A novel reassortant strain of influenza A (H1N1) virus containing swine, avian, and human elements (1) emerged in Mexico in March 2009. The virus initially spread within North America, causing severe respiratory illnesses in Mexico (2) and the United States (3,4), and then began to spread rapidly worldwide. On June 11, 2009, the World Health Organization confirmed an influenza pandemic.

In Japan, the first case of pandemic (H1N1) 2009 was confirmed on May 16, 2009. The first outbreak occurred in western Japan, where the number of cases increased then decreased quickly. The second outbreak started in early June and quickly spread to all parts of Japan. The first death associated with pandemic (H1N1) 2009 in Japan was confirmed August 15, and the first death of a child occurred September 17. As of March 31, 2010, the Ministry of Health, Labour, and Welfare (MHLW) reported on its website (www.mhlw.go.jp/kinkyu/kenkou/influenza/houdou.html) that 198 patients in Japan with pandemic (H1N1) 2009 had died, of whom 41 were children <20 years of age.

Several authors have reported that respiratory diseases associated with pandemic (H1N1) 2009, including viral pneumonia and acute lung injury, that required intensive care occurred most often in children (5–16). In Japan, hospitalizations of children because of severe pneumonia or other respiratory complications increased (17). Concerns were raised regarding deaths among children from acute encephalopathy in association with pandemic (H1N1) 2009 because acute encephalopathy has been associated with death from seasonal influenza in Japan (18,19). Neurologic complications associated with pandemic (H1N1) 2009, including acute encephalopathy, altered mental status, and status epilepticus, also have been reported from other countries (20–23).

Accurate data on the causes of death associated with pandemic (H1N1) 2009 among children are necessary for making a counterplan against future pandemic influenza. We investigated detailed clinical data collected by MHLW for children whose deaths were associated with pandemic (H1N1) 2009. We focused on the direct cause of death and clinical differences by cause of death.

After the first patient was identified in May 2009, all medical professionals were required to report deaths associated with pandemic (H1N1) 2009 to MHLW. Press releases on patient deaths were provided on MHLW’s website. As of March 31, 2010, a total of 41 patients <20 years of age were listed.

Infection with pandemic (H1N1) 2009 virus was confirmed with nasal swab specimens or aspirates from the nose, throat, or tracheal tube by using real-time reverse transcription PCR (RT-PCR) at local public health laboratories or the National Institute of Infectious Diseases in Japan, according to the institute’s recommended protocol. Samples for RT-PCR could not be obtained for 3 patients; however, rapid antigen tests were positive for influenza A for all 41 patients. Because influenza A viruses other than pandemic (H1N1) 2009 virus were rarely isolated in Japan during the study, these 3 patients were included in our analysis.

Two research groups collaborated to collect detailed data on deaths associated with pandemic (H1N1) 2009 among children. The collaborative study group comprised 3 chief members (A.O., S.N., and H.K.) and 6 assistant members (T.M., O.S., J.F., C.T., S.K., and T.I.). During February–June 2010, members of the collaborative study group contacted the attending physician of each child who died and visited the hospital to obtain detailed information. We abstracted data from medical records by using a structured report form and obtained demographic, clinical, laboratory, and radiologic data from interviews with attending physicians and chart reviews. Onset of influenza was considered the time at which a temperature >38°C was first recorded. The chief members of the study group reevaluated chest radiographs; computed tomography (CT) scan of the head, chest, and abdomen; and magnetic resonance images of the head, including those obtained at autopsy.

Cause of death (Table 1) for each patient was categorized after the 3 chief members reviewed the detailed clinical course and laboratory and radiologic data. At first, each chief member independently presumed the cause of death for each patient. When they agreed on the presumed cause of death, it was adopted as a cause of death. When the chief members disagreed, they reached a consensus on the cause of death after discussion.

Because the study was considered to be a public health activity entailing surveillance of deceased persons, approval from an ethics committee or institutional review boards at participating hospitals and informed consent were not required. Anonymous data were collected retrospectively and were kept confidential.

Statistical analyses were performed to identify differences among patients by cause of death. Because the number of patients who died of myocarditis and viral sepsis was small, these cases were excluded from statistical analyses. We also excluded 1 patient who died of presumed incidental intracranial hemorrhage. The Kruskal-Wallis test was used to compare numerical variables. When a p value <0.05 was obtained by Kruskal-Wallis test, post hoc testing was performed by using the Tukey test. We compared categorical variables by using the χ² test. When the χ² test gave a p value <0.05, adjustment residual analysis was performed. An absolute value of the adjustment residual >2 was considered significant.

We investigated the causes of death associated with pandemic (H1N1) 2009 among children in Japan. Most cases were in young, previously healthy children who died after a brief fulminant illness. Unexpected CPA and acute encephalopathy were the leading causes of death. Children who died of respiratory failure often had preexisting conditions, whereas unexpected CPA occurred among younger children without preexisting conditions.

