Patients with chronic liver disease are classified as a high-risk group for influenza-related complications [1, 2]. Influenza infection can cause hepatic decompensation and hospitalization in patients with advanced liver disease [3, 4]. Thus, preventing severe influenza that requires hospitalization has been an important issue in patients with chronic liver disease.
As influenza vaccination is the most effective method for preventing influenza and its complications, the Advisory Committee on Immunization Practices in the USA has recommended annual influenza vaccination for patients with chronic liver disease since 2007 . In Japan, however, no recommendations about influenza vaccination for these patients had been proposed prior to the 2009 influenza A (H1N1) pandemic. One of the reasons for this lack of recommendations might have been little scientific evidence regarding the clinical effectiveness of influenza vaccine among patients with chronic liver disease. To the best of our knowledge, there has been only one study on this topic until now. The Korean study indicated that seasonal influenza vaccine decreased the incidence of laboratory-confirmed influenza and associated symptoms in cirrhotic patients . However, no studies so far have demonstrated the effectiveness of influenza vaccine to prevent hospitalization in these patients.
Thus, the primary objective of this study was to examine the effectiveness of influenza A(H1N1)pdm09 vaccine in preventing hospitalization among patients with chronic liver disease. Using these data, the other characteristics associated with hospitalization were also assessed as a secondary objective.
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- Material and methods
In this study among patients with chronic hepatitis C, there was an indication of vaccine effectiveness for preventing severe outcomes requiring hospitalization during an epidemic. Although the limited number of outcome events made it difficult to detect significant vaccine effectiveness, the present results support the usefulness of influenza vaccine for patients with chronic hepatitis C.
To date, no study has reported the effectiveness of influenza A(H1N1)pdm09 vaccine against hospitalization in patients with specific underlying medical conditions including chronic liver disease. However, based on the reports about vaccine effectiveness among subjects with any high-risk condition, a cohort study in Denmark showed that vaccine conferred protection against influenza-related hospitalization to 44% (−19–73%) among subjects <65 years with underlying illnesses . A matched case–control study in the Netherlands indicated that the vaccine effectiveness for influenza-related hospitalization was 19% (−28–49%) among subjects with high-risk conditions . Although these studies did not refer to vaccine effectiveness in patients with individual underlying illnesses, the present results among patients with chronic hepatitis C would correspond to those in subjects with any high-risk conditions.
Influenza infection occasionally causes hepatic decompensation without typical influenza symptoms in patients with chronic liver disease [4, 6], which might bring about delayed antiviral therapy and increase influenza-related mortality. Thus, it was an important finding that influenza vaccine had some effect for reducing hospitalization during the epidemic period, although the present results were not significant. According to the previous studies, vaccination for cirrhotic patients lowered the incidence of laboratory-confirmed influenza and atypical influenza symptoms such as myalgia, hepatic decompensation, oliguria and uncontrolled ascites during influenza season . Furthermore, some reports have indicated that influenza vaccine was sufficiently immunogenic in patients with cirrhosis [12-15]. Taken together, it would be reasonable to advise vaccination for patients with chronic liver disease. In fact, the Advisory Committee on Immunization Practices in the USA has recommended annual influenza vaccination for patients with chronic liver disease since 2007 , and the WHO position paper has indicated that patients with specific chronic medical conditions continue to be an appropriate target group for annual influenza vaccination .
In this study, however, subjects with advanced liver disease (represented by lower albumin level) had a higher risk for hospitalization during the epidemic period, irrespective of their vaccination status (Table 3). These results corresponded to a previous case report in which influenza infection caused hepatic decompensation and hospitalization in patients with advanced liver disease . Influenza virus itself could cause hepatitis , and influenza infection could induce toxic metabolites and proinflammatory cytokines such as TNF-α, IL-1 and IL-6, which contribute to hepatic damage [18, 19]. These seemed to result in disease deterioration, especially in patients with advanced liver disease. Thus, it would be better for subjects with advanced liver disease to be followed with special attention during the season, even when vaccinated.
In addition, steroid treatment and the presence of other chronic diseases were related to hospitalization during the epidemic period, independent of vaccination status or liver function. Steroid treatment and the presence of chronic diseases have been the known high-risk factors for influenza and its complications . In the 2009 influenza pandemic, immunosuppressive therapy and chronic diseases (especially asthma) were among the highest comorbid conditions in critically ill patients with influenza A(H1N1)pdm09 infection in the USA , Canada , Australia  and Mexico . The present results agreed with these findings. Patients on immunosuppressive therapy have impaired vaccine responses , and patients with asthma are expected to have similar vaccine responses, as they often receive steroid treatment. These backgrounds of poor immunological responses might bring about the high sensitivity for influenza infection and severe outcomes owing to influenza.
When interpreting the present results, however, the following limitations should be considered. Firstly, the insufficient statistical power owing to the small sample size and the limited number of outcome events is obviously important. This limitation made it difficult to detect significant vaccine effectiveness. If more subjects could be recruited, more meaningful results would be obtained. However, studies on pandemic influenza vaccine must be conducted under strict time constraints, as pandemic influenza virus had circulated and pandemic influenza vaccines became available during the epidemic. In addition, the epidemic subsided after sufficient distribution of the vaccines. This tight time schedule represented a major obstacle to recruiting a sufficient number of vaccinated and unvaccinated subjects for any observational prospective cohort study.
Secondly, voluntary enrolment in the observational study might lead to selection bias in the vaccination status. In fact, female patients, non-smokers and non-drinkers tended to receive vaccination in this study, which might lead to a healthy vaccinee effect. However, even when additional analyses that adjusted for these variables were conducted, similar results were obtained (ORs of vaccination were 0.45 (95%CI = 0.16–1.26). On the other hand, the determination of vaccination status relied on patients’ self-reports and could not be confirmed by their medical records, as patients usually received any vaccination in their neighbouring clinic. Thus, some non-differential misclassification in the vaccination status might have occurred.
Thirdly, there might be some concern about outcome misclassification, as hospitalization is a less specific outcome for influenza. In this study, however, the methods in which outcomes were confined into the epidemic period would have helped to minimize outcome misclassification and obtain a higher specificity of influenza for hospitalization. Furthermore, hospitalization is essentially considered an objective outcome that can be verified by the medical records, and therefore misclassification owing to non-influenza illness, if any, would be non-differential between vaccinated and unvaccinated patients . Such misclassification leads to an underestimation of vaccine effectiveness and does not materially affect the validity of the results.
Finally, previous immunity in unvaccinated patients might affect the underestimation of vaccine effectiveness to some extent. Based on a serological study, about one-third of subjects aged ≥65 years was reported to have pre-existing antibody before the epidemic, as many had been exposed to antigens similar to influenza A(H1N1)pdm09 virus during childhood . In this study, however, although about two-thirds of subjects were ≥65 years old, the proportion of subjects with pre-existing antibody was expected to be lower than in previous studies, because the immunogenicity study of influenza A(H1N1)pdm09 vaccine, in which part of this study subjects participated, indicated that only about 5% of subjects had the pre-existing antibody at the beginning of the pandemic . Thus, the effect of previous immunity, if any, would be very minimal.
In conclusion, among patients with chronic hepatitis C, influenza A(H1N1)pdm09 vaccine was suggested to have some protective effect against hospitalization during the epidemic period. As patients with advanced liver disease, steroid treatment and other chronic diseases (especially asthma) are considered to be at higher risk for hospitalization during the epidemic period, they should be followed up with special attention during the season, even when vaccinated.