Duration of fever and PA/I38X-substituted virus emergence in patients treated with baloxavir in the 2018-2019 influenza season.

Duration of fever and virus persistence after baloxavir administration were investigated in 81 outpatients, 16 with A(H1N1)pdm09 and 65 with A(H3N2) in the Japanese 2018-2019 influenza season. Only eight cases of A(H3N2) viruses were detected post-dose. PA/I38T-substituted viruses were detected in four (6.2%) of 65 A(H3N2) patients, at days 3 and 4, constituting 50% (4/8) of A(H3N2) detected post-dose. The median duration of fever was 26.0 h for A(H1N1)pdm09 and 20.3 h for A(H3N2). The median duration of fever for patients with PA/I38T-substituted viruses was 22.0 h, without significant difference to that of the patients in whom the mutated virus was not detected. Emergence of PA/I38T-substituted viruses after treatment with baloxavir was confirmed, but no significant prolongation of fever was observed in the four patients with PA/I38T-substituted virus emergence.

Increased symptom severity but unchanged neuraminidase inhibitor effectiveness for A(H1N1)pdm09 in the 2010-2011 season: comparison with the previous season and with seasonal A(H3N2) and B.

BACKGROUND: No studies of the clinical symptoms before starting therapy or of the effectiveness of neuraminidase inhibitors (NAIs) have been carried out of the 2009-2010 and 2010-2011 seasons that compare A(H1N1)pdm09 or the three circulating types of influenza virus. METHODS: The clinical symptoms and duration of fever (body temperature ≥37·5°C) after the first dose of an NAI (oseltamivir, zanamivir, laninamivir) were analyzed. PCR was carried out for 365 patients with A(H1N1)pdm09 in the 2009-2010 season and for 388 patients with one of the three types of influenza circulating in the 2010-2011 season. IC50 for the three NAIs was also analyzed in 51 patients in the 2010-2011 season. RESULTS: The peak body temperature was significantly higher in 2010-2011 than in 2009-2010 for patients under 20 years with A(H1N1)pdm09, and in the 2010-2011 season for children 15 years or younger with A(H1N1)pdm09 than for those with other virus types. The percentage of A(H1N1)pdm09 patients with loss of appetite or fatigue was significantly higher in 2010-2011 than in the previous season. The duration of fever was not affected by the kind of NAI or by age in multiple regression analysis. The percentage of patients afebrile at 48 hours after the first dose of NAI was significantly higher for A(H1N1)pdm09 than for A(H3N2) (laninamivir) or B (oseltamivir and laninamivir). CONCLUSION: Although the clinical symptoms of A(H1N1)pdm09 were slightly more severe in the 2010-2011 season, the effectiveness of the NAIs remained high in comparison with 2009-2010 and with other types of seasonal influenza.

Persistence of pandemic influenza H1N1 virus in young patients after oseltamivir therapy in the 2009-2010 season: a comparison with seasonal H1N1 with or without H275Y mutation.

Comparison of the viral persistence of pandemic H1N1 (H1N1pdm) and seasonal H1N1 with or without H275Y mutation after oseltamivir therapy has not been adequately done. Virus was isolated before and on days 4-6 from the start of oseltamivir treatment for 158 cases of seasonal (2007-2008 and 2008-2009 seasons) or pandemic (2009-2010 season) H1N1 influenza. Sequence analysis was done for each season and NA inhibition assay (IC(50)) was done in the 2009-2010 season. H275Y mutation before therapy was 0% in the 2007-2008 and 2009-2010 seasons, but 100% in the 2008-2009 season. Fever and other symptoms were noticeably prolonged after oseltamivir therapy for children with H275Y mutated seasonal H1N1 (2008-2009 season), but not in patients with seasonal H1N1 without mutation (2007-2008) or H1N1pdm (2009-2010). The viral persistence rate was significantly higher for patients 15 years or younger than for those 16 years and older with H275Y mutated seasonal H1N1 (46.2% and 10.5%, respectively) or with H1N1pdm (43.3% and 11.5%, respectively). The H275Y mutation emerged after oseltamivir treatment in 2.4% (2/82) of all patients with H1N1pdm. In two children, the H275Y mutation emerged after therapy and the IC(50) increased more than 200 fold; however, the prolongation of fever was not so prominent. In conclusion, oseltamivir was effective for fever and other clinical symptoms; however, the virus persisted longer than expected after treatment in H1N1pdm influenza-infected children in the 2009-2010 season, similar to seasonal H1N1 with H275Y mutation in the 2008-2009 season.

