During the peak phase of the pandemic, active surveillance in pediatric hospitals identified 93 severe cases of pandemic (H1N1) 2009 in children with available information on prior medical history, course of disease, and outcome. When we compared absolute numbers, deaths of children caused by pandemic (H1N1) 2009 were reported 23× more frequently in our study than in a prospective study on seasonal influenza (14). In this study, which used an analogous case definition and the same hospital network, the deaths of only 2 patients were reported for 3 influenza seasons (2005–06, 2006–07, and 2007–08 seasons) in Germany. Similarly, in the United States, more deaths in children caused by pandemic (H1N1) 2009 were reported than for each of the 3 previous influenza seasons (15).

The higher number of reported deaths caused by pandemic (H1N1) 2009 might be partially explained by the high level of suspicion among physicians during the pandemic, which resulted in more frequent testing and diagnosis of influenza. This hypothesis is supported by a prospective study for seasonal influenza in the United States, in which only 43% of children admitted to a PICU with laboratory-confirmed influenza were independently given a diagnosis of influenza by the treating physician (16).

Our study indicated a PICU case-fatality rate of 12%, which is consistent with results from a study in Canada, which reported a case-fatality rate of 7% among 57 case-patients admitted to a PICU (11). However, case-fatality rates for children with pandemic (H1N1) 2009 vary considerably across study sites, as shown in 2 other studies in PICU settings. In a cohort of 147 children in Argentina, a case fatality rate of 39% was reported (9), which was similar to a case-fatality rate of 38% in a cohort of 13 patients in the United Kingdom (12). Both studies reported a higher case-fatality rate than for seasonal influenza. Differences in health care organization, including PICU admission criteria, age structure of the cohorts, and selection of study sites may partly explain the different findings.

The incidence rate for severe cases in PICU-admitted patients <15 years of age was 8.0 cases/million children, which was 5× times as high as the cumulative incidence over the 3 previous influenza seasons in the same population group reported by Liese et al. (1.7 cases/million children in the same age group) (14). This finding is consistent with studies from Australia and New Zealand, which showed the highest age-specific incidence in this age group (6).

Children <1 year of age represented 20% of our cohort, and thus a higher proportion than in the cohort investigated in the Netherlands (15%) (13). Special awareness is clearly needed for diagnosing influenza in infants because of the variable clinical manifestations in this age group. This awareness might be particularly relevant in low-resource settings that have limited virologic diagnostic capacities.

In our study, ARDS and pneumonia were the most frequent diagnoses among those who died. ARDS was the only diagnosis strongly associated with a fatal outcome (PICU case-fatality rate 32%). In Argentina, 80% of the children in a PICU had ARDS, and this condition was also associated with death (9). The frequency of other complications, which included 6 cases of encephalopathy and 2 cases of myocarditis did not differ between survivors and those who died.

Nine of 93 children in our study had acquired pandemic (H1N1) 2009 while hospitalized. The risk for nosocomial transmission of pandemic (H1N1) 2009 has also been documented in other studies (17,18). In both of these reports, pandemic (H1N1) 2009 was likely transmitted by health care workers. Additionally, children with underlying chronic medical conditions might have a higher risk for being hospitalized and therefore are particularly exposed to the risk for nosocomial infection. As reported for seasonal influenza (19,20), this result stresses the need for appropriate preventive strategies in hospital settings, such as early use of diagnostic tests and vaccination of health care workers who are involved in the care of patients with risk factors for severe disease.

We observed that patients who died had a median time in the hospital of 3 days, including 2 days in a PICU. Death occurred despite maximum intensive care therapy, as demonstrated by the higher rate of catecholamine treatment and mechanical ventilation among those who died. This observed rapid course of fatal disease despite intensive care, which was also reported in the United Kingdom (12), underlines the need for prevention.

