Ridgway JP, Bartlett AH, Garcia-Houchins S, Cariño S, Enriquez A, Marrs R, Perez C, Shah M, Guenette C, Mosakowski S, Beavis KG, Landon E.
Influenza among afebrile and vaccinated healthcare workers.
Clin Infect Dis. 2015 Jun 1;60(11):1591-5. doi: 10.1093/cid/civ163. Epub 2015 Mar 2.
Abstract/Text
BACKGROUND: To prevent transmission of influenza from healthcare workers (HCWs) to patients, many hospitals exclude febrile HCWs from working, but allow afebrile HCWs with respiratory symptoms to have contact with patients. During the 2013-2014 influenza season at our hospital, an influenza-positive HCW with respiratory symptoms but no fever was linked to a case of possible healthcare-associated influenza in a patient. Therefore, we implemented a temporary policy of mandatory influenza testing for HCWs with respiratory symptoms.
METHODS: From 3 January through 28 February 2014, we tested HCWs with respiratory symptoms for influenza and other respiratory pathogens by polymerase chain reaction of flocked nasopharyngeal swabs. HCWs also reported symptoms and influenza vaccination status, and underwent temperature measurement. We calculated the proportion of influenza-positive HCWs with fever and prior influenza vaccination.
RESULTS: Of 449 HCWs, 243 (54%) had a positive test for any respiratory pathogen; 34 (7.6%) HCWs tested positive for influenza. An additional 7 HCWs were diagnosed with influenza by outside physicians. Twenty-one (51.2%) employees with influenza had fever. Among influenza-infected HCWs, 20 had previously received influenza vaccination, 18 had declined the vaccine, and 3 had unknown vaccination status. There was no significant difference in febrile disease among influenza-infected employees who had received the influenza vaccine and those who had not received the vaccine (45% vs 61%; P = .32).
CONCLUSIONS: Nearly half of HCWs with influenza were afebrile prior to their diagnosis. HCWs with respiratory symptoms but no fever may pose a risk of influenza transmission to patients and coworkers.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Miyamoto A, Watanabe S.
Influenza follicles and their buds as early diagnostic markers of influenza: typical images.
Postgrad Med J. 2016 Sep;92(1091):560-1. doi: 10.1136/postgradmedj-2016-134271. Epub 2016 Jul 27.
Abstract/Text
Lee CS, Lee JH, Kim CH.
Time-dependent sensitivity of a rapid antigen test in patients with 2009 H1N1 influenza.
J Clin Microbiol. 2011 Apr;49(4):1702. doi: 10.1128/JCM.02247-10. Epub 2011 Jan 19.
Abstract/Text
Seki Y, Oda Y, Sugaya N.
Very high sensitivity of a rapid influenza diagnostic test in adults and elderly individuals within 48 hours of the onset of illness.
PLoS One. 2020;15(5):e0231217. doi: 10.1371/journal.pone.0231217. Epub 2020 May 6.
Abstract/Text
During influenza epidemics, Japanese clinicians routinely perform rapid influenza diagnostic tests (RIDTs) in the examination of patients who have an influenza-like illness, and patients with positive test results, including otherwise healthy individuals, are treated with anti-influenza drugs. However, it was recently reported that the sensitivity of RIDTs was extremely low in adult patients. We examined the sensitivity and specificity of an RIDT that is widely used in Japan, ImunoAce Flu (TAUNS, Shizuoka, Japan), in comparison to reverse transcriptase polymerase chain reaction (RT-PCR). The sensitivity and specificity of the ImunoAce Flu test were 97.1% (95%CI: 93.8-98.9) and 89.2% (95%CI: 84.1-93.1), respectively. The ImunoAce Flu test is designed to not only detect influenza A or B, but also to detect H1N1pdm09 with the use of an additional test kit (Linjudge FluA/pdm). Its sensitivity and specificity for A/H1N1pdm09 were 97.6% (95%CI: 87.4-99.9) and 92.6% (95%CI: 82.1-97.9), respectively. Thus, by consecutively testing patients with the ImunoAce Flu test followed by the Linjudge FluA/pdm test, we are able to diagnose whether a patient has A/H1N1pdm09 or A/H3N2 infection within a short time. The reliability of rapid test results seems to be much higher in Japan than in other countries, because approximately 90% of influenza patients are tested and treated within 48 hours after the onset of illness, when the influenza viral load in the upper respiratory tract is high. From the Japanese experience, RIDTs are sufficiently sensitive and highly useful, if patients are tested within 48 hours after the onset of illness.
