Copyright © 2010 Massachusetts Medical Society. During the spring of 2009, a novel influenza A (H1N1) virus of swine origin caused human infection and acute respiratory illness in Mexico.1,2 After initially spreading among persons in the United States and Canada,3,4 the virus spread globally, resulting in the first influenza pandemic since 1968 with circulation outside the usual influenza season in the Northern Hemisphere (see the Supplementary Appendix, available with the full text of this article at NEJM.org). As of March 2010, almost all countries had reported cases, and more than 17,700 deaths among laboratory-confirmed cases had been reported to the World Health Organization (WHO).5 The number of laboratory-confirmed cases significantly underestimates the pandemic’s impact. In the United States, an estimated 59 million illnesses, 265,000 hospitalizations, and 12,000 deaths had been caused by the 2009 H1N1 virus as of mid-February 2010.6 This article reviews virologic, epidemiologic, and clinical data on 2009 H1N1 virus infections and summarizes key issues for clinicians worldwide.

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Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection.

This report updates previous recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of antiviral agents for the prevention and treatment of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]).This report contains information on treatment and chemoprophylaxis of influenza virus infection and provides a summary of the effectiveness and safety of antiviral treatment medications. Highlights include recommendations for use of 1) early antiviral treatment of suspected or confirmed influenza among persons with severe influenza (e.g., those who have severe, complicated, or progressive illness or who require hospitalization); 2) early antiviral treatment of suspected or confirmed influenza among persons at higher risk for influenza complications; and 3) either oseltamivir or zanamivir for persons with influenza caused by 2009 H1N1 virus, influenza A (H3N2) virus, or influenza B virus or when the influenza virus type or influenza A virus subtype is unknown; 4) antiviral medications among children aged <1 year; 5) local influenza testing and influenza surveillance data, when available, to help guide treatment decisions; and 6) consideration of antiviral treatment for outpatients with confirmed or suspected influenza who do not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset. Additional information is available from CDC's influenza website at http://www.cdc.gov/flu, including any updates or supplements to these recommendations that might be required during the 2010-11 influenza season. Health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information. Recommendations related to the use of vaccines for the prevention of influenza during the 2010-11 influenza season have been published previously (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2010. MMWR 2010;59[No. RR-8]).

Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP).

Objective To evaluate risk factors for severe outcomes in patients with seasonal and pandemic influenza. Design Systematic review. Study selection Observational studies reporting on risk factor-outcome combinations of interest in participants with influenza. Outcomes included death, ventilator support, admission to hospital, admission to an intensive care unit, pneumonia, and composite outcomes. Data sources Medline, Embase, CINAHL, Global Health, and the Cochrane Central Register of Controlled Trials to March 2011. Risk of bias assessment Newcastle-Ottawa scale to assess the risk of bias. GRADE framework to evaluate the quality of evidence. Results 63 537 articles were identified of which 234 with a total of 610 782 participants met the inclusion criteria. The evidence supporting risk factors for severe outcomes of influenza ranged from being limited to absent. This was particularly relevant for the relative lack of data for non-2009 H1N1 pandemics and for seasonal influenza studies. Limitations in the published literature included lack of power and lack of adjustment for confounders was widespread: adjusted risk estimates were provided for only 5% of risk factor-outcome comparisons in 39 of 260 (15%) studies. The level of evidence was low for “any risk factor” (odds ratio for mortality 2.77, 95% confidence interval 1.90 to 4.05 for pandemic influenza and 2.04, 1.74 to 2.39 for seasonal influenza), obesity (2.74, 1.56 to 4.80 and 30.1, 1.74 to 2.39), cardiovascular diseases (2.92, 1.76 to 4.86 and 1.97, 1.06 to 3.67), and neuromuscular disease (2.68, 1.91 to 3.75 and 3.21, 1.84 to 5.58). The level of evidence was very low for all other risk factors. Some well accepted risk factors such as pregnancy and belonging to an ethnic minority group could not be identified as risk factors. In contrast, women who were less than four weeks post partum had a significantly increased risk of death from pandemic influenza (4.43, 1.24 to 15.81). Conclusion The level of evidence to support risk factors for influenza related complications is low and some well accepted risk factors, including pregnancy and ethnicity, could not be confirmed as risks. Rigorous and adequately powered studies are needed.

https://www.bmj.com/content/bmj/347/bmj.f5061.full.pdf

Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis

The 2009 A (H1N1) influenza virus pandemic: A review.

Effects of influenza on pregnant women and infants.