The proportion of patients having >1 underlying chronic medical condition was high (75% overall) and increased with age. Our findings are consistent with those from a case series of 235 hospitalized children with pandemic (H1N1) 2009 in Canada (median age 4.8 years, range 0–16 years). A total of 60% of the patients in this study had >1 underlying chronic medical conditions (33% were children <2 years of age and 72% were older children) (21). Neurodevelopmental disorders were reported for more than half of the children and in more than three fourths of those who died. These results are consistent with the results from other PICU-setting studies in which neurodevelopmental disorders were the first or second most prevalent risk factor (9–12). According to the surveillance system for pediatric deaths associated with pandemic (H1N1) 2009 in the United States, 92% of the children with high-risk medical conditions had neurodevelopmental disorders (22).

In our study, only 5 children had been vaccinated against pandemic (H1N1) 2009. Their vaccination dates were not given, and it remains unclear whether the interval was sufficient to acquire immune protection. A considerable proportion of the patients with investigated cases could not benefit from immunization because the pandemic (H1N1) 2009 vaccine was not publicly available in Germany until after November 2, 2009, and 17% of all children in this study were <6 months of age. In Germany, neurodevelopmental disorders had not been explicitly included in the chronic medical conditions in the vaccination recommendations for seasonal influenza (23) and were only specified in recommendations for pandemic (H1N1) 2009 vaccine (24). In contrast, in the United States, neurodevelopmental disorders had already been recognized as a risk factor for seasonal influenza in 2005 (25).

Recent reports on adults and children with pandemic (H1N1) 2009 suggested that oseltamivir therapy benefitted patients with severe cases. Early treatment within 2 days after symptom onset was statistically associated with a lower risk for ICU admission and death in hospitalized pandemic (H1N1) 2009 patients (n = 272; median age 21 years) than with later treatment (26). In our study, the median time to oseltamivir treatment was 4 days and did not differ between survivors and those who died. Therefore, our study might not have been able to detect the benefit of this treatment. Nevertheless, this finding should be viewed with caution because our study was not designed to evaluate the effectiveness of oseltamivir for treatment of children with pandemic (H1N1) 2009. However, 1 ICU-setting study (n = 58; median age 44 years) suggested a benefit for patients who were treated with oseltamivir >48 hours after illness onset (7).

The representativeness of our study was assessed by comparing our data with those from the national databases. First, the timeline of our cases was compared with the Praxis Index, which derives from the syndromic surveillance system of the national working group on influenza and accounts for all notifications of influenza-like illness cases in Germany. The Praxis Index curve and the epidemiologic curve of patients investigated in our study show similar shapes. Second, of the 15 identified deaths in our study, 14 could be matched with the 29 deaths in children <15 years of age reported in the National Surveillance System. This difference might be explained by the fact that only children admitted to pediatric hospitals were captured in our study. Because our study was a nationwide study, the 93 cases originated from 55 hospitals in 14 of the 16 Federal States of Germany.

Our study has several limitations. These limitations include potential underreporting, although this might have been minimized by increased awareness during the influenza pandemic in Germany. In addition, patients with influenza could not be included when the questionnaires were not returned despite written reminders. Another limitation might be that not all children are hospitalized in pediatric hospitals. However, patients with severe cases requiring intensive care would likely have been transferred to a PICU and thus should have been captured in our study. This suggestion is supported by the fact that 11 patients had been transferred from other hospitals. An additional limitation might be that knowledge of clinical features of patients was only based on information provided in the questionnaires. Furthermore, ascertainment of underlying chronic medical conditions was not standardized and may differ from 1 physician to another. Because the survey instrument captured temporal information in days, the time from symptom onset to initiation of treatment could not be calculated in hours. Finally, even with an unexpected high number of reported severe cases, the total number of deaths in PICUs was too small to perform a multivariable analysis for factors associated with death.

This study identified a considerable number of severe cases of pandemic (H1N1) 2009 among children in Germany, confirming observations in the Americas. Our results stress the role of underlying risk factors, especially neurodevelopmental disorders, in children with severe cases of pandemic (H1N1) 2009. The results also indicate that measures that would prevent severe disease and adverse outcomes in children, including vaccination and other preventive measures, as well as early diagnosis and prompt treatment of this infection, are not used to their full extent despite availability of maximum care resources.