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October 2008
Vol. 18 No. 10
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IDSA Journal Club, September 2008

In this feature, a panel of IDSA members identifies and critiques important new studies that have a significant impact on the practice of infectious diseases medicine.

For more from Clinical Infectious Diseases and The Journal of Infectious Diseases, see the "In the IDSA Journals" section of IDSA News.


Influenza Definition Misses Many Hospitalized Patients
Sara Cosgrove, MD, MS

The traditional definition of influenza-like illness (ILI)—presence of fever plus cough or sore throat—does not accurately predict infection with influenza in hospitalized patients, particularly those with asthma, according to a study in the October issue of Infection Control and Hospital Epidemiology

The authors hypothesized that influenza may present differently in hospitalized patients compared to ambulatory patients due to underlying conditions, especially pulmonary conditions. Over three influenza seasons (2001-2004), investigators compared 123 general medicine patients found to have laboratory-confirmed influenza infection with 246 control patients who tested influenza-free.

 Although cough, fever, myalgia, and sore throat were more common in patients with influenza than controls, only 43 percent of case patients (53 of 123) met the definition of ILI.  The ILI definition was only 43 percent sensitive and 86 percent specific. The sensitivity increased to 91 percent if cough alone was used to predict influenza.  In patients with asthma, the sensitivity of using the ILI definition was 21 percent. 

This study further confirms the difficulty in predicting which hospitalized patients have influenza and identifies adult patients with asthma as a group where the diagnosis is particularly likely to be missed.  In addition to ensuring that patients are offered and encouraged to receive annual influenza vaccination, providers should strongly consider ruling out influenza in any adult patient with asthma or a new cough being admitted to the hospital during influenza season.  (Babcock et al., Infect Control Hosp Epidemiol 2008;29:921-926.)

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Oseltamivir Resistance Rising
Sara Cosgrove, MD, MS

In another report, published in the September issue of Antimicrobial Agents and Chemotherapy, 8.6 percent of A(H1N1) influenza viruses in the United States during the 2007-2008 influenza season were found to be resistant to oseltamivir, the most commonly used neuraminidase inhibitor.  This represents a significant increase from previous seasons and emphasizes the importance of judicious use of neuraminidase inhibitors in the management of patients with suspected influenza. (Sheu et al., Antimicrob Agents Chemother. 2008;52:3284-92.)

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Hepatitis C Therapy Can be Effective in Cirrhotic Patients
Khalil Ghanem, MD

A study published in the September 16 issue of the Annals of Internal Medicine found that the treatment of hepatitis C in cirrhotic patients can lead to regression of cirrhosis and improved clinical outcomes.

Some clinicians question the value of antiviral therapy for hepatitis C patients with cirrhosis. To address this issue, the authors retrospectively evaluated 96 cirrhotic patients infected with hepatitis C who were treated between 1988 and 2001 with various interferon-based regimens, with or without ribavirin, and who had pre- and post-treatment liver biopsies available. Eighteen of these patients experienced regression of cirrhosis following therapy.

The authors then compared those who experienced histological regression of cirrhosis to those who did not. The outcome measures of interest were a combined liver end-point (ascites, hepatic encephalopathy, bleeding, bacterial peritonitis, liver cancer, and liver transplantation) and death.

After a median of 118 months of follow-up, none of the patients who demonstrated regression of cirrhosis experienced any of the liver-related complications described above, compared to 27 patients in the group that did not. Similarly, no patient with regression of cirrhosis experienced liver-related death or transplantation compared to 22 of those without regression.

Although the study was retrospective and many patients were treated with interferon regimens that are currently not considered standard of care, this study clearly demonstrates that regression of cirrhosis is possible and that antiviral treatment of patients with hepatitis C and liver cirrhosis is justified. (Mallet et al., Ann Intern Med. 2008:149;399-403.)

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Bartonella Bacteremia and Neurological Symptoms
Khalil Ghanem, MD

A case series published in the September issue of the Journal of Clinical Microbiology suggests an association between chronic neurological symptoms and Bartonella species bacteremia in patients with documented animal or arthropod exposures.

The authors report six cases of immunocompetent patients who presented with a myriad of subacute to chronic neurological symptoms (including seizures, paralysis, headaches, fatigue, memory loss, and visual disturbances) and who were found to have bacteremia with Bartonella henslea and/or Bartonella vinsonii subspecies berkhoffii. All six patients reported clear exposures to cats (mostly scratches or bites), arthropods, farms, or farm animals. The duration of neurological symptoms lasted from one month to five years. In most of these cases, treatment of the infection led to subjective improvement of the neurological symptoms.

