Unchanged Severity of Influenza A(H1N1)pdm09 Infection in Children during First Postpandemic Season

Improvement is needed in preventing severe disease and nosocomial transmission in children beyond pandemic situations.

I n Germany during the infl uenza A(H1N1)pdm09 pandemic, there were ≈1,070,000 infl uenza-related medical consultations and ≈1,800 hospitalizations for children 0-14 years of age during October 12, 2009-January 15, 2010, as determined using data provided by the German syndromic surveillance system for acute respiratory infections (1). Moreover, 29 laboratory-confi rmed A(H1N1)pdm09 infection-related deaths in children were notifi ed through the mandatory German surveillance system for infectious diseases (2). The highest number of notifi ed hospitalizations and deaths were among children 10-14 years of age (3,4). In a nationwide hospital-based observational study investigating severely ill children who had been admitted to pediatric intensive care units (PICUs) or had died with laboratory-confi rmed A(H1N1)pdm09, we reported a high proportion (75%) of case-patients with underlying risk factors, of which neurodevelopmental disorders were most prevalent (5). In addition, we found that in 10% of the cases, children had acquired their infection while hospitalized and that few had been vaccinated, revealing a need for improving preventive measures to reduce severe disease and adverse outcomes (5).
On August 10, 2010, the general director of the World Health Organization declared the world was no longer in phase 6 of infl uenza pandemic alert; we were moving into the postpandemic phase (6). Experience from past pandemics suggested that the pandemic virus would gradually take on the behavior of a seasonal infl uenza virus and circulate for several years. However, in view of the potential for transformation of the virus into a more virulent form (7), as suggested by higher rates of mortality during second pandemic waves in Copenhagen (1918), the United States (1957), and Eurasia (1968)(1969)(1970) (8,9), the World Health Organization acknowledged the unpredictability of pandemic viruses; recommended continued vigilance; and issued advice on surveillance, vaccination, and prompt clinical management of cases during the postpandemic phase (6).
Little is known about the severity of A(H1N1)pdm09 in children during the fi rst postpandemic season (10). To obtain information on critically ill A(H1N1)pdm09-infected children and to compare risk factors and disease course, outcome, and severity for patients during the pandemic and fi rst postpandemic season, we prospectively and continuously performed a nationwide study in Germany during August 3, 2009-July 29, 2011.

Study Design
We conducted a nationwide prospective observational study in Germany by using the German Survey Center for Rare Pediatric Diseases (ESPED; an established children's hospitals network comprising all 375 pediatric hospitals in Germany) to identify children <15 years of age admitted to PICUs with confi rmed A(H1N1)pdm09 infection and related deaths. Cases and related deaths during August 3, 2009-July 29, 2011 were reported by using a standardized form. In pandemic season 2009-10 (August 3, 2009-August 9, 2010), the case defi nition included only A(H1N1) pdm09 infection; in postpandemic season 2010-11 (August 10, 2010-July 29, 2011), the case defi nition included all infl uenza virus infections.

Data Collection
On notifi cation by treating physicians of patients with A(H1N1)pdm09 infection, the ESPED study center distributed and subsequently collected a structured questionnaire, which had been adapted by the authors from an earlier study on seasonal infl uenza (11). Of 284 distributed questionnaires requested by 186 hospitals, 95% (271/284) were returned to the study center ( Figure 1). After excluding 3 questionnaires that had been notifi ed twice and 101 questionnaires for patients who did not meet the case definition, 62% (167/271) of the questionnaires from 83 hospitals remained. Reasons for not meeting the case defi nition included patient age >15 years and patient not admitted to PICU. In accordance with the case defi nition, only cases of A(H1N1)pdm09 infection were reported during the pandemic season (2009-10), and 9 cases of infl uenza A (not further subtyped) and 2 cases of infl uenza B infection were reported in the postpandemic season (2010-11). Therefore, further analyses were restricted to A(H1N1)pdm09 cases.
The structured questionnaire covered anonymous patient information and information regarding the hospital stay, clinical signs and symptoms, clinical and laboratory fi ndings, specifi c treatments, status of infl uenza vaccination, disease complications, and underlying chronic medical conditions (chronic respiratory diseases; cardiac diseases; immunodefi ciency; and neurodevelopmental disorders, including developmental delay, cerebral palsy, epilepsy, and other cognitive disorders). Answer categories were predetermined, but free space was designated for respondents to provide information about other diagnoses and coexisting illnesses/medical conditions. Hospital-acquired infection was defi ned by a date of symptom onset being >2 days after the date of hospital admission; 2 days corresponds with the median incubation time for A(H1N1)pdm09 according to Cao et al. (12). Data were double entered by using EpiData 3.1 software (www.epidata.dk/) in an electronic database.