Hou N, Wang K, Zhang H, Bai M, Chen H, Song W, Jia F, Zhang Y, Han S, Xie B.
Comparison of detection rate of 16 sampling methods for respiratory viruses: a Bayesian network meta-analysis of clinical data and systematic review.
BMJ Glob Health. 2020 Nov;5(11). doi: 10.1136/bmjgh-2020-003053.
Abstract/Text
BACKGROUND: Respiratory viruses (RVs) is a common cause of illness in people of all ages, at present, different types of sampling methods are available for respiratory viral diagnosis. However, the diversity of available sampling methods and the limited direct comparisons in randomised controlled trials (RCTs) make decision-making difficult. We did a network meta-analysis, which accounted for both direct and indirect comparisons, to determine the detection rate of different sampling methods for RVs.
METHODS: Relevant articles were retrieved comprehensively by searching the online databases of PubMed, Embase and Cochrane published before 25 March 2020. With the help of R V.3.6.3 software and 'GeMTC V.0.8.2' package, network meta-analysis was performed within a Bayesian framework. Node-splitting method and I2 test combined leverage graphs and Gelman-Rubin-Brooks plots were conducted to evaluate the model's accuracy. The rank probabilities in direct and cumulative rank plots were also incorporated to rank the corresponding sampling methods for overall and specific virus.
RESULTS: 16 sampling methods with 54 438 samples from 57 literatures were ultimately involved in this study. The model indicated good consistency and convergence but high heterogeneity, hence, random-effect analysis was applied. The top three sampling methods for RVs were nasopharyngeal wash (NPW), mid-turbinate swab (MTS) and nasopharyngeal swab (NPS). Despite certain differences, the results of virus-specific subanalysis were basically consistent with RVs: MTS, NPW and NPS for influenza; MTS, NPS and NPW for influenza-a and b; saliva, NPW and NPS for rhinovirus and parainfluenza; NPW, MTS and nasopharyngeal aspirate for respiratory syncytial virus; saliva, NPW and MTS for adenovirus and sputum; MTS and NPS for coronavirus.
CONCLUSION: This network meta-analysis provides supporting evidences that NPW, MTS and NPS have higher diagnostic value regarding RVs infection, moreover, particular preferred methods should be considered in terms of specific virus pandemic. Of course, subsequent RCTs with larger samples are required to validate our findings.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Marty FM, Chen K, Verrill KA.
How to Obtain a Nasopharyngeal Swab Specimen.
N Engl J Med. 2020 May 28;382(22):e76. doi: 10.1056/NEJMvcm2010260. Epub 2020 Apr 17.
Abstract/Text
Grijalva CG, Poehling KA, Edwards KM, Weinberg GA, Staat MA, Iwane MK, Schaffner W, Griffin MR.
Accuracy and interpretation of rapid influenza tests in children.
Pediatrics. 2007 Jan;119(1):e6-11. doi: 10.1542/peds.2006-1694.
Abstract/Text
BACKGROUND: Influenza rapid antigen detection (rapid tests) can provide timely identification of infection and aid in clinical decision-making. Although the interpretation of test results depends on test characteristics and influenza prevalence, this information is limited in routine clinical practice.
OBJECTIVE: We sought to assess the times at which rapid tests are most predictive of influenza infection.
METHODS: The New Vaccine Surveillance Network enrolled children aged < 5 years who were hospitalized with respiratory symptoms or fever from October 2000 through September 2004. Nasal and throat swabs were obtained, and influenza virus was detected by culture and reverse-transcription polymerase chain reaction. Provider-ordered rapid influenza tests were compared with the criterion standard (culture and reverse-transcription polymerase chain reaction) to determine their sensitivity and specificity. The New Vaccine Surveillance Network also enrolled children in outpatient settings during the 2002-2003 and 2003-2004 influenza seasons and determined the weekly influenza prevalence among symptomatic children. Trends in weekly predictive values of the rapid tests were estimated over the influenza seasons.
