4 DISCUSSION
Influenza remains a heavy clinical burden worldwide. Recent reports have suggested estimated annual hospitalization rates in various countries varying from 13 to 141 per 100,000 population 5-10. In Japan, 1.0% of influenza-positive patients aged under 75 years were hospitalized between 2012 and 2016 11. However, those reports included pediatric patients, and focused mainly on respiratory complications such as pneumonia.
The JRS conducted a surveillance of adults and adolescent patients with influenza requiring hospitalization. All causes for hospitalization related to influenza infection were enrolled. For this study, we introduced a new surveillance system that worked via the internet. By using this internet-based system, prospective real-time data can be registered and renewed rapidly from many institutions throughout Japan, and reminder mails can be sent.
In our study, most cases of influenza-related hospitalization in Japan occurred in the elderly, as has been previously in papers from various countries 7, 10, 12-14. However, the age distribution during the 2015-2016 season was significantly younger than those of other seasons. This distribution was thought to reflect the fact that the predominant influenza virus strain in the 2015-2016 season was A (H1N1) pdm. This observation confirms a previous report indicating that the median age of hospitalized cases in the 2009 A (H1N1) pdm pandemic was younger than is typically seen for seasonal influenza14. A considerable number of younger adults who were naïve for A (H1N1) pdm in the preceding seasons might have been infected for the first time during the 2015-2016 season, and some of these individuals presumably were hospitalized due to complications.
The most common cause of hospitalization was pneumonia, an observation that is consistent with the results of another Japanese study by Maruyama and colleagues 15. Primary viral pneumonia was recognized in only 7.6% of all pneumonia cases. However, 68% of those primary viral pneumonia cases were reported in the 2015-2016 season. This pattern also is thought to be attributable to the predominance of A (H1N1) in the 2015-2016 season. Diagnosis of primary viral pneumonia seems to depend on attending physicians’ decisions based on clinical findings. However, some cases were diagnosed via the PCR method using bronchoalveolar lavage fluid (BALF). Recently, a multiplex real-time PCR method has been introduced for diagnosis of CAP16, which might lead to an apparent increase in the frequency of influenza viral pneumonia. In the present study, the major pathogens in secondary bacterial pneumonia were S. pneumoniae, H. influenzae, and S. aureus consistent with previous report17. However, none of these bacterial species appeared to be an independent risk factor for mortality.
The second-most common cause of hospitalization in our study was “poor general condition”. Most of our patients were elderly people who had multiple medical conditions, and thus were fragile in the face of influenza infection. In Japan, the threshold of hospitalization generally is lower than in other countries. Therefore, in Japan, the elderly were more typically hospitalized when suffering from influenza.
Our study enrolled patients over 15 years old. Thus, there were few cases of encephalopathy with influenza. Additionally, our cases included few pregnant women, though such patients have been defined as having a high risk of complication from influenza 18. In Japan, there have not been many severe cases of pregnant women with influenza, and no fatal cases of pregnant women with influenza were reported during the pandemic of 2009 A (H1N1) 19.
Most patients (97%) received antiviral therapy from the early stage of the illness in this study. In Japan, those who are suspected to have influenza undergo rapid diagnostic antigen testing, and antiviral therapy is initiated for those with positive results or on a clinical basis as a standardized strategy 20, 21. Peramivir was the most-commonly used antiviral agent because this medication is provided as an injection drug, a format that is useful for treatment of inpatients. In Japan, baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, was introduced to the market in March, 2018. An effect of baloxavir marboxil is expected because this medication has an antiviral mechanism that is distinct from that of neuraminidase inhibitors (NAIs) 22, 23. However, there is some concern that viral strains with reduced baloxzavir susceptibility will emerge especially in younger children, seriously ill patients, or the immunocompromised 24. Few patients underwent antiviral therapy with baloxavir in the present study. It will be necessary to monitor the future trends of baloxavir use. Treatment of hospitalized patients with the combination of barloxavir and NAIs has been reported to be effective 25. This combination treatment is thought to be a possible strategy that deserves further examination in future studies.
In total, 4.8% of the hospitalized cases were fatal. This rate was lower than that reported in other countries 8, 14,26, 27. The lower value was thought to reflect the generally lower threshold for hospitalization in Japan compared to other countries. As mentioned above, early diagnosis and treatment are the essential strategies against influenza in Japan. In our study, pneumonia was overwhelmingly the leading cause of death associated with influenza as reported previously 8, 11, 12, 14, 15. Secondary bacterial pneumonia following influenza infection remains a serious problem, especially in the elderly. Our multivariate analysis proved that nursing home resident and obesity were independent risk factors for mortality. Obesity has been identified as a prognostic factor for influenza 28.29. Recently, the number of obese people has increased in Japan, which has lead in turn to several clinical problems including increased susceptibility to infection.
This study had several limitations. First, the number of participating institutions was small because this research was conducted as a pilot study. Moreover, about one third of the enrolled cases came from a single hospital (Kurashiki Central Hospital), which might lead to institutional bias. Second, the scale of the participating institutions varied from primary physician’s clinics to educational hospitals; thus, clinical levels were not uniform. Sufficient examinations could not be done in all of the cases. The detailed data obtained from a single center will be reported as a supplement to this report. Third, the influence of vaccination could not be analyzed because vaccination status was not obtained for many patients despite of a prospective nature of this study. Fourth, detailed clinical data for each case were not obtained because of the limits of the internet-surveillance system.
In conclusion, complications of influenza infection remain a heavy burden especially among the elderly. Continuous nationwide surveillance will be required to clarify the actual situation of influenza.