Our finding that encephalopathy was a leading cause of death associated with pandemic (H1N1) 2009 among children in Japan differs from reports from other countries that few children have died of neurologic complications (5,24). Children with acute encephalopathy or encephalitis associated with pandemic (H1N1) 2009 have been reported outside Japan (20–23), but most survived with no or mild neurologic sequelae. Most children with acute encephalopathy, such as acute necrotizing encephalopathy (25) and acute encephalopathy with biphasic seizures and late reduced diffusion (26), were of Japanese or east Asian descent. Children in Japan are presumed to have an underlying genetic predisposition for development of acute encephalopathy (26). The median age of children who died of encephalopathy (62 months) was older than that of patients with encephalopathy associated with seasonal influenza (median 2–3 years) (19,27). This difference in age may be related to the age of infected patients; in Japan, more patients 5–9 years or 10–14 years of age were infected with pandemic (H1N1) 2009 than were those 0–4 years (28). A fulminant clinical course and marked brain edema were characteristic and common in the encephalopathy patients in our study, irrespective of age, presence or absence of preexisting conditions, and neuroradiologic findings.

Unexpected CPA was another leading cause of death associated with pandemic (H1N1) 2009 among children in Japan. Most cases of unexpected CPA occurred in previously healthy children <5 years of age. The elevated alanine transaminase and creatine kinase levels in these children could be attributable to postmortem changes. The direct cause of unexpected CPA is difficult to determine. One possible explanation is severe brain damage resulting in CPA; however, none of the patients in our study had obvious neurologic signs or symptoms until CPA, nor did they have any evidence of brain herniation. Abrupt onset of CPA suggests a cardiogenic origin such as fatal arrhythmia from undetected myocarditis (29,30). Myocarditis associated with pandemic (H1N1) 2009 has been reported (31,32). Gdynia et al. reported an unexpected death of a young adult caused by pandemic (H1N1) 2009–associated myocarditis (31). The clinical course in this patient was characterized by sudden collapse at home followed by fatal arrhythmia. Viral sepsis may also be related to unexpected CPA. Clinical signs of viral sepsis are nonspecific and may be missed. Considering that most cases of unexpected CPA occurred outside the hospital, rapid progression of viral sepsis may have occurred. Unexpected CPA has also been reported in some case series (5–7,24,33). Cardiac arrest outside the hospital was observed for 67 of 270 children who died in the United States (24). In a report from England, 16 of 70 children who died were in CPA when seen in an emergency department (7). Detailed postmortem examinations are necessary to clarify the mechanism of unexpected CPA.

Respiratory failure was an uncommon cause of death among children in Japan. In other countries, diffuse viral pneumonia or pneumonitis with severe hypoxemia were strongly associated with intensive care unit admission associated with pandemic (H1N1) 2009 (8–13). Several reports on cases of pandemic (H1N1) 2009 in children also showed that respiratory distress is most common among hospitalized children (5–7,14–16,24,34,35). In a study of children in Argentina, refractory hypoxemia caused 62% of all deaths (14). A report from England described predominantly respiratory symptoms when care was sought in 53 of 70 children who died (7). Most children who died of respiratory failure in Japan had preexisting neurologic or respiratory disorders or both; this finding is similar to reports from other countries (5–7,10,12,14–16,24,34). Children with preexisting neurologic or respiratory disorders are at increased risk for severe illness or death with influenza, and influenza vaccination should be a priority for these children.

The infrequency of preexisting conditions appears to be a feature of deaths associated with pandemic (H1N1) 2009 among children in Japan. Only one third of the participants in our study had >1 preexisting conditions. In contrast, research in Argentina showed that 9 of 13 patients who died of pandemic (H1N1) 2009 had a preexisting condition, including neurologic disorders and chronic lung disease (14). In England, preexisting severe or incapacitating systemic diseases were recognized in all deaths in children <5 years of age and in most of those 5–14 years of age (15). According to the US Centers for Disease Control and Prevention, 205 of 301 children in the United States whose deaths occurred in association with pandemic (H1N1) 2009 had high-risk medical conditions as defined by the Advisory Committee on Immunization Practices (24).

The strength of our study is use of the detailed and precise information obtained during interviews with attending clinicians. Clinical course and demographic data were accurate and detailed, and laboratory data, chest radiographs, and other radiologic data were directly assessed by the study team. Data were standardized by use of a structured report form. In addition, cause of death was determined on the basis of the consensus of the chief study members rather than by the attending clinicians. We thus consider that the data from our study are objective.

Nevertheless, our study has some limitations. First, in some cases, infection might not have been confirmed by PCR; thus, the number of deaths associated with pandemic (H1N1) 2009 among children might have been underestimated. Second, complete data on the number of all children infected with pandemic (H1N1) 2009 virus were not available. In Japan, data on the number of patients with influenza-like symptoms are collected from ≈3,000 sentinel pediatric physicians and 2,000 sentinel internal medicine physicians participating in the surveillance system. Because an accurate number of all infected children could not be obtained, the case-fatality rate could not be determined.

Several authors have suggested that neuraminidase inhibitors will be effective for preventing severe illness in patients with pandemic (H1N1) 2009 virus infection (36,37), and the usefulness of early treatment with neuraminidase inhibitors has been emphasized. However, neuraminidase inhibitors did not appear to be effective in our patients, even though the drugs had been used without delay, which indicates the difficulty of improving the outcome for children with the most severe illness. Prevention and control of influenza with vaccine use and public education is necessary for reducing illness and deaths associated with influenza not only in high-risk children but also in previously healthy ones.