RESULTS: Rapid influenza tests had an overall sensitivity of 63% and specificity of 97%. In 2002-2003, the prevalence of influenza in symptomatic outpatient children peaked at 21% and stayed above 10% for approximately 4 weeks. In contrast, in 2003-2004, influenza prevalence peaked at 60% and remained above 20% for approximately 6 weeks. The positive predictive value of the rapid tests approached 80% when influenza prevalence was > or = 15% but decreased to < 70% when influenza prevalence was < 10%.
CONCLUSIONS: Influenza prevalence varies between and within seasons. On the basis of our estimates, rapid tests are of limited use when prevalence is < 10%. The appropriate interpretation of rapid influenza tests requires local influenza surveillance and timely communication of this information to the practitioners.
Ghebremedhin B, Engelmann I, König W, König B.
Comparison of the performance of the rapid antigen detection actim Influenza A&B test and RT-PCR in different respiratory specimens.
J Med Microbiol. 2009 Mar;58(Pt 3):365-370. doi: 10.1099/jmm.0.004358-0.
Abstract/Text
Nowadays, influenza antigen detection test kits are used most frequently to detect influenza A or B virus to establish the diagnosis of influenza rapidly and initiate appropriate therapy. This study was conducted to evaluate the performance of the actim Influenza A&B test (Medix Biochemica). Overall, 473 respiratory specimens were analysed in the actim Influenza A&B test and the results were compared with those from an RT-PCR assay; 461 of these samples originated from paediatric patients aged 7 weeks to 6.5 years either with influenza-related symptoms or from the intensive care unit, and 12 samples originated from adults with underlying lung or haematological diseases. Diagnosis of influenza A or B virus could be established using the actim Influenza A&B test (9/473 samples for influenza A virus and 6/473 for influenza B virus). RT-PCR revealed 23 patients with influenza virus (13/473 for influenza A virus and 10/473 for influenza B virus). The sensitivity and specificity of the actim Influenza A&B test were 65 and 100 % compared with the RT-PCR assay. However, 32 external quality assessment samples containing seven different strains of influenza A subtypes H1N1 and H3N2 and the avian H5N1 were detected correctly by the actim Influenza A&B test. No cross-reactivity to a range of bacterial, fungal and other viral pathogens was observed. In conclusion, the actim Influenza A&B test is reliable for positive results due to its high specificity. Nevertheless, negative results from this test need to be confirmed by a more sensitive assay because of the low sensitivity observed with diagnostic samples.
Rouleau I, Charest H, Douville-Fradet M, Skowronski DM, De Serres G.
Field performance of a rapid diagnostic test for influenza in an ambulatory setting.
J Clin Microbiol. 2009 Sep;47(9):2699-703. doi: 10.1128/JCM.00762-09. Epub 2009 Jul 8.
Abstract/Text
Provided test characteristics are adequate, point-of-care rapid antigen detection tests for influenza could improve the timeliness and appropriateness of clinical decisions. Our objective was to estimate the field sensitivity and specificity of the Quidel QuickVue Influenza A+B test in an ambulatory setting. The sensitivity and specificity of the Quidel QuickVue test was evaluated against reverse-transcriptase PCR (RT-PCR) on nasopharyngeal specimens collected over two consecutive influenza seasons from ambulatory patients consulting for influenza-like illness (ILI) within 7 days of ILI onset. A total of 491 patients with ILI (180 in 2006 to 2007 and 311 in 2007 to 2008) provided specimens that were tested both by PCR and by the Quidel QuickVue test. Among the 267 patients positive by PCR (55%), 52 were also positive by the QuickVue test, for an overall sensitivity of 19.5% (95% confidence interval [95% CI], 14.7% to 24.2%). Among the 221 PCR-negative patients, 2 were positive for influenza B virus by the rapid test (<1%), for an overall specificity of 99.1% (95% CI, 97.9 to 100%). The field sensitivity of the test varied little with the age or gender of the patient, immunization status, delay since the onset of symptoms, or influenza season. The sensitivity of the test was slightly but nonsignificantly higher for influenza B virus (23%) than for influenza A virus (18%). Despite its high specificity, the low sensitivity of the Quidel QuickVue Influenza A+B test is too poor to direct clinical decisions for ambulatory patients with ILI. Negative results cannot rule out the diagnosis of influenza, and in that context, this test is of questionable utility for routine application in the clinical setting.
