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July 2009
Vol. 19 No. 7
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Journal Club
July 2009

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

An Evolving Story: The Novel H1N1 Outbreak and Recent Triple-Reassortant Swine Influenza A (H1) Strains
Reviewed by Ed Dominguez, MD

In March, two children in Southern California developed routine respiratory tract infections. As participants in surveillance studies, the children had viral cultures taken and, by April, were found to have been infected with swine-origin influenza A (H1N1) virus—representing the first two identified cases of the current pandemic in the United States. In the June 18 issue of The New England Journal of Medicine, two articles provide a snapshot of the U.S. outbreak through early May and describe the clinical aspects of 11 domestic triple-reassortant swine influenza A (H1) viruses, which were reported to the Centers for Disease Control and Prevention (CDC) between December 2005 and February 2009, just before the pandemic began.

The triple-reassortant viruses identified were of two types: H1N1 (10 patients) and H1N2 (one patient). In these viruses, the polymerase PB1 gene was of human influenza origin, the polymerase PB2 and polymerase PA genes were of avian influenza origin, and the remaining five genes were of classic swine influenza origin. The median age of the 11 patients was 10 years (16 months to 48 years). Exposure to pigs was reported in nine patients. Ten patients developed symptoms: fever (90 percent), cough (100 percent), headache (60 percent), and diarrhea (30 percent). Four patients were hospitalized, including two who required mechanical ventilation. However, all recovered from their illness, although only four patients received the neuraminidase inhibitor, oseltamivir.

The second article describes the scope of the novel influenza A:H1N1 outbreak in the United States from April 15 through May 5, when 642 confirmed domestic cases had been reported. (For more current data about probable and confirmed cases, visit CDC’s H1N1 web page.) Although 60 percent of the patients were under the age of 19, ages ranged from 3 months to 81 years. Only 18 percent were noted to have recently travelled to Mexico. Symptoms included: fever (94 percent), cough (92 percent), sore throat (66 percent), diarrhea (25 percent), and vomiting (25 percent). Although the database was incomplete, 9 percent of those with information available were hospitalized, at least half having increased risk for severe seasonal influenza. Two deaths were identified in the cohort. Genetically, this latest novel H1N1 strain is related to, but distinct from, the triple-reassortant viruses described above. While it possesses the same human and avian genes seen before, the two genes encoding neuraminidase (NA) and M protein (M) are related to swine influenza A strains from Eurasia. Thus, this H1N1 strain indeed represents a triple-reassortant virus not previously described anywhere. The story of this virus is evolving rapidly, but these articles provide insight on what to expect in the future.

(Shinde et al. N Engl J Med 2009; 360:2616-2625 and Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. N Engl J Med 2009; 360:2605-2615.)

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Determining the Pandemic Potential of Novel H1N1 Influenza
Reviewed by Christopher J. Graber, MD, MPH

The pandemic potential of the novel H1N1 influenza strain that emerged in Mexico in April was assessed by investigators affiliated with the World Health Organization (WHO) in an article published in the June 19 issue of Science.

Investigators used the incidence of H1N1 infection among travelers returning from Mexico to estimate that approximately 23,000 patients had been infected in Mexico by late April. Based on 117 deaths in Mexico suspected to be related to H1N1 as of May 4, the case fatality ratio (CFR) was initially estimated at 0.4 percent and later adjusted to 0.091 percent by April 23, when only 21 H1N1-related deaths had been confirmed. No deaths were reported among 616 residents with presumed H1N1 infection in the small, isolated community of La Gloria in Veracruz, where the earliest cases in the outbreak were described, leading to an estimate of the upper limit of the CFR at 0.6 percent, lower than that associated with the 1918 influenza pandemic (2-3 percent).

The first case in La Gloria was reported Feb. 15; 616 suspected cases among 1,575 residents were reported by April 14. Genetic analysis of viral samples determined the time of the most recent common viral ancestor to be Jan. 12, with a doubling time of the epidemic estimated at 10 days. This data yielded reproductive number estimates (Ro: number of cases one case generates, on average, over the course of its infectious period) in the range of 1.2-1.6, higher than that associated with seasonal flu and approaching Ro estimates associated with the 1918 pandemic (1.3-2.1). Fourteen to 73 generations of human-to-human transmission were estimated to have occurred in Mexico by late April, indicating sustained human-to-human transmission.