Data Analysis
Reported values are those for children with available information. Descriptive statistics comprised the calculation of median and interquartile ranges (IQRs) for con-tinuous variables and absolute numbers and proportions (together with 95% binomial exact CIs, when appropriate) for categorical variables. Comparative analyses were based on the Wilcoxon rank-sum test for continuous variables and Fisher exact test for categorical variables. Odds ratios (ORs) and 95% CIs were calculated. Multivariable analysis was performed by using a logistic regression with a stepwise approach to compare cases of hospital-acquired infection with cases of community-acquired infection and survivors with nonsurvivors in PICUs. In doing so, risk factors with a p value <0.2 were considered for multivariable analysis, with the exception of age, sex, and season, which were included in all models. Reported p values are 2-sided, and p<0.05 was considered signifi cant. Statistical analyses were performed by using Stata 11.0 (StataCorp LP, College Station, TX, USA).

Data Protection and Ethics Clearance
Adherence to national data protection laws was approved by the Federal Commissioner for Data Protection and Freedom of Information of Germany. Ethical approval was granted by the Ethics Committee, Charité-Universitätsmedizin, Berlin, Germany.

Comparison of 2009-10 and 2010-11 Seasons
We identifi ed 156 critically ill children with con-  The proportion of boys among case-patients was higher in 2009-10 than 2010-11 (59% vs. 37%, p = 0.02) ( Table 1). The median age of case-patients was 5.3 and 3.2 years in 2009-10 and 2010-11, respectively, and differed statistically (p = 0.007) between the 2 seasons. The age distribution in 2010-11 compared with that in 2009-10 was characterized by a markedly higher proportion of children < 2 years of age and a lower proportion of children 10-14 years of age ( Figure 3). In both seasons, infants <1 year of age represented the age group with the highest number of cases ( Figure 4).
Of the 146 children with available information, 114 (78%) had >1 chronic underlying medical condition; the difference between seasons for these conditions was not statistically signifi cant (Table 1). In both seasons, neurodevelopmental disorders were the most prevalent underlying medical condition. Of the 156 critically ill casepatients, 130 were >6 months age and thus eligible for vaccination against A(H1N1)pdm09 virus; however, for children with available information on vaccination status, only 5 (7%) of 67 vaccine-eligible case-patients had been vaccinated in the 2009-10 season, and none had been vaccinated in the 2010-11 season. Of the 69 total children in both seasons with underlying chronic medical conditions, 64 (93%) had not been vaccinated against A(H1N1) pdm09 virus.
More cases of sepsis were reported during the postpandemic season than during the pandemic season (21% vs. 8%; p = 0.048) ( Table 1). Treatment with oseltamivir was used equally (in ≈62% of children) during both seasons. The time to oseltamivir administration after symptom onset (median 4 days) was similar throughout both seasons. The use of catecholamine and mechanical ventilation was more frequent in 2010-11 than in 2009-10, but the difference was not statistically different.

Hospital-acquired Infections
Hospital-acquired infections accounted for 11% (11 of 101) of the cases in 2009-10 and for 23% (8/35) in 2010-11 (p = 0.0931) ( Table 1). Of the total study cohort, 14% (19/136) of the patients (9 in a general ward and 10 in a PICU) most likely had hospital-acquired infection. For these case-patients, the median time from hospital admission to symptom onset was 29 days (IQR 12-73 days). The median age for patients with hospital-acquired infection was 1.1 years, and 56% (10/18) were boys (difference not statistically signifi cant between seasons).

