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March 31, 2011
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IDSA Journal Club
March 2011

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

Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases.

Refining the Picture of Chronic HIV Infection: The Impact of Pulmonary Disease
Reviewed by Christian B. Ramers, MD, MPH

While the importance of pulmonary infections is well known to HIV providers, the burden of non-infectious pulmonary disease is less clear.  Studies suggest that HIV-infected patients have higher rates of emphysema, pulmonary hypertension and lung cancer, even after controlling for tobacco exposure.  A study in the February 2011 issue of the American Journal of Respiratory and Critical Care Medicine adds to this evidence, providing a broad view of the changing spectrum of pulmonary disease in a large HIV-infected cohort.

The authors analyzed data from 33,420 HIV-infected veterans and compared incidence rates of various pulmonary diseases with a carefully selected age, sex, race, ethnicity, and site-matched control group of 66,840 veterans.  Groups were well matched demographically, but the HIV-infected group has significantly higher rates of hepatitis C infection, alcohol and drug abuse, smoking history, and baseline lung disease.  To obtain more accurate information on tobacco exposure, a nested sample of 3,707 HIV-infected and 9,980 uninfected subjects was created, using additional survey data on self-reported tobacco use.

Overall, the incidence of COPD, lung cancer, pulmonary hypertension, and pulmonary fibrosis was higher in the HIV-infected cohort than controls throughout age groups.  When adjusted for self-reported smoking history and stratified by age, the incidence rate ratios (IRR’s) for COPD (1.25, 95 percent CI 1.08-1.43), and lung cancer (2.28, 95 percent CI 1.29-4.02), remained significant in HIV-infected persons < 50 years of age, albeit at lower ratios than pulmonary infections such as bacterial pneumonia (4.24, 95 percent CI 3.55-5.05), tuberculosis (4.96, 95 percent CI 2.96-8.29), and pneumocystis (>100).

This large cohort study highlights the growing importance of chronic, non-infectious pulmonary diseases in the management of HIV patients throughout their lifespan.  As more patients bring their HIV viremia under control, providers will be increasingly faced with managing chronic pulmonary conditions.  Given these changes, a preventive medicine perspective including tobacco cessation will become increasingly important for those caring for HIV patients.

(Crothers et al.  Am J Resp Crit Care Med. 2011 Feb 1;183(3): 388-95.)

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Extended Courses of Voriconazole, Fluoride Excess, and Periostitis in Transplant Patients
Reviewed by Christopher J. Graber, MD, MPH

Long-term voriconazole use in transplant patients may be associated with fluoride excess and periostitis, according to a report published in the March 1 issue of Clinical Infectious Diseases.

The authors initially describe a 64-year-old female heart transplant recipient who began experiencing painful bony growths on her fingers, wrists, elbows, and legs after receiving voriconazole, a fluorine-containing compound, for six months following an episode of pulmonary aspergillosis.  These findings were associated with high bone turnover markers and plasma and bone fluoride levels.  Within two months of replacing voriconazole with itraconazole, serum alkaline phosphatase and plasma fluoride levels had markedly decreased, as had her bony pain.

The authors subsequently measured alkaline phosphatase and fluoride levels in 10 other transplant patients who had received voriconazole for > 6 months (five with renal insufficiency and five without) and compared them to 10 control transplant patients who had not received voriconazole.  All patients in the voriconazole group had elevated plasma fluoride levels versus none of the controls (p < .001), and alkaline phosphatase levels were significantly higher in the voriconazole group (p=.003).  Five of the voriconazole patients had symptoms consistent with periostitis, and two had evidence of multiple exostoses.  Among the four symptomatic patients who received follow-up after voriconazole discontinuation, all had improvement in bone pain and reduction in alkaline phosphatase and fluoride levels within two months.

While the exact mechanism by which long-term voriconazole use may cause fluoride excess and periostitis is unknown, this issue clearly deserves larger study, particularly since long-term voriconazole therapy has gained acceptance at many transplant centers for varying indications.

(Wermers et al. Clin Infect Dis. 2011; 52: 604–11.)

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H1N1 Vaccine Safety in China: A Large Surveillance Study
Reviewed by Rachel Simmons, MD

Despite influenza vaccination recommendations, some patients and health care workers, citing concerns about side effects, continue to choose not to get vaccinated. The results of a large, post-marketing surveillance safety study of the H1N1 vaccine in China during the 2009 pandemic, published in the Feb. 17 issue of the New England Journal of Medicine, may aid in discussions with both groups about the safety of influenza vaccination.

During the country’s massive vaccination campaign, almost 90 million people were vaccinated over six months.  Targeted populations included those at higher risk of complications from influenza, teachers, health care workers, and children. Ten Chinese vaccine manufacturers produced split-virion H1N1 vaccine.  Twenty-nine provinces reported adverse events to the National Immunization Information System's National Adverse Events Following Immunization Surveillance System.