Comparison of the clinical symptoms and the effectiveness of neuraminidase inhibitors for patients with pandemic influenza H1N1 2009 or seasonal H1N1 influenza in the 2007-2008 and 2008-2009 seasons.

The clinical symptoms and effectiveness of neuraminidase inhibitors (NAI) have not been adequately compared among pandemic H1N1 2009 patients, seasonal H1N1 patients, and patients with H1N1 with the H275Y mutation. The data of 68 seasonal H1N1 patients in 2007-2008, 193 seasonal H1N1 patients in 2008-2009, and 361 pandemic H1N1 2009 patients diagnosed by PCR who received an NAI were analyzed. The duration of fever (body temperature ≥ 37.5 ºC) after the first dose of NAI and from onset was calculated. The H275Y neuraminidase mutation status was determined for 166 patients. Significantly lower mean age (18.4 ± 13.2 years) and a higher percentage of teenagers (53.7%) were found for pandemic 2009 influenza than for seasonal influenza (P < 0.001). The peak body temperature was equivalent (mean, 39.0 ºC) in the three seasons, and the frequency of symptoms was the same or lower for pandemic influenza compared with seasonal H1N1. None of the 34 analyzed pandemic H1N1 virus isolates contained the H275Y mutation, which was commonly detected in the 2008-2009 season. The duration of fever after the start of oseltamivir therapy was significantly shorter for patients with pandemic (23.0 ± 11.6 h) than with seasonal H1N1 in both the 2008-2009 (49.7 ± 32.3 h) and 2007-2008 seasons (32.0 ± 18.9 h). The mean duration of fever after the first dose of zanamivir was not different among the three seasons (26.9-31.5 h). Clinical symptoms were the same or somewhat milder, and oseltamivir was more effective, for pandemic 2009 than for seasonal H1N1 influenza with or without H275Y mutation.

Clinical effectiveness of oseltamivir and zanamivir for treatment of influenza A virus subtype H1N1 with the H274Y mutation: a Japanese, multicenter study of the 2007-2008 and 2008-2009 influenza seasons.

BACKGROUND: Influenza A virus subtype H1N1 with the H274Y mutation emerged and spread worldwide. However, the clinical effectiveness of the neuraminidase inhibitors, oseltamivir and zanamivir, has not been adequately reevaluated. METHODS: Data from 164 patients with H1N1 virus infection and 59 patients with H3N2 virus infection during the 2008-2009 influenza season and 68 patients with H1N1 virus infection during the 2007-2008 influenza season who received a neuraminidase inhibitor were analyzed. The duration of fever (body temperature 37.5 degrees C) after the first dose of oseltamivir or zanamivir and from onset of symptoms was calculated from patient reports. The influenza virus was isolated, and its subtype was determined by hemagglutinin inhibition assay and polymerase chain reaction. The H274Y neuraminidase mutation status was determined by sequencing the neuraminidase segment. RESULTS: Of 68 patients with H1N1 virus infection during the 2007-2008 season, 41 were treated with oseltamivir, and 27 were treated with zanamivir. During the 2008-2009 season, 77 patients with H1N1 virus infection were treated with oseltamivir, and 87 were treated with zanamivir; 31 and 28 patients with H3N2 virus infection were treated with oseltamivir and zanamivir, respectively. All 49 analyzed H1N1 virus isolates obtained during the 2008-2009 season, but none of the isolates obtained during the 2007-2008 season, contained the H274Y mutation. The mean +/- standard deviation duration of fever after the start of oseltamivir therapy was significantly longer for patients with H1N1 virus infection (49.1+/-30.2 h) than it was for patients with H3N2 virus infection (33.7+/-20.1 h; P < .01) during the 2008-2009 season and patients with H1N1 virus infection during the 2007-2008 season (32.0+/-18.9 h; P < .001). The duration of fever was significantly longer after the first dose of oseltamivir than it was after the first dose of zanamivir for patients with H1N1 virus infection during the 2008-2009 season (P <.001). The duration of fever from onset of H1N1 virus infection was significantly longer for children 15 years of age during 2008-2009 (70.6+/-34.5 h) than it was for such children during 2007-2008 (48.4+/-21.2). CONCLUSION: The effectiveness of oseltamivir, but not that of zanamivir, decreased significantly for H1N1 virus infection during the 2008-2009 season.