BACKGROUND While the Northern Hemisphere experiences the effects of the 2009 pandemic influenza A (H1N1) virus, data from the recent influenza season in the Southern Hemisphere can provide important information on the burden of disease in children. METHODS We conducted a retrospective case series involving children with acute infection of the lower respiratory tract or fever in whom 2009 H1N1 influenza was diagnosed on reverse-transcriptase polymerase-chain-reaction assay and who were admitted to one of six pediatric hospitals serving a catchment area of 1.2 million children. We compared rates of admission and death with those among age-matched children who had been infected with seasonal influenza strains in previous years. RESULTS Between May and July 2009, a total of 251 children were hospitalized with 2009 H1N1 influenza. Rates of hospitalization were double those for seasonal influenza in 2008. Of the children who were hospitalized, 47 (19%) were admitted to an intensive care unit, 42 (17%) required mechanical ventilation, and 13 (5%) died. The overall rate of death was 1.1 per 100,000 children, as compared with 0.1 per 100,000 children for seasonal influenza in 2007. (No pediatric deaths associated with seasonal influenza were reported in 2008.) Most deaths were caused by refractory hypoxemia in infants under 1 year of age (death rate, 7.6 per 100,000). CONCLUSIONS Pandemic 2009 H1N1 influenza was associated with pediatric death rates that were 10 times the rates for seasonal influenza in previous years.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0907673

Pediatric Hospitalizations Associated with 2009 Pandemic Influenza A (H1N1) in Argentina

Objectives: To assess incidence, burden of illness, and risk factors for human rhinoviruses (HRVs) in a cohort of very low birth weight (VLBW) infants. Methods: A 2-year prospective cohort study was conducted among VLBW premature infants in Buenos Aires, Argentina. Infants were enrolled in the NICU from June 1, 2003, to May 31, 2005, and managed monthly and with every acute respiratory illness (ARI) during the first year of life. Nasal wash samples were obtained during every respiratory episode and tested for HRV, respiratory syncytial virus (RSV), human parainfluenza viruses, influenza viruses, and human metapneumovirus using reverse transcriptase-polymerase chain reaction. Results: Of 119 patients, 66 (55%) had HRV-associated ARIs. The incidence of HRV-associated ARI was 123 events per 100 child-years of follow-up. Of those infants experiencing an episode of bronchiolitis, 40% had HRV versus 7% with RSV. The incidence of HRV-associated bronchiolitis was 75 per 100 infant-years of follow-up. HRV was associated with 12 of 36 hospitalizations (33%), and RSV was associated with 9 of 36 hospitalizations (25%). The incidence of HRV-associated hospitalization was 12 per 100 infant-years of follow-up. The risk of HRV-associated hospitalization was higher for infants with bronchopulmonary dysplasia and those who were not breastfed. Conclusions: HRV is an important and frequent pathogen associated with severe respiratory infections in VLBW infants. Bronchopulmonary dysplasia and the absence of breastfeeding are risk factors for hospitalization. The results of our study reveal that HRV is the predominant pathogen of respiratory infections in premature infants.

Human rhinoviruses in severe respiratory disease in very low birth weight infants.

BACKGROUND The immune response to dengue virus (DENV) primary infection in infants and young children is not well characterized. In Northern Argentina, >90% of the population was DENV-naive before the 2009 outbreak, allowing evaluation of age-dependent primary responses to infection. METHODS We conducted a comparative study of the immune response to DENV in 27 infected infants, young children and their mothers. Lymphocyte T helper (Th) 1, Th2, Th17 and inflammatory responses were assayed in blood during the 2009 DENV-1 epidemic. RESULTS The immune response to DENV-1 was significantly biased to Th2 in infected infants and young children, compared to infants with other febrile illnesses (for IL-4 p < 0.001) and to their infected mothers (for IL-4 p < 0.01). In addition, IL-17 suppression was observed in the memory response to DENV-1 in infected infants (p < 0.01 vs placebo). CONCLUSION Age-related differences in the primary response to DENV, characterized by an immature Th2 polarization and Th17 suppression in infants, should be studied further in order to expand our understanding of the mechanism of dengue pathogenesis.

Natalia Reynoso

Papers

Pediatric Hospitalizations Associated with 2009 Pandemic Influenza A (H1N1) in Argentina

Human rhinoviruses in severe respiratory disease in very low birth weight infants.

T helper type 2 bias and type 17 suppression in primary dengue virus infection in infants and young children.