These findings provided the rationale for WHO’s decision to raise the global pandemic influenza alert to Phase 5 and later to Phase 6, indicating a global influenza pandemic. Ongoing study of clinical severity associated with—and transmissibility of—this novel H1N1 strain will be vital in informing public health efforts to mitigate its spread.

(Fraser et al. Science 2009;324:1557-61.)

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Universal Antenatal Group B Streptococcus Screening: Successful, But There Is Room for Improvement
Reviewed by Shireesha Dhanireddy, MD

Implementation of universal antenatal screening for group B streptococcus (GBS) has led to a decline in the overall incidence of early-onset GBS disease in infants, according to a recent study in the June 18 issue of The New England Journal of Medicine.

Early-onset GBS disease, which occurs during the first seven days of life, is a major cause of infant mortality. In 2002, universal GBS screening by culture was adopted for pregnant women in the United States. This retrospective cohort study examined more than 7,000 live births in 10 states in the United States from 2003 to 2004 and compared them to births that occurred from 1998 to 1999, prior to implementation of universal screening guidelines. The authors found that screening increased dramatically from 48.1 percent to 85 percent after adoption of the guidelines. However, only 49.4 percent of women screened had documented testing during the appropriate time period, after 35 weeks gestation. Factors associated with missed screening included absence of prenatal care, drug use, preterm delivery, as well as black race and Hispanic ethnicity. Mothers who delivered preterm were also less likely to receive chemoprophylaxis for GBS when indicated.

Despite the high rates of testing in mothers of term infants, 74.4 percent of cases of early-onset GBS disease occurred in term infants. The majority (61.4 percent) of these cases occurred in infants of mothers who had received appropriate screening but tested negative for GBS. These false negative cases, which may be explained by transient colonization, were greater in number than expected.

Adoption of universal screening for GBS has led to a significant decrease in the incidence of early-onset GBS disease. But increased screening for preterm deliveries, as well as improved timing and documentation of testing, would likely lead to a further decrease in disease incidence.

(Van Dyke et al. N Engl J Med 2009;360:2626-2636.)

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The Diarylquinoline TMC207 and MDR-TB Treatment
Reviewed by Ed Dominguez, MD

As a cause of death from infection worldwide, tuberculosis ranks second only to HIV/AIDS. One-third of the world’s population is thought to be living with latent TB infection, a situation made even worse by emerging resistance to TB drugs. Resistant to both rifampin and isoniazid, multi-drug-resistant TB (MDR-TB) accounts for about 5 percent of new cases and 6 percent of TB deaths globally. Existing therapy for MDR-TB consists of prolonged treatment with multiple second-line agents, often with limited efficacy.

A South African study of the mycobacterial ATP synthase agent, TMC207, published in the June 4 issue of The New England Journal of Medicine, offers some hope. In this Phase II, randomized, placebo-controlled trial, the authors report on the safety, adverse events, and antibacterial activity of the drug. The study is admittedly small (47 patients), but the efficacy of standard therapy—in this case, kanamycin, ofloxacin, ethionamide, pyrazinamide, and cycloserine or terizodone—is so low that smaller-scale trials might be sufficient to show a relevant effect of the new agent. In this eight-week trial, participants with MDR-TB were randomly assigned to treatment with: (1) TMC207 400 mg daily for two weeks, followed by 200 mg TID for the remaining five weeks in conjunction with standard five-drug therapy; or (2) placebo in conjunction with standard five-drug therapy for eight weeks. The primary endpoint was conversion of sputum cultures from positive to negative.

Adding TMC207 to the standard regimen resulted in quicker conversion to a negative sputum culture compared to placebo (hazard ration, 11.8; 95 percent CI, 2.3 to 61.3; P=0.003). The actual rates were 48 percent in the TMC207 group compared with 9 percent in the placebo group. Rates of smear negativity were also greater at week four (77 percent vs. 57 percent) and at week eight (84 percent vs. 68 percent) for the TMC207 group. Nausea was significantly more common in the TMC207 group (26 percent vs. 4 percent, P=0.04) but did not lead to attrition from the study in either arm, suggesting it was overall mild and manageable.

Encouraging as these results are, a second stage of this Phase II study remains to be completed. This second stage will be a proof-of-efficacy phase and should further elucidate the role of TMC207 for the treatment of MDR-TB, and as importantly, the potential of ATP synthase as an important target for further drug development.

(Diacon et al. N Engl J Med 2009;360:2397-2405.)

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