Clinical effectiveness of oseltamivir for influenza A(H1N1) virus with H274Y neuraminidase mutation.

OBJECTIVE: To evaluate the clinical effectiveness of oseltamivir therapy started within 48h of the onset for influenza A(H1N1) virus with H274Y neuraminidase (NA) mutation. METHODS: Virus was isolated before and four to six days after starting oseltamivir treatment from 73 outpatients with influenza A(H1N1) virus in the 2007-2008 and 2008-2009 seasons. NA inhibition assays (IC(50)) and sequence analyses were done using influenza viruses isolated from these patients. Body temperature was evaluated before and on the second, third, and fourth days after starting treatment. RESULTS: H274Y mutation was not shown in the 2007-2008 season (44 patients) and shown in all 29 patients in the 2008-2009 season by NA sequence analyses. The mean IC(50) before oseltamivir treatment was significantly higher in 2008-2009 (319.3+/-185.4 nM) than in 2007-2008 (1.5+/-0.8 nM; p<.001). Patients < or =15 years with oseltamivir-resistant virus infection had a higher ratio of patients persisted virus after oseltamivir treatment than patients >15 years (50% and 11.8%, respectively, p=0.038), and a significant higher body temperature during oseltamivir treatment, compared to patients < or =15 years treated for oseltamivir-sensitive virus infection. CONCLUSION: The clinical effectiveness of oseltamivir for the A(H1N1) virus was reduced in the 2008-2009 season compared with the previous season, especially in children, probably due to the H274Y mutation. Oseltamivir seems to be not recommended for children and patients with high-risk underlying diseases infected with H274Y mutated A(H1N1) virus.

[Detection of respiratory syncytial virus with nested RT-PCR and a new rapid detection test kit in patients with influenza-like illness, including elderly adults].

Respiratory syncytial virus (RSV) infection, a common lower respiratory infection in infants, is now recognized in the USA as a significant problem in elderly adults. RSV infection has rarely been reported in adults in Japan. Nasal samples from 77 patients with influenza-like illness (ILI) and negative for influenza in a rapid antigen detection kit were also tested by polymerase chain reaction (PCR) to identify RSV. A clinical trial was also conducted using a new antigen detection test kit for RSV based on immunochromatography. RSV was detected by nested RT-PCR in samples from nasal swabs of 10 patients--3 children and 5 adults--and nasal aspiration samples in 2 children. The frequency of RSV detection by nested RT-PCR in ILI patients with a negative response for influenza virus using the rapid detection kit was 27.3% (3/11) for children aged 0 to 1 year and 33.3% (2/6) for children aged 2-3 years. The frequency was 10% (1/10) for adults aged 30-39 years, 25% (1/4) for those aged 70-79 years, and 60% (3/5) for those aged 80-89 years. By month, the frequency was 25% (2/8) for December, 27.3% (6/22) for January, and 4.4% (2/45) for February. The main clinical symptoms of the 10 patients with RSV were: peak body temperature during the clinical course of 37.2-39.7 degrees C, cough, and rhinorrhea in 9. Stridor was observed in all five children, but not in the five adults. Clinical examination showed CRP to be 0.2-3.4 (mean 1.3) mg/dL and WBC to be 3070-8000 (mean 5584) /microL for nine patients. Lymphocytopenia was observed in the four adults from whom WBC fraction data was obtained. Chest X-ray was within normal limits. RSV was detected by the new rapid antigen detection kit in 9 of the 10 patients in whom RSV was detected by PCR, but not in any of the 67 patients in whom RSV was not detected. The diagnostic accuracy of the new antigen detection kit for RSV was thus excellent at 98.7% compared to PCR. RSV was detected from nasal swab specimens of a substantial number of elderly Japanese by PCR or the antigen detection kit.

A comparison of the effectiveness of zanamivir and oseltamivir for the treatment of influenza A and B.