Administration of 89.6 million doses of H1N1 vaccine, manufactured by 10 different Chinese companies, resulted in 8,067 adverse events, for a rate of 90 events per 1 million vaccine doses (weekly cumulative event rates ranged from 90 to 265 events per 1 million doses).  Serious adverse events occurred in 711 people (7.9 events per 1 million doses). The majority of the adverse events were fever and local skin reactions; 1,050 people (11.7 events per million doses) had moderate to severe allergic reactions including urticaria and, more rarely, anaphylaxis.  Eleven cases of Guillain-Barré syndrome (GBS) developed following vaccination.  Eight cases were thought to be related to the vaccine, one case was felt to be a coincidental illness, and an additional two cases were unclassifiable. The total rate of GBS among all children during the vaccination campaign was actually lower compared to the same interval during the prior year (1.9 cases per million persons versus 2.7 cases per million). Ten deaths occurred after vaccination (0.1 deaths per 1 million doses).  Of those 10, nine had a pre-existing health condition or were found to have a heart condition or skeletal malformation on autopsy.

Although reporting of adverse events in this prospective evaluation was via a voluntary, passive reporting system which could lead to under reporting of events, H1N1 vaccination was associated with minimal risk of adverse events.

(Liang et al. N Engl J Med. 364:638-47.)

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Increase in Herpes Zoster Among the Insured: Role of Varicella Vaccine Unclear
Reviewed by Nina Kim, MD, MSc

Herpes zoster (HZ), the clinical manifestation of varicella-zoster virus (VZV) reactivation, is a common condition and a significant cause of debility if accompanied by post-herpetic neuralgia. The varicella vaccine, introduced in the U.S. in 1995, has substantially reduced the incidence of primary VZV infection, but its impact on HZ remains unclear. Some have hypothesized that immunity is naturally boosted by periodic VZV exposure and that the reduced burden of VZV cases may result in a greater number of individuals with waning immunity and a rise in HZ. An ecological study, published in the Feb. 1 issue of Clinical Infectious Diseases, casts some doubt on this hypothesis.

Investigators from the Centers for Disease Control and Prevention examined medical claims data from 1993 (prior to the licensure of varicella vaccine) to 2006 (prior to licensure of HZ vaccine) that included more than 100 private and public insurance plans in all states. All patients with a first outpatient visit with an HZ ICD-9 code were counted as incident cases with total insurance plan enrollees in the denominator. Incidence of herpes zoster rose from 1.7 to 4.4 per 1000 persons from 1993 to 2006, an overall increase of 98 percent, a pattern observed across all age groups and in both sexes. Surprisingly, the rise was steeper in the early years predating licensure of varicella vaccine and did not differ between states with high versus low vaccine coverage. The authors controlled for secular trends in health care access and behavior, as well as immunosuppression and regional differences, and still observed these age-specific increases.

This increase in HZ incidence is a striking and robust finding in this large-scale population-based study and confirms observations in smaller cohorts. The lack of evidence implicating varicella vaccine, or even age or immunosuppression, for this trend is intriguing and highlights the gaps in our understanding of HZ susceptibility.

(Leung et. al. Clin Infect Dis. 2011; 52:332-340.)

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Combination and Monotherapy for Staphylococcus aureus Foreign Body Osteomyelitis
Reviewed by Ed Dominguez, MD

Staphylococcus aureus foreign body osteomyelitis is a common conundrum faced by clinicians. Staphylococci exploit the presence of biofilm on the foreign body to counter the effects of systemic antibiotics, often requiring a combined surgical and medical therapeutic approach. Yet there are cases where retention of the foreign body is necessary, and rifampin is often used as a second antibiotic. In the March issue of Antimicrobial Agents and Chemotherapy, investigators used an experimental animal model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body osteomyelitis to study the effects of monotherapy with rifampin, and combination therapy with rifampin plus linezolid or rifampin plus vancomycin.

Using a reference strain of MRSA, investigators injected a standard inoculum into the tibias of rats, and then implanted titanium wires to act as foreign bodies. Four weeks afterwards, 61 rats were assigned to one of four study groups for treatment: no treatment; rifampin alone; rifampin plus vancomycin; and rifampin plus linezolid. Treatment was administered for 21 days. Within 12 hours of completing therapy, the animals were sacrificed, and the involved tibias were aseptically removed and processed for quantitative culture and for antibiotic resistance.

The median quantitative colony counts for all three antibiotic treatment groups were approximately 3.5 to 4 log10 colony-forming units/gram of bone less than the control group (P < 0.0001). However, there were no differences between the treatment groups. Titanium wire cultures were positive for all the control animals; treatment groups were negative in 86 percent (rifampin/linezolid) to 100 percent (rifampin/vancomycin). Rifampin resistance was 63 percent in the monotherapy group but 14 percent in the rifampin/linezolid group and 8 percent in the rifampin/vancomycin group (P ≤ 0.010).

Combination therapy with rifampin/vancomycin or rifampin/linezolid was effective in this animal model. These findings provide a good start for additional research in this area, including possible human trials.

(Vergidis et al. Antimicrob Agents and Chemother. 2011; 55(3): 1182-1186.)

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For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, in each issue of Clinical Infectious Diseases:

March 15

  • Chagas Disease by Mouth
  • Itraconazole and Rituximab Do Not Raft Well Together
  • Falciparum Malaria—from Gorillas, not Chimpanzees

March 1

  • Monkeypox Makes a Comeback: a Downside of Discontinuation of Smallpox Vaccination
  • Nice and Dengue
  • Anaplasma and Ixodes: Keeping warm with Snuggling and Antifreeze

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