Louie JK, Guevara H, Boston E, Dahlke M, Nevarez M, Kong T, Schechter R, Glaser CA, Schnurr DP.
Rapid influenza antigen test for diagnosis of pandemic (H1N1) 2009.
Emerg Infect Dis. 2010 May;16(5):824-6. doi: 10.3201/eid1605.091797.
Abstract/Text
We compared the QuickVue Influenza test with PCR for diagnosing pandemic (H1N1) 2009 in 404 persons with influenza-like illness. Overall sensitivity, specificity, and positive and negative predictive values were 66%, 84%, 84%, and 64%, respectively. Rapid test results should be interpreted cautiously when pandemic (H1N1) 2009 virus is suspected.
Hawkes M, Richardson SE, Ipp M, Schuh S, Adachi D, Tran D.
Sensitivity of rapid influenza diagnostic testing for swine-origin 2009 a (H1N1) influenza virus in children.
Pediatrics. 2010 Mar;125(3):e639-44. doi: 10.1542/peds.2009-2669. Epub 2010 Feb 15.
Abstract/Text
BACKGROUND: The rapidly evolving pandemic of novel 2009 swine-origin influenza A (H1N1) virus (S-OIV) demands that accurate and practical diagnostics be urgently evaluated for their potential clinical utility.
OBJECTIVE: To determine the diagnostic accuracy of a rapid influenza diagnostic test (RIDT) and direct fluorescent antibody (DFA) assay for S-OIV by using reverse-transcription polymerase chain reaction (RT-PCR) as the reference standard.
METHODS: We prospectively recruited children (aged 0-17 years) assessed in the emergency department of a pediatric referral hospital and a community pediatric clinic for influenza-like illness between May 22 and July 25, 2009. RIDT (performed on-site) and DFA were compared with RT-PCR to determine their sensitivity and specificity for S-OIV. We also compared the sensitivity of RIDT for S-OIV to that for seasonal influenza over 2 preceding seasons.
RESULTS: Of 820 children enrolled, 651 were from the emergency department and 169 were from the clinic. RIDT sensitivity was 62% (95% confidence interval [CI]: 52%-70%) for S-OIV, with a specificity of 99% (95% CI: 92%-100%). DFA sensitivity was 83% (95% CI: 75%-89%) and was superior to that of RIDT (P < .001). RIDT sensitivity for S-OIV was comparable to that for seasonal influenza when using DFA supplemented with culture as the reference standard. RIDT sensitivity for influenza viruses was significantly higher in children 5 years of age or younger (P = .003) and in patients presenting < or =2 days after symptom onset (P < .001).
CONCLUSIONS: The sensitivity of RIDT for detection of S-OIV is higher than recently reported in mixed adult-pediatric populations but remains suboptimal.
Choi YJ, Kim HJ, Park JS, Oh MH, Nam HS, Kim YB, Cho BK, Ji MJ, Oh JS.
Evaluation of new rapid antigen test for detection of pandemic influenza A/H1N1 2009 virus.
J Clin Microbiol. 2010 Jun;48(6):2260-2. doi: 10.1128/JCM.02392-09. Epub 2010 Mar 31.
Abstract/Text
We evaluated the SD Bioline Influenza Ag A/B/A(H1N1) Pandemic test kit and compared it with real-time reverse transcriptase PCR (RT-PCR) for its ability to detect H1N1 2009. The sensitivity and specificity of the test kit for H1N1 2009 were 77% and 100%, respectively.
Shim SS, Kim Y, Ryu YJ.
