Effect of four neuraminidase inhibitors on influenza in Osaka, Japan: An eight‐year survey

Abstract Background After the A/H1N1 influenza pandemic in 2009, two new drugs against influenza, namely laninamivir and peramivir, were released in 2010 in Japan. We investigated prescription trends of four neuraminidase inhibitors (NAIs), which are laninamivir, peramivir, oseltamivir, and zanamivir, and assessed clinical data related to influenza for 8 years. Methods Patients living in Osaka Prefecture and diagnosed with influenza responded to a postcard questionnaire that collected data regarding their demographic characteristics, symptoms including fever, prescribed drugs, and influenza type. Results Laninamivir was most prescribed to patients aged ≥ 10 years, and oseltamivir was most prescribed to patients aged < 10 years. All four NAIs had similar effects on influenza. Patients with type A influenza experienced fever alleviation earlier than those with type B influenza. Older patients tended to have lower fever. Most seasons had similar results. Conclusions Our descriptive epidemiologic study revealed the status of patients with influenza and their medication use.

Patients diagnosed with influenza are prescribed NAIs in outpatient clinics, after which they rarely revisit the hospital or clinic.
Therefore, it is difficult for doctors to know the treatment outcomes of these patients. During the winter season, doctors are too busy to investigate detailed treatment outcomes owing to the volume of patients with viral infections, cardiovascular diseases, or respiratory diseases. Therefore, we conducted a less time-intensive self-reported survey using a postcard questionnaire. This method poses a lower burden for doctors and for patients with influenza previously treated with NAIs. [3][4][5][6] To investigate the status of patients with influenza and their medication use, we distributed postcard survey questionnaires to patients in Osaka Prefecture from the 2010-2011 winter season.
During 2010-2011 season, laninamivir appeared to alleviate fever faster, with fewer adverse events. 3 During 2011-2012 season, laninamivir was prescribed more often than during the previous season and the four NAIs had similar fever-alleviating effects. 4 Furthermore, we had reported that during the 2012-2013 and 2013-2014 seasons, fever in patients with type A influenza was alleviated earlier than those with type B influenza. 5,6 This descriptive epidemiologic study was performed to reveal three points. (a) Difference of each NAI's effects: We report prescription trends of four NAIs and time course of fever in patients after taking these inhibitors; (b) difference between influenza type; and (c) difference of fever in patients of influenza by ages. We present data of eight seasons.

| MATERIAL S AND ME THODS
This study is observational, cross-sectional study of influenza for eight years. This study was conducted in 72 hospitals or clinics in Osaka Prefecture, and some institutions were changed by the season. In the first year of this survey, we recruited institutions which are recommended by department of respiratory medicine, pediatric medicine, and otolaryngology of Osaka City University.
As of hospitals, specialists of internal medicine, pediatric medicine, and otolaryngology were in charge of this survey. Each clinic was in charge of 10-30 postcards, depending on their institutional capacity. Overall, 833-1050 postcards were prepared for distribution by clinics. Inclusion criteria were that patients were diagnosed using rapid influenza diagnostic tests, and NAIs were Cases with missing data on age, sex, influenza type, or prescribed NAIs were excluded.
We defined the duration of fever as the time from NAI administration until the patients became afebrile. Fever reduction was defined as temperatures < 37.5°C in patients aged < 10 years or < 37.0°C in those aged ≥ 10 years, as previously described. 7,8 This study was ap-

| Statistical analysis
Statistical analyses were performed with JMP (version 10; SAS Institute, Inc). Mann-Whitney test was performed to compare the proportion of NAIs between two age groups of type A influenza.
A log-rank test was used to compare about fever alleviation among NAIs or influenza type. A Fisher's exact test was used to compare the proportion of highest fever among age groups. For all statistical analysis, P values of <.05 were considered significant.

| RE SULTS
Characteristics of this survey are displayed in Table 1  2). As seen in Figure 2C, only around 20 patients were diagnosed with type B influenza during each season. Zanamivir was prescribed to approximately 20% of patients with type B influenza. This NAI was preferred for use in patients with type B influenza compared to those with type A.

| All NAIs had similar effects on influenza
The time until fever alleviation did not differ according to the NAI used except the 2016-2017 season. Figure 3A

| Patients with type A influenza achieved fever alleviation earlier than those with type B influenza
The time until fever alleviation was compared between patients with type A influenza and those with type B influenza during the  We did not show the data before 2013-2014 season because they were already published. [3][4][5][6] The number of patients with fever ≥39°C gradually decreased and that of patients with fever <38°C gradually increased with age (P < .0001). Thus, older patients with influenza may not uniformly exhibit high fever. Although this postcard survey was relatively easy to conduct and produced results with a low burden for doctors and patients, three limitations exist. The first limitation is bias of doctors and patients.

| D ISCUSS I ON
Doctors' biases involve a prescription bias and a selection bias.
Doctors deciding which NAI to prescribe could produce a prescription bias, which is influenced by prescribers' belief, drug access, or other social factors. We had previously reported that there were no significant differences in sex, age distribution, or choice of prescribed drugs between our survey and the Japan Physicians Association report, which is one of the most reliable investigations of influenza in Japan. [3][4][5][6]10 This study used the convenience selection which led to a selection bias of doctors. This survey only included patients who visited clinics and underwent rapid influenza diagnostic tests, which also led to a selection bias, too. Patients' biases involve a reporting bias and a recall bias, which lead to an information bias. This type of study may include some inaccurate data of patients. The second limitation was the postcard return rate. Our observed return rate was approximately 40%, which was not very high. Therefore, the sample may not be representative of all patients with influenza. Only patients who could measure fever twice a day might return postcards.
These results may reflect that all patients did not measure fever twice a day. The Ministry of Health, Labour and Welfare had provided the number of prescriptions of NAIs in 2012-2013 based on data furnished by pharmaceutical companies. 18 These data showed the proportions of prescribed NAIs to be 45% 14%, 39%, and 2% for oseltamivir, zanamivir, laninamivir, and peramivir, respectively. These proportions are similar to our findings: 45% oseltamivir, 12% zanamivir, 39% laninamivir, and 4% peramivir. Therefore, our survey population might be representative supporting the reliability of our data.
The third limitation is not to show a comparison between patients with NAIs and without NAIs. It is not possible to verify whether NAI is effective compared to nonuse.
It is very important for them to know the current status of the four NAIs. This study supported NAIs had mostly the same effect and better to alleviate fever in type A influenza patients than type B, or elderly patients did not have high fever in influenza infection.
In conclusion, our descriptive epidemiologic study about influenza patients for eight years revealed the status on patients of influenza and their medication use.