD executive committee recognised this necessity and it has now included a definition of exacerbation in the guidelines for COPD which is an important step forward in the management of the disease. This definition is pragmatic and compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication") in the definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiologal process which characterizes exacerbations. It should be also noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions (i.e. congestive cardiac failure or pulmonary embolism) that can masquerade as exacerbations but they should not be considered as causes of them. The authors therefore suggest that an inclusion of the etiologic factors of COPD exacerbations in the definition. Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation and significant deterioration in lung fuction. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. The authors acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations meets certain difficulties related to performing lung function tests or to sampling during exacerbations. However, the introduction of a test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward in the management of COPD.

Commentary article

Chronic Obstructive Pulmonary Disease (COPD) is characterized by exacerbations which are caused mainly by infections of the tracheobronchial tree or by inhalation of toxic gases [1]. During an exacerbation airway inflammation augments and a sustained worsening of patient's condition from the stable state and beyond normal day-to-day variations is observed. COPD exacerbations are a major cause of hospital admissions and frequent exacerbations are associated with increased mortality and impaired health-related quality of life [2]. Previous studies reported also that patients who experience frequently exacerbations may present an accelerating rate of lung function decline [3,4]. In this respect, the management of exacerbations by prompt diagnosis and effective treatment that reduces exacerbation frequency [5,6], should be a major goal in COPD.

However, despite the considerable progress in the understanding of the pathobiology of exacerbations and in the evaluation of their consequences, yet, there is no standardised definition of an exacerbation. The landmark study of Fletcher and Peto[7] published in seventies used the definition of "bronchial infections" (chest cold or illnesses during which phlegm production had increased). Later, the Lung Health Study[8] used the definition of "physician visits for lower respiratory illness", while in recent studies such as in the East London Study[3] and in a study performed in Greece[4], the definition of an exacerbation was based on criteria described previously by Anthonisen [9]. These criteria require either, increase of at least two major respiratory symptoms (dyspnea, sputum amount, and sputum purulence) or, increase of one major symptom in addition to at least one minor symptom (wheeze, cough, fever, nasal discharge, sore throat), for at least two consecutive days. Thus, in those previous studies, definitions were based either on patient reported symptom changes [3,4] or, on "healthcare utilisation" due to the worsening of patients condition [10,11]. However, it is not known which definition has been better.

Both these two types of definition presented certain drawbacks. Exacerbations definition, based on symptoms and signs, is limited by the fact that respiratory symptoms and signs (increased dyspnea, cough, sputum) which are used to characterize exacerbations, are not specific and can be also found in other clinical conditions. In this respect, common colds, respiratory infections or congestive cardiac failure may mimic an exacerbation in a patient with underlying COPD [12-14]. In addition, COPD patients experience chronic symptoms and mild changes in their baseline symptoms which may be undetected by the physician while many patients do not report their symptoms to physicians or they report it with a delay [15,16]. On the other hand, the "healthcare utilisation" definition (such as the need for supplementary medications (i.e. oral corticosteroids)[10,11], may be related to the access to health care services (such as the social and financial situation of the patient) which vary between countries [4,10]. Consequently, the reported average annual rates noted in most studies on COPD varied approximately between 1 to 3 depending on the definition used [4,10,11,16]. Hence, in previous recent years there has been much debate about how exactly an exacerbation should be defined [11,12].

The introduction and acceptance of a standard definition can be helpful in the clinical management of COPD patients. First, exacerbations could be detected and treated promptly. This is important since a delay in starting appropriate treatment is associated with a delay in the recovery from an exacerbation [15]. Second, frequent exacerbators [3,4] who require treatment that reduces exacerbation frequency could be identified in early stages of the disease and could be treated appropriately.

The latest GOLD executive committee recognised the necessity for a standard definition of exacerbations [1]. Although GOLD executive summary in 2001 used a general description of exacerbations based on the worsening of the clinical condition of the patient, avoiding the use a standard definition [17], GOLD has now included a definition of exacerbation in the guidelines for COPD [1]. This is an important step forward.

The current definition states that: "an exacerbation of COPD is defined as an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant a change in regular medication in a patient with underlying COPD"[13]. This definition is pragmatic and it is not in disagreement with previous definitions. Actually, the current definition compromises the different approaches for exacerbation. However, the inclusion of the "healthcare utilisation" approach (".. may warrant a change in regular medication") in the current definition may introduce in the diagnosis of exacerbation factors related to the access to health care services which may not be related to the underlying pathophysiologal process which characterizes exacerbations [14,15].

In addition, it should be noted that the aetiology of COPD exacerbations has not yet been included in the current definition. In this respect, the definition does not acknowledge the fact that many patients with COPD may suffer from additional conditions, such as community acquired pneumonia, congestive cardiac failure or pulmonary embolism that can masquerade as exacerbations but they should not be considered as causes of COPD exacerbations. In these cases the management may be challenging for physicians and mandatory for the patients. For example, patients presenting with symptoms of exacerbation may have pulmonary embolism [17] which requires anticoagulation. However, warfarin (a common oral anticoagulative therapeutic agent) interacts with steroids or with antibiotics which are required for exacerbations treatment and thus, more intensive monitoring of the anticoagulative effect is required. Therefore, inclusion of the etiologic factors of COPD exacerbations in the definition might improve further the management of these cases.