OBJECTIVE: To compare the effectiveness of zanamivir with oseltamivir for influenza A and B. METHODS: 1113 patients with influenza A or B were enrolled in the 2006-2007 influenza season. The duration of fever (temperature, >or=37.5 degrees C) and the percentage of patients afebrile at 24 and 48 h after the first dose of zanamivir or oseltamivir were calculated. Virus persistence after zanamivir therapy was also evaluated. RESULTS: There were marginally significant differences between the duration of fever after the first dose of zanamivir (31.8+/-18.4h) and oseltamivir (35.5+/-23.9h) for influenza A (p<0.05). The duration of fever after starting zanamivir therapy (35.8+/-22.4h) was significantly shorter than that of oseltamivir (52.7+/-31.3h) for influenza B (p<0.001). There were no significant differences between influenza A and B in the percentage of patients afebrile at 24 or 48 h after the first inhalation of zanamivir. The reisolation rate after zanamivir therapy showed marginally significant differences between influenza A and B (<0.05). By multiple regression analysis, therapy (zanamivir or oseltamivir) was the major determinant affecting the duration of fever for influenza B. CONCLUSION: Zanamivir therapy is more effective than oseltamivir for the treatment of influenza B infection.

Longer virus shedding in influenza B than in influenza A among outpatients treated with oseltamivir.

OBJECTIVE: To compare the persistence, susceptibility and resistance of influenza A and influenza B viruses in oseltamivir therapy in outpatients of various ages. METHODS: Virus isolation was done before and 4-6 days after the initiation of oseltamivir therapy for 148 patients with influenza A/H3N2 and for 66 with influenza B in the 2003-2004 and 2004-2005 influenza seasons. Neuraminidase inhibition assay and neuraminidase or hemagglutinin sequence analysis were done using influenza viruses isolated from these patients. RESULTS: The virus isolation rate after oseltamivir therapy was significantly higher for influenza B (33.3%) than for influenza A/H3N2 (12.8%, p<0.001). The mean IC(50) values before and after oseltamivir therapy were significantly higher in patients with influenza B (10.82 and 11.32nM, respectively) than in patients with influenza A/H3N2 (0.94 and 0.81nM, respectively, both p<0.001). No significant differences in IC(50) among each age group, or no significant increase in IC(50) from before to after oseltamivir therapy was observed. Neuraminidase or hemagglutinin sequence analysis revealed no known genotype with resistance to oseltamivir. CONCLUSION: Virus persistence after oseltamivir therapy was longer and IC(50) values were higher in influenza B than influenza A.

A comparison of the effectiveness of oseltamivir for the treatment of influenza A and influenza B: a Japanese multicenter study of the 2003-2004 and 2004-2005 influenza seasons.

BACKGROUND: To compare the effectiveness of oseltamivir for treatment of influenza A and influenza B, we conducted a prospective, multicenter study of the 2003-2004 and 2004-2005 influenza seasons. The study included 3351 patients in whom influenza had been diagnosed by use of an antigen detection test kit. METHODS: Oseltamivir was administered to 1818 patients with influenza A and 1485 patients with influenza B. No anti-influenza drugs were administered to 21 patients with influenza A or to 27 patients with influenza B. Patients receiving oseltamivir therapy were divided into 4 groups according to the time between the onset of fever (temperature, > or = 37.5 degrees C) and administration of the first dose of oseltamivir (0-12 h, 13-24 h, 25-36 h, and 37-48 h). The patients were also divided into 4 subgroups on the basis of age (0-6 years, 7-15 years, 16-64 years, and >64 years). Virus isolation was performed after completion of oseltamivir therapy for 44 patients with influenza A and 31 patients with influenza B. RESULTS: The duration of fever was significantly shorter for patients with influenza A and B who were treated with oseltamivir than for patients who were not treated with an anti-influenza drug (P<.001 for both). The time until the patient became afebrile after the initial administration of oseltamivir and the duration of fever were significantly longer for patients with influenza B than for patients with influenza A for the 0-12 h, 13-24 h, 25-36 h, and 37-48 h groups (P<.001) and for all age groups (P<.001). After 4-6 days of oseltamivir therapy, the influenza B virus reisolation rate (51.6%) was significantly higher than the influenza A virus reisolation rate (15.9%) (P<.001). CONCLUSION: Oseltamivir is less effective for influenza B than for influenza A with regard to duration of fever and virus persistence, irrespective of patient age or the timing of administration of the first dose.

Factors influencing the effectiveness of oseltamivir and amantadine for the treatment of influenza: a multicenter study from Japan of the 2002-2003 influenza season.