Novel influenza A (H1N1) infection: chest CT findings from 21 cases in Seoul, Korea.
Clin Radiol. 2011 Feb;66(2):118-24. doi: 10.1016/j.crad.2010.07.011. Epub 2010 Nov 27.
Abstract/Text
AIM: To retrospectively evaluate the computed tomography (CT) appearances of novel influenza A (H1N1) infection.
MATERIALS AND METHODS: Chest CT images obtained at clinical presentation in 21 patients (eight men, 13 women; mean age, 37 years; age range, 6-82 years) with confirmed novel influenza A (H1N1) infection were assessed. The radiological appearances of pulmonary parenchymal abnormalities, distribution, and extent of involvement on initial chest CT images were documented. The study group was divided on the basis of age [group 1, patients <18 years old (n=8); group 2, patients ≥ 18 years old (n=13)]. Medical records were reviewed for underlying medical conditions and laboratory findings. The occurrence of recognizable CT patterns was compared for each group using the images from the initial CT examination.
RESULTS: The most common CT pattern observed in all patients was ground-glass attenuated (GGA) lesions (20/21, 95%). Bronchial wall thickening (9/21, 43%) was the second most common CT finding. Other common CT findings were consolidation (6/21, 29%), pleural effusion (6/21, 29%), pneumothorax or pneumomediastinum (5/21, 24%), and atelectasis (5/21, 24%). Among these, atelectasis and pneumomediastinum (pneumothorax) were only observed in group 1. The GGA lesions showed predilections for diffuse multifocal (10/20, 50%) or lower zone (8/20, 40%) distribution. Involvement of central lung parenchyma (12/20, 60%) was more common than a mixed peripheral and central pattern (6/20, 30%) or a subpleural pattern (2/20, 10%) at the time of presentation. Patchy GGA lesions were more frequent (18/20, 90%) than diffuse GGA lesions, and 75% (15/20) of these lesions had a bronchovascular distribution. Bilateral disease was present in all patients with GGA lesions. Bronchial wall thickening was predominantly centrally located and the distribution of the consolidation was non-specific.
CONCLUSION: The predominantly centrally located GGA lesions, with common multifocal or bilateral involvement, peribronchovascular distribution, and patchy appearance are the more distinctive CT findings of novel influenza A (H1N1) infection. Pneumomediastinum and atelectasis resulting from this disease are more common in young patients under the age of 18 years.
Copyright © 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Guo WL, Wang J, Zhou M, Sheng M, Eltahir YM, Wei J, Ding YF, Zhang XL.
Chest imaging findings in children with influenza A H1N1.
Saudi Med J. 2011 Jan;32(1):50-4.
Abstract/Text
OBJECTIVE: To assess imaging findings at presentation in children diagnosed with influenza A (H1N1) infection.
METHODS: This is a retrospective observational cohort study conducted at The Children's Hospital affiliated to Soochow University, Suzhou, China between September 2009 and March 2010. Nasopharyngeal swabs and bronchial aspirate samples from 81 children with acute respiratory infections were tested positive for influenza A (H1N1) using quantitative real-time polymerase chain reaction. Chest imaging for these patients was analyzed retrospectively by 2 independent radiologists for the presence and distribution of abnormalities.
RESULTS: Chest radiograph findings consisted of bilateral patchy areas of consolidation (n=48), diffuse areas of air-space consolidation (n=18), and lobar consolidation (n=7). Eight chest x-rays were normal. Abnormalities were observed more frequently in the lower lobes (bilateral [n=66], unilateral [n=7]). Computed tomography (CT) scans were performed in 18 cases with air-space consolidation and interstitial opacities. Cases with diffuse areas of air-space consolidation were followed-up after 3 months by high resolution CT imaging, which showed interstitial thickening.
CONCLUSION: The predominant imaging findings in childhood influenza A (H1N1) were bilateral patchy areas of consolidation, followed by diffuse areas of air-space consolidation, normal radiographs, and lobar consolidation.
Abbo L, Quartin A, Morris MI, Saigal G, Ariza-Heredia E, Mariani P, Rodriguez O, Muñoz-Price LS, Ferrada M, Ramee E, Rosas MI, Gonzalez IA, Fishman J.