Discussion
During the fi rst postpandemic season, fewer cases of A(H1N1) pdm09 infection were reported, but the severity and outcome of cases did not differ between the pandemic and postpandemic seasons. We further analyzed data from the 2 seasons as 2 outbreak waves of 1 virus and identifi ed a high number of hospital-acquired infections and ARDS and myocarditis as 2 predictors for a fatal outcome.
Compared with the 2009-10 pandemic season, the 2010-11 postpandemic season started later in the winter and had less than half the number of cases. High disease awareness during the pandemic season may have enhanced testing and reporting during 2009-10; thus the reduced case number for 2010-11 should be interpreted with caution. However in the United States, where reporting of infl uenza-related deaths in children is mandatory, a similar decline in the number of fatal A(H1N1)pdm09-associated cases was noted between the 2009-10 and 2010-11 infl uenza seasons (282 and 71 deaths among children, respectively) (13). Before the 2009-10 pandemic and similar to the postpandemic season, an average of 82 (range 46-153) children in the United States died each year from seasonal infl uenza-related illnesses (14). However, in the postpandemic 2010-11 season, different proportions of all circulating infl uenza subtypes might have led to different numbers of persons exposed to A(H1N1)pdm09, which makes comparisons between seasons and across countries diffi cult.   For the 2010-11 season, we assumed a more limited number of susceptible persons because exposure to infl uenza virus during the pandemic might have provided immunologic protection (15)(16)(17). This hypothesis is supported by our results showing a shift toward infection in younger age groups in 2010-11. A similar fi nding was reported in a prospective study of children with A(H1N1)pdm09 infection in a Spanish hospital (median age 7.0 and 0.8 years in 2009-10 and 2010-11, respectively) (10). During both seasons, children <1 year of age were more affected than those in other age groups, and the numbers infected in the 2 seasons were similar; therefore, infl uenza infection in this immunologically naive age group might always refl ect a pandemic-like situation. It remains unexplained why more boys in 2009-10 (59%, 65/111) than in 2010-11 (37%, 16/43) had serious A(H1N1)pdm09 infection, although it has been suggested that the difference in age distribution between the 2 seasons could have infl uenced the sex distribution (18).
Our results show that case-fatality ratios for the 2 seasons were similar. In Greece (19) and New-Zealand (20), according to the respective national surveillance systems in intensive care unit settings, case-fatality ratios among all age groups were also similar for the 2 seasons. This result is reassuring, in view of concerns of a possible transformation of the strain into a more severe form (7), and is in agreement with the antigenic and genetic homogeneity of the virus since its emergence (21).
In both seasons, we identifi ed a large number of probable hospital-acquired A(H1N1)pdm09 infections. Immunodefi ciency, most often reported as acute lymphoblastic leukemia, was associated with hospital-acquired infection, and this underlying chronic medical condition, has also been identifi ed as a risk factor for community-acquired A(H1N1)pdm09 (22,23   infection reported that 40% of the respiratory infections were acquired during the hospital stay, and infl uenza A virus was the second most prevalent respiratory infection (24). In our study, patients with hospital-acquired infection had more complications, including ARDS and sepsis, than patients with community-acquired infections. However, a signifi cant association between hospital-acquired infection and death was not found, possibly because of the small number of cases, as found by Spaeder et al. (25) in a retrospective cohort study in PICU setting. In this study, hospital acquisition of viral respiratory infection was shown to be associated with an increased risk for death, even after adjusting for chronic medical conditions that predispose to an increased risk for complications from viral illness. Our fi ndings emphasize the need for isolation of and preventive measures for children with immunodefi ciency, as reported (26). Preventive measures should include the vaccination of health care workers. Indeed, a survey in Germany showed that only 35% (n = 3,900) of the health care workers in a university hospital setting were vaccinated during the 2010-11 infl uenza season (27). Studies in earlier seasons showed even lower infl uenza vaccination rates among health care workers (28). We identifi ed 25 A(H1N1)pdm09-associated deaths among children admitted to PICUs during the pandemic and postpandemic seasons. ARDS was the most prevalent complication among case-patients who died (60% of cases) and was highly associated with death. Myocarditis was also highly associated with death in children; this fi nding supports those among adults (29,30) and other fi ndings among A(H1N1)pdm09-infected children (31).
During both seasons, 62% of the children received oseltamivir treatment. This proportion is lower than described in other studies in PICU settings, e.g., 81% in an inception-cohort study in Australia and New Zealand (32), 88% in a US cohort (31), 96% in a retrospective observational multicenter study in Turkey (33), and 100% of children in a retrospective Dutch cohort (34). Observational and random clinical trials have shown the potential of oseltamivir to reduce the length of hospitalization when started <24 hours of illness onset (35,36). The Infectious Diseases Society of America recommends that any person with confi rmed or suspected infl uenza who requires hospitalization receive infl uenza antiviral therapy, even if the patient enters care >48 hours after illness onset (37). The German Society for Pediatric Infectious Diseases recommends that immunocompetent children without underlying chronic medical conditions should not receive infl uenza antiviral therapy >48 hours after onset of infl uenza symptoms (38). Most A(H1N1)pdm09 virus isolates tested worldwide remain sensitive to oseltamivir; thus, strategies to optimize the use of oseltamivir should be considered, and additional evidence should be collected with respect to reduction of nosocomial spread of A(H1N1)pdm09 virus and to potential benefi ts from late treatment in severely ill children. We showed that 93% of the children with underlying chronic medical conditions who were eligible for vaccination had not been vaccinated. This fi nding highlights a need to improve vaccine coverage among this population, for which infl uenza vaccination is recommended in Germany (39). Children who did not survive received more intensive treatment (mechanical ventilation and catecholamine) than those who survived, and nearly all infl uenza A viruses tested continue to be antigenically similar to those found in the current trivalent vaccine (40); thus, enhanced prevention in children through vaccination, especially among those with underlying chronic medical conditions, remains a high priority.
Our study is subject to several limitations. Factors such as physicians' awareness, diagnostic testing, and reporting behavior, which may have had different infl uences in the 2 seasons, were not assessed. Only children hospitalized in pediatric hospitals were included in the study; however, it can be assumed that critically ill children hospitalized in general hospitals were transferred to pediatric hospitals covered by the ESPED network. In addition, our knowledge of the clinical features of patients was based only on information provided in the structured questionnaires. Ascertainment of underlying chronic medical conditions was not standardized and, thus, may have differed among treating physicians.

Conclusions
During the fi rst postpandemic A(H1N1)pdm09 season, the situation for children with severe A(H1N1)pdm09 disease did not differ from that for children with severe disease during the pandemic. Signs of pulmonary failure or suspected myocarditis in such children should alert health care providers to immediately initiate maximum care, and prevention of nosocomial transmission of infl uenza virus should be reinforced, especially in immunosuppressed children. The unchanged severity of infl uenza A(H1N1)pdm09 virus infections in the fi rst postpandemic season (2010-11) and the constant high proportion of possibly hospital-acquired infections stress the challenge of preventing severe cases in children beyond the pandemic situation.