BACKGROUND: To evaluate the effectiveness of oseltamivir and amantadine for the treatment of influenza with respect to various clinical factors, a prospective multicenter study of the influenza season of 2002-2003 was done with 2163 patients whose condition was diagnosed by an antigen-detection test kit. METHODS: Oseltamivir was administered to 803 patients with influenza A (A+Os group) and 684 patients with influenza B (B+Os group). Amantadine was administered to 676 patients with influenza A (A+Am group). RESULTS: For each group, the duration of fever (i.e., body temperature, > or = 37.5 degrees C) was significantly shorter in patients who received the drug within 12 h after the onset of symptoms than in patients who received the drug > 12 h after the onset. For all 3 groups, the duration of fever was shorter in patients with a highest temperature < 39 degrees C than in patients with temperatures > or = 39 degrees C. The duration of fever was significantly longer for the B+Os group than for the A+Os group. Multiple regression analysis found that the type of influenza, the highest body temperature, and the time between the onset of symptoms and the start of treatment are independent factor that influence the duration of fever. CONCLUSIONS: Early administration increases the benefit of anti-influenza drugs--not only the benefit of oseltamivir treatment for influenza A, but also the benefit of amantadine treatment for influenza A and oseltamivir treatment for influenza B. Oseltamivir may be less effective as a treatment for influenza B than for influenza A. A highest body temperature of > or = 39 degrees C was an indicator of a longer duration of fever.

[Clinical symptoms of influenza infection in the 2002-2003 season].

The highest body temperature and clinical symptoms during the influenza infection were analyzed on 2,145 patients with influenza, (type A: 1,408cases, type B: 737cases: confirmed by a rapid diagnosis kit, Capilia FluA, B), and for 670 patients with a negative response to the rapid diagnosis kit (controls). The study was a multi-center study of the 2002-2003 influenza season. The percentages of patients with fever over 38 degrees C, 38.5 degrees C and 39 degrees C were significantly higher in influenza A than in influenza B or controls (16-64 yrs). Over 80% of the patients in all age groups of 0-6 yrs, 7-15 yrs, 16-64 yrs or over 64 yrs with influenza A or B had a cough. The percentage of patients with cough was significantly higher for patients with influenza A or B than for controls under 65 yrs. The percentages of influenza A or B patients with rhinorrhea or loss of appetite were significantly higher than in controls under 65 yrs. The percentage of patients reporting fatigue, headache or myalgia was significantly higher for influenza A than for controls of 16-64 yrs. Differences in symptoms, including fever, were minimal between influenza A and B patients under 16 yrs, and also among influenza A, B and controls in patients over 64 yrs. The percentage of patients with cough was not different among the three age groups by influenza A or B. However, the percentage of patients with rhinorrhea, loss of appetite, vomiting or diarrhea was higher in children under 16 yrs than in adults aged 16-64 yrs in influenza A or B. In conclusion, consideration must be given to the patient's age and the type of influenza when doing a symptomatic diagnosis of influenza. In addition, the use of a rapid diagnosis kit seems necessary for the diagnosis of influenza in elderly patients, who may have no specific symptoms of influenza.

[An analysis of the 2002-2003 influenza epidemic focusing on patients infected with types A and B in the same season sequentially].

A total of 2,320 cases of influenza A (1,517 cases) and B (803 cases) in the 2002-2003 influenza season were analyzed. Influenza infection was confirmed by a rapid diagnosis kit, based on the immunochromatography method, at 24 clinics in 18 of the 47 prefectures of Japan. Influenza A/H3N2 was reported between November 22 and April 12 (the median at January 21), and influenza B was reported between December 24 and April 20 (the median at February 16). The mean age of type B patients (16.7 years old) was significantly younger than that of type A patients (26.7 years old) (p < 0.001). Pneumonia was more frequently a complication of type A (0.63%) than of type B (0%, p < 0.05). Although 5 type A patients needed hospitalization, neither hospitalization nor death was associated with type B. Of the 2,293 cases, 27 (1.2%) were infected with both influenza of A and B. The age of these 27 patients ranged from 2 to 51 years (mean of 11.2 years), but 20 of the 27 patients were 9 years of age or under. Type B followed type A in 25 patients. The median date of these 25 type A patients was January 22, similar to that of all cases of type A, January 21. However, the median date of type B infection was March 3, 15 days later than that of all patients with type B, February 16. The mean age of the 27 cases was significantly younger than that of all cases of type A (p < 0.001) and type B (p < 0.05). In epidemics consisting of multiple types of influenza viruses, patients may be infected by more than one virus. This is especially true for children.