Pulmonary imaging of pandemic influenza H1N1 infection: relationship between clinical presentation and disease burden on chest radiography and CT.
Br J Radiol. 2010 Aug;83(992):645-51. doi: 10.1259/bjr/53692814. Epub 2010 Jun 15.
Abstract/Text
The potential for pulmonary involvement among patients presenting with novel swine-origin influenza A (H1N1) is high. To investigate the utility of chest imaging in this setting, we correlated clinical presentation with chest radiographic and CT findings in patients with proven H1N1 cases. Subjects included all patients presenting with laboratory-confirmed H1N1 between 1 May and 10 September 2009 to one of three urban hospitals. Clinical information was gathered retrospectively, including symptoms, possible risk factors, treatment and hospital survival. Imaging studies were re-read for study purposes, and CXR findings compared with CT scans when available. During the study period, 157 patients presented with subsequently proven H1N1 infection. Hospital admission was necessary for 94 (60%) patients, 16 (10%) were admitted to intensive care and 6 (4%) died. An initial CXR, carried out for 123 (78%) patients, was abnormal in only 40 (33%) cases. Factors associated with increased likelihood for radiographic lung abnormalities were dyspnoea (p<0.001), hypoxaemia (p<0.001) and diabetes mellitus (p = 0.023). Chest CT was performed in 21 patients, and 19 (90%) showed consolidation, ground-glass opacity, nodules or a combination of these findings. 4 of 21 patients had negative CXR and positive CT. Compared with CT, plain CXR was less sensitive in detecting H1N1 pulmonary disease among immunocompromised hosts than in other patients (p = 0.0072). A normal CXR is common among patients presenting to the hospital for H1N1-related symptoms without evidence of respiratory difficulties. The CXR may significantly underestimate lung involvement in the setting of immunosuppression.
Semionov A, Tremblay C, Samson L, Chandonnet M, Chalaoui J, Chartrand-Lefebvre C.
Pandemic influenza A (H1N1) 2009: chest radiographic findings from 147 proven cases in the Montreal area.
Can Assoc Radiol J. 2010 Oct;61(4):233-40. doi: 10.1016/j.carj.2010.03.008. Epub 2010 May 26.
Abstract/Text
OBJECTIVE: To describe chest radiographic findings in patients with isolated and complicated acute novel influenza A (H1N1) virus infection.
METHODS: Retrospective study of 147 patients (64 men, mean age 41) with reverse-transcriptase polymerase chain reaction confirmed acute influenza A (H1N1) infection, who also had a chest radiograph <72 hours of viral specimen collection. Radiographs were analysed for acute findings. A correlation with bacterial cultures results was performed. The unpaired 2-sample equal-variance Student t test was applied to continuous variables and the Pearson χ(2) test of association to discrete variables.
RESULTS: In 71% of cases, chest radiograph was normal. The presence of acute imaging findings was associated with older age (P < .05), increased number of comorbidities (most commonly, chronic obstructive pulmonary disease, diabetes, asthma) (P < .05), higher rate of hospitalization (P < .05) and intensive care unit admission, and increased mortality. Predominant acute radiographic finding in isolated influenza A (H1N1) was alveolar opacity (88%), either unifocal or multifocal, most often in the lower lobes. In the subgroup of patients with positive imaging findings and for whom nonviral microbiologic data was available, 62% had superimposed bacterial or fungal infection.
CONCLUSION: In the majority of patients with acute influenza A (H1N1) infection, the chest radiograph is normal. Acute imaging findings are associated with older age, an increased number of comorbidities, and a higher rate of complications and mortality. The predominant radiographic finding of isolated primary influenza A (H1N1) infection is alveolar opacity. Superimposed bacterial infection is frequent and must be excluded in patients with abnormal imaging.
Copyright © 2010 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.
Lyytikäinen O, Hoffmann E, Timm H, Schweiger B, Witte W, Vieth U, Ammon A, Petersen LR.
Influenza A outbreak among adolescents in a ski hostel.
