Romina Libster

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

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.

Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex–mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition—a marker of complement activation mediated by immune complexes—was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.

Long-term Outcomes of Group B Streptococcal Meningitis

OBJECTIVE: Group B Streptococcus (GBS) is the leading cause of meningitis in young infants. We evaluated long-term outcomes among GBS meningitis survivors. We hypothesized that despite reduced mortality, GBS meningitis would remain a significant cause of morbidity among GBS survivors. METHODS: Ninety term and near-term infants diagnosed with GBS meningitis from 1998 through 2006 were identified from 2 children’s hospitals. Five died acutely, and 5 died at 6 months to 3 years of age. Forty-three survivors (54%; mean age 6.8, range 3–12 years) were consented for evaluation and underwent physical and neurologic examinations, hearing and vision screening, and standardized developmental assessments. Associations among presenting features, laboratory parameters, neurologic status at hospital discharge, and later developmental outcomes were explored by using descriptive statistics and logistic regression. RESULTS: Twenty-four of 43 (56%) children evaluated demonstrated age-appropriate development, 11 (25%) had mild-to-moderate impairment, and 8 (19%) had severe impairment. Admission features associated with death after hospital discharge or severe impairment included lethargy (P = .003), respiratory distress (P = .022), coma or semicoma (P = .022), seizures (P = .015), bulging fontanel (P = .034), leukopenia (P = .026), acidosis (P = .024), cerebrospinal fluid protein >300 mg/dL (P = .006), cerebrospinal fluid glucose <20 mg/dL (P = .026), and need for ventilator (P = .002) or pressor support (P < .001). Features at discharge associated with late death or severe impairment included failed hearing screen (P = .004), abnormal neurologic examination (P < .001), and abnormal end of therapy brain imaging (P = .038). CONCLUSIONS: Survivors of GBS meningitis continue to have substantial long-term morbidity, highlighting the need for ongoing developmental follow-up and prevention strategies such as maternal immunization.

A Mechanistic Role for Type III IFN-λ1 in Asthma Exacerbations Mediated by Human Rhinoviruses

RATIONALE Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear. OBJECTIVES To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing. METHODS We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma. MEASUREMENTS AND MAIN RESULTS HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66). CONCLUSIONS Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

Re-emergence of pertussis: what are the solutions?

Whooping cough, due to Bordetella pertussis and Bordetella parapertussis, is an important cause of childhood morbidity and mortality. Despite widespread pertussis immunization in childhood, there are an estimated 50 million cases and 300,000 deaths due to pertussis globally each year. Infants who are too young to be vaccinated, children who are partially vaccinated and fully-vaccinated persons with waning immunity are especially vulnerable to disease. Since pertussis is one of the vaccine-preventable diseases on the rise, additional vaccine approaches are needed. These approaches include vaccination of newborns, additional booster doses for older adolescents and adults, and immunization of pregnant women with existing vaccines. Innovative new vaccines are also being studied. Each of these options will be discussed and their potential impact on pertussis control assessed.

Human Rhinoviruses in Severe Respiratory Disease in Very Low Birth Weight Infants

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.

TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

Breastfeeding prevents severe disease in full term female infants with acute respiratory infection.

Background: Breastfeeding is a well-known protective factor against severe respiratory tract infections. Recently, a gender specific role for human milk has been described in very low birth weight infants and neonates: breast milk protected girls but not boys. Objective: To determine whether the protective effect of breastfeeding on the severity of acute respiratory infections in full term infants is different for girls and boys. Methods: A prospective cross-sectional study of infants seeking medical care for acute respiratory infection. The protective role of breastfeeding against viral pneumonia and hospitalization were assessed by univariate and multivariate analyses. Analyses were adjusted for important confounders. Results: A total of 323 patients were enrolled in this study. Breastfeeding protected girls against pneumonia and hospitalization, but did not protect boys. Nonbreastfeeding females were particularly susceptible to severe acute respiratory infections. Conclusions: Breastfeeding had a protective effect against severe disease in infant girls experiencing their first symptomatic respiratory infection. Nonbreastfeeding females are at significant risk for severe acute lung disease and should be targeted intensively by breastfeeding campaigns.