In addition to serological testing, the investigators used broth enrichment methods coupled with molecular diagnostics to document infection. These methods are not routinely available in clinical laboratories.

The association noted in this paper is interesting but far from definitive. Given that infectious diseases clinicians are often asked to evaluate patients with neurological symptoms of unclear etiology, the possibility of Bartonella infection can be entertained when evaluating patients with clear animal or arthropod exposures.  (Breitschwerdt et al., J Clin Microb. 2008:46; 2856-2861.)

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HPV Infection: Common in Men, But a Little Bit Different.
Jason Weinberg, MD

Human papillomavirus (HPV) infection is common in men, but its epidemiology is somewhat different than in women, according to a study in the September 15 edition of The Journal of Infectious Diseases.

HPV infection is associated with cancers both in women and men, and sexual transmission of HPV from men affects disease in women.  HPV vaccine trials are underway in men, but very little is known about the natural history of HPV infection in men.  In this prospective cohort study, samples were obtained from 290 adult male subjects every 6 months. Subjects were followed for a median of 15.5 months.

HPV prevalence and incidence in men in this study were similar to those previously reported for women: 52.8 percent of men were infected with HPV over the course of this study, compared to 53.8 percent of women in the authors’ previous work; and both studies found an incidence rate of 29.4 per 1000 person-months.  However, while studies have shown women are more likely to acquire HPV at a younger age, men did not show as clear an age trend in this study. Men cleared both oncogenic and nononcogenic HPV infections within six months on average, while oncogenic infections have appeared to linger longer in women.

Although not the focus of the study, the behavioral data highlight the fact that many men become sexually active at an early age, have multiple sexual partners, and do not consistently use condoms, which emphasize the potential for HPV infection in men to directly affect women's health.

While the study provides valuable information about the natural history of HPV infection in men, it has a relatively small sample size and limited duration of follow-up.   I would also note that uncircumcised men, who some studies suggest may be at increased risk for HPV infection, were underrepresented in the patient population. (Giuliano et al. J Infect Dis. 2008;198:827-35.)

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New Data on HAART Risk for Heart Disease in Adults and Children
Sabrina Kendrick, MD

Abacavir—but not didanosine—was associated with an increased risk of cardiovascular disease (CVD) in a study in the September 12 issue of AIDS. Also, a separate pediatric study found protease inhibitor therapy was a significant contributor to increased risk of CVD in HIV-infected children.

Both abacavir and didanosine have been associated with CVD in previous studies. In the AIDS study, from the Strategies for Management of Anti-Retroviral Therapy (SMART) and the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Groups, patients receiving abacavir were compared to those receiving didanosine and to those receiving other nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs).

Compared to other NRTIs in the multivariate analysis, abacavir use was associated with a more than four-fold increased risk of clinical myocardial infarction and nearly double the risk of other major CVD events including stroke, coronary artery disease, and death. In a subset of patients at study entry, the inflammation biomarkers C-reactive protein and interleukin-6 were each significantly higher for patients receiving abacavir compared to those receiving other NRTIs. The authors propose that abacavir may precipitate a CVD event through subclinical atherosclerosis manifested clinically by vascular inflammation. Didanosine was not associated with abnormal biomarker levels nor altered CVD risk.

There are several limitations, the main being the observational design and the inability to assign causal effect of potential underlying biological mechanisms. Also, the numbers associated with the CVD outcomes were small and limited the power of the analysis. It’s compelling that two observational studies come to the same result (co-authors of this study reported similar findings in Lancet 2008;371:1417-1426), but I don’t believe it is enough evidence to change patterns of abacavir use. (SMART/INSIGHT and D:A:D Study Groups, AIDS. 2008;22:F17-F24.)

The second study, a small prospective longitudinal analysis to determine risk factors for CVD in HIV-infected children, appears in the October issue of The Journal of Pediatrics. Forty-two perinatally infected children were compared with controls from National Health and Nutrition Examination Survey (NHANES) data. The significant findings suggest protease inhibitor therapy—but not nonnucleoside reverse-transcriptase inhibitor therapy—is associated with adverse lipid profiles, increasing risk for premature CVD. (Miller et al., J Pediatr 2008;153:491-7.)

Both studies underscore the increasing problem of cardiac morbidity and mortality as adult and pediatric HIV-infected populations live longer. Larger, randomized control trials are needed to elucidate the problems.

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