Eur J Clin Microbiol Infect Dis. 1998 Feb;17(2):128-30. doi: 10.1007/BF01682171.
Abstract/Text
An outbreak of influenza A H3N2 with a high attack rate (49%) and abrupt onset (69% became ill within 2 days) occurred among 81 ski school participants who stayed in a crowded hostel in Austria in early 1997. Two students were hospitalized with pneumonia; one of them died. Cultures of blood and/or respiratory secretions from the hospitalized students yielded toxin-producing Staphylococcus aureus. Influenza A H3N2 was confirmed serologically in four participants, including one surviving hospitalized student, and by polymerase chain reaction of lung tissue from the deceased student. This investigation demonstrates that influenza can cause an explosive outbreak among skiers in a crowded hostel, leading to severe complications among previously healthy adolescents.
Schwarzmann SW, Adler JL, Sullivan RJ Jr, Marine WM.
Bacterial pneumonia during the Hong Kong influenza epidemic of 1968-1969.
Arch Intern Med. 1971 Jun;127(6):1037-41.
Abstract/Text
Bisno AL, Griffin JP, Van Epps KA, Niell HB, Rytel MW.
Pneumonia and Hong Kong influenza: a prospective study of the 1968-1969 epidemic.
Am J Med Sci. 1971 May;261(5):251-63. doi: 10.1097/00000441-197105000-00004.
Abstract/Text
Fujimoto S, Kobayashi M, Uemura O, Iwasa M, Ando T, Katoh T, Nakamura C, Maki N, Togari H, Wada Y.
PCR on cerebrospinal fluid to show influenza-associated acute encephalopathy or encephalitis.
Lancet. 1998 Sep 12;352(9131):873-5. doi: 10.1016/S0140-6736(98)12449-2.
Abstract/Text
BACKGROUND: Except for Reye's syndrome, influenza-associated acute encephalopathy or encephalitis is not universally recognised. We did a multicentre study of laboratory and clinical data for patients with influenza-associated acute encephalopathy or encephalitis.
METHODS: In Nagoya, Japan, ten patients with acute encephalopathy or encephalitis associated with influenza-like illness were admitted to our hospitals between April, 1996, and March, 1997. We collected clinical, laboratory and serological data and assessed cerebrospinal fluid samples by PCR for influenza A and B.
FINDINGS: Seven patients, aged 22 months to 4 years, had evidence of recent influenza infection, six with type-A/Hong Kong (H3N2) and one with type B. The first sign in the central nervous system appeared within 2 days of fever in all but one patient. The first sign of involvement of the central nervous system was generalised convulsions in all patients. Two patients died, one had sequelae, and four survived without sequelae. PCR for influenza type A was positive for five patients.
INTERPRETATION: The results of PCR suggest that at least part of the influenza type A genome existed in the central nervous system. Influenza-associated acute encephalopathy or encephalitis in young children deserves wider recognition.
Steininger C, Popow-Kraupp T, Laferl H, Seiser A, Gödl I, Djamshidian S, Puchhammer-Stöckl E.
Acute encephalopathy associated with influenza A virus infection.
Clin Infect Dis. 2003 Mar 1;36(5):567-74. doi: 10.1086/367623. Epub 2003 Feb 14.
Abstract/Text
Twenty-one patients aged 4-78 years with influenza A virus-associated acute encephalopathy were studied. Influenza A virus could be detected only in a cerebrospinal fluid (CSF) specimen obtained from 1 of 18 patients, despite the use of a highly sensitive polymerase chain reaction assay. Six patients experienced influenzal encephalopathy during the course of respiratory illness. Five of these patients had hypoprothrombinemia and 4 had increased serum creatinine levels, indicating hepatic and/or renal dysfunction. Fourteen patients experienced postinfluenzal encephalopathy
Goenka A, Michael BD, Ledger E, Hart IJ, Absoud M, Chow G, Lilleker J, Lunn M, McKee D, Peake D, Pysden K, Roberts M, Carrol ED, Lim M, Avula S, Solomon T, Kneen R.
Neurological manifestations of influenza infection in children and adults: results of a National British Surveillance Study.