Macronutrients during Pregnancy and Life-Threatening Respiratory Syncytial Virus Infections in Children

RATIONALE Respiratory syncytial virus (RSV) is an important cause of hospitalization and death in infants worldwide. Most RSV deaths occur in developing countries, where burden and risk factors for life-threatening illness are unclear. OBJECTIVES We defined the burden of life-threatening (O(2) saturation [O(2) sat] ≤ 87%) and fatal RSV infection, and characterized risk factors for life-threatening disease in hospitalized children. Special emphasis was placed on studying the impact of dietary habits during pregnancy. We hypothesized that dietary preferences, differing from those of our remote ancestors, would negatively impact childrens pulmonary health. For instance, a diet rich in carbohydrates is a signature of recent millennia and typical of low-income populations, heavily burdened by life-threatening RSV disease. METHODS Prospective study in a catchment population of 56,560 children under 2 years of age during the RSV season in Argentina. All children with respiratory signs and O(2) sat less than 93% on admission were included. MEASUREMENTS AND MAIN RESULTS Among 1,293 children with respiratory infections, 797(61.6%) were infected with RSV: 106 of these had life-threatening disease; 1.9 per 1,000 children (95% confidence interval [CI], 1.5-2.2/1,000) under 24 months. A total of 22 hospitalized children died (9 RSV(+)), 26 died at home due to acute respiratory infection (14 attributed to RSV); all were under 12 months old. The annual attributable mortality rate for RSV was 0.7 per 1,000 infants (95% CI, 0.4-1.1/1,000). Life-threatening disease was dose-dependently associated with carbohydrate ingestion during pregnancy (adjusted odds ratio from 3.29 [95% CI, 1.15-9.44] to 7.36 [95% CI, 2.41-22.5] versus the lowest quartile). CONCLUSIONS Life-threatening and fatal RSV infections are a heavy burden on infants in the developing world. Diets rich in carbohydrates during pregnancy are associated with these severe outcomes.

Mortality due to Respiratory Syncytial Virus. Burden and Risk Factors.

Rationale: Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization and an important cause of death in infants in the developing world. The relative contribution of social, biologic, and clinical risk factors to RSV mortality in low‐income regions is unclear. Objectives: To determine the burden and risk factors for mortality due to RSV in a low‐income population of 84,840 infants. Methods: This was a prospective, population‐based, cross‐sectional, multicenter study conducted between 2011 and 2013. Hospitalizations and deaths due to severe lower respiratory tract illness (LRTI) were recorded during the RSV season. All‐cause hospital deaths and community deaths were monitored. Risk factors for respiratory failure (RF) and mortality due to RSV were assessed using a hierarchical, logistic regression model. Measurements and Main Results: A total of 2,588 (65.5%) infants with severe LRTI were infected with RSV. A total of 157 infants (148 postneonatal) experienced RF or died with RSV. RSV LRTI accounted for 57% fatal LRTI tested for the virus. A diagnosis of sepsis (odds ratio [OR], 17.03; 95% confidence interval [CI], 13.14‐21.16 for RF) (OR, 119.39; 95% CI, 50.98‐273.34 for death) and pneumothorax (OR, 17.15; 95% CI, 13.07‐21.01 for RF) (OR, 65.49; 95% CI, 28.90‐139.17 for death) were the main determinants of poor outcomes. Conclusions: RSV was the most frequent cause of mortality in low‐income postneonatal infants. RF and death due to RSV LRTI, almost exclusively associated with prematurity and cardiopulmonary diseases in industrialized countries, primarily affect term infants in a developing world environment. Poor outcomes at hospitals are frequent and associated with the cooccurrence of bacterial sepsis and clinically significant pneumothoraxes.