Moreover, COPD exacerbations are characterized by increased airway and systemic inflammation [18-20] and significant deterioration in lung function [13]. These fundamental aspects should be accounted in diagnosis/definition of exacerbations. This could be done by the introduction of a "laboratory" marker in the diagnosis of these acute events. Previous investigations have shown that lung function is deteriorated during exacerbations and that these tests can be performed even in patients with advanced disease [16,21]. On the other hand, there are several biomarkers in sputum and exhaled breath condensate which are significantly increased during exacerbations, reflecting the underlying airway inflammation. In addition, recent studies demonstrated that the measurement of non invasive biological markers of systemic inflammation such as plasma CRP or serum amyloid A could confirm exacerbations [22,23]. Therefore, the diagnostic value of lung function tests or of inflammatory markers in the differential diagnosis of COPD exacerbations should be further investigated in order to find the best of them for the diagnosis or the follow up of COPD exacerbations. We certainly acknowledge that the use of a test or a biomarker in the diagnosis of exacerbations requires prospective studies and meets certain difficulties related to performing lung function tests or to sampling during exacerbations [21]. However, the introduction of a diagnostic test that reflects airway or systemic inflammation in the diagnosis of exacerbations might be another step forward in the management of exacerbations for which we are all looking forward.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Supported by a grant from the society for the pneumonologic research and intensive care of Eastern Macedonia and Thrace.

References

Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J, Global Initiative for Chronic Obstructive Lung Disease: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
Am J Respir Crit Care Med 2007, 176:532-55. PubMed Abstract | Publisher Full Text
Return to text
Miravitlles M, Murio C, Guerrero T: Factors associated with relapse after ambulatory treatment of acute exacerbations of chronic bronchitis. DAFNE Study Group.
Eur Respir J 2001, 17:928-33. PubMed Abstract | Publisher Full Text
Return to text
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA: Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
Thorax 2002, 57:847-52. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Makris D, Moschandreas J, Damianaki A, Ntaoukakis E, Siafakas NM, M Emili J, Tzanakis N: Exacerbations and lung function decline in COPD: new insights in current and ex-smokers.
Respir Med 2007, 101:1305-12. PubMed Abstract | Publisher Full Text
Return to text
Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK: Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.
BMJ 2000, 320:1297-303. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C: TRial of Inhaled STeroids ANd long-acting beta2 agonists study group.
Lancet 2003, 369:449-56. Publisher Full Text
Return to text
Fletcher C, Peto R: The natural history of chronic airflow obstruction.
Br Med J 1977, 1(6077):1645-1648. PubMed Abstract | PubMed Central Full Text
Return to text
Kanner RE, Anthonisen NR, Connett JE, Lung Health Study Research Group: Lower respiratory illnesses promote FEV1 decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001, 164:358-64. PubMed Abstract | Publisher Full Text
Return to text
Bouros D, Pneumatikos I: The clinician through the looking glass: sputum microbiology in COPD exacerbations.
Respiration 2007, 74:13-4. PubMed Abstract | Publisher Full Text
Return to text
Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL, Masa F, Verea H, Murio C, Ros F, Vidal R, IMPAC Study Group: Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study.
Thorax 2004, 59:387-95. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Rodriguez-Roisin R: Toward a consensus definition for COPD exacerbations.
Chest 2000, (Suppl 2):398-401. Publisher Full Text
Return to text
Hurst JR, Wedzicha JA: What is (and what is not) a COPD exacerbation: thoughts from the new GOLD guidelines.
Thorax 2007, 62:198-9. PubMed Abstract | Publisher Full Text
Return to text
Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG, Infectious Diseases Society of America; American Thoracic Society: Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults.
Clin Infect Dis 2007, (Suppl 2):27-72. Publisher Full Text
Return to text
Tillie-Leblond I, Marquette CH, Perez T, Scherpereel A, Zanetti C, Tonnel AB, Remy-Jardin M: Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors.
Ann Intern Med 2006, 144(6):390-396. PubMed Abstract
Return to text
Steiropoulos P, Tzouvelekis A, Bouros D: Formoterol in the management of chronic obstructive pulmonary disease.
Int J Chron Obstruct Pulmon Dis 2008, 3:205-15. PubMed Abstract
Return to text
Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA: Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2000, 161:1608-13. PubMed Abstract | Publisher Full Text
Return to text
Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, GOLD Scientific Committee: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.
Am J Respir Crit Care Med 2001, 163:1256-76. PubMed Abstract | Publisher Full Text
Return to text
Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE: Granulocyte Inflammatory Markers and Airway Infection during Acute Exacerbation of Chronic Obstructive Pulmonary Disease.
Am J Respir Crit Care Med 2001, 163:349-355. PubMed Abstract | Publisher Full Text
Return to text
Makris D, Lazarou S, Alexandrakis M, Kourelis TV, Tzanakis N, Kyriakou D, Gourgoulianis KI: Tc2 response at the onset of COPD exacerbations.
Chest 2008, 134:483-8. PubMed Abstract | Publisher Full Text
Return to text
Biernacki WA, Kharitonov SA, Barnes PJ: Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD.
Thorax 2003, 58:294-8. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Return to text
Tzanakis N, Chrysofakis G, Tsoumakidou M, Kyriakou D, Tsiligianni J, Bouros D, Siafakas NM: Induced sputum CD8+ T-lymphocyte subpopulations in chronic obstructive pulmonary disease.
Respir Med 2004, 98:57-65. PubMed Abstract | Publisher Full Text
Return to text
Hurst JR, Donaldson GC, Perera WR, Wilkinson TM, Bilello JA, Hagan GW, Vessey RS, Wedzicha JA: Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2006, 174:867-74. PubMed Abstract | Publisher Full Text
Return to text
Bozinovski S, Hutchinson A, Thompson M, Macgregor L, Black J, Giannakis E, Karlsson AS, Silvestrini R, Smallwood D, Vlahos R, Irving LB, Anderson GP: Serum amyloid-a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2008, 177:269-78. PubMed Abstract | Publisher Full Text

Source : http://www.biomedcentral.com/1471-2466/9/6

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