Clin Infect Dis. 2014 Mar;58(6):775-84. doi: 10.1093/cid/cit922. Epub 2013 Dec 18.
Abstract/Text
BACKGROUND: The emergence of influenza A(H1N1) 2009 was met with increased reports of associated neurological manifestations. We aimed to describe neurological manifestations of influenza in adults and children in the United Kingdom that presented at this time.
METHODS: A 2-year surveillance study was undertaken through the British adult and pediatric neurological surveillance units from February 2011. Patients were included if they met clinical case definitions within 1 month of proven influenza infection.
RESULTS: Twenty-five cases were identified: 21 (84%) in children and 4 (16%) in adults. Six (29%) children had preexisting neurological disorders. Polymerase chain reaction of respiratory secretions identified influenza A in 21 (81%; 20 of which [95%] were H1N1) and influenza B in 4 (15%). Twelve children had encephalopathy (1 with movement disorder), 8 had encephalitis, and 1 had meningoencephalitis. Two adults had encephalopathy with movement disorder, 1 had encephalitis, and 1 had Guillain-Barré syndrome. Seven individuals (6 children) had specific acute encephalopathy syndromes (4 acute necrotizing encephalopathy, 1 acute infantile encephalopathy predominantly affecting the frontal lobes, 1 hemorrhagic shock and encephalopathy, 1 acute hemorrhagic leukoencephalopathy). Twenty (80%) required intensive care, 17 (68%) had poor outcome, and 4 (16%) died.
CONCLUSIONS: This surveillance study described a cohort of adults and children with neurological manifestations of influenza. The majority were due to H1N1. More children than adults were identified; many children had specific encephalopathy syndromes with poor outcomes. None had been vaccinated, although 8 (32%) had indications for this. A modified classification system is proposed based on our data and the increasing spectrum of recognized acute encephalopathy syndromes.
Bayer WH.
Influenza B encephalitis.
West J Med. 1987 Oct;147(4):466.
Abstract/Text
Hjalmarsson A, Blomqvist P, Brytting M, Linde A, Sköldenberg B.
Encephalitis after influenza in Sweden 1987-1998: a rare complication of a common infection.
Eur Neurol. 2009;61(5):289-94. doi: 10.1159/000206854. Epub 2009 Mar 17.
Abstract/Text
The aim of this study was to investigate the incidence of influenza-related encephalitis in Sweden during 11.5 years. Studies from Japan report an increased incidence of influenza-related encephalitis/encephalopathy. Few other studies are available. We conducted a retrospective register-based study on the Swedish National Inpatient Register, which covers all Swedish hospitals. In 1987-1998, a total number of 14,250 hospitalized individuals had an influenza diagnosis (population incidence: 137 per million person-years). In-hospital mortality was 4.1%. Using three different approaches, only 21 cases of influenza-related encephalitis were found, corresponding to a rate of 1.5 per 1,000 hospitalized persons with an influenza diagnosis (population incidence 0.21 per million person-years). We conclude that encephalitis following influenza occurs rarely, or is an infrequently recognized, diagnosed or reported complication. The cases we studied in detail have all recovered without sequels.
Copyright 2009 S. Karger AG, Basel.
Dietzman DE, Schaller JG, Ray CG, Reed ME.
Acute myositis associated with influenza B infection.
Pediatrics. 1976 Feb;57(2):255-8.
Abstract/Text
An epidemic of acute myositis affecting children occurred in association with influenza B infections. The myositis followed the initial influenza-like episode, and almost exclusively involved the gastrocnemius and soleus muscles. Patients improved without specific treatment and made a complete recovery in four to five days. Laboratory studies characteristically showed elevated CPK, SGOT values, and a low peripheral white blood cell count. Influenza B virus was isolated from 11 of the 17 patients studied. This influenza-associated acute myositis of childhood is a recognized syndrome that should not be confused with dermatomyositis.
Dell KM, Schulman SL.
Rhabdomyolysis and acute renal failure in a child with influenza A infection.
Pediatr Nephrol. 1997 Jun;11(3):363-5. doi: 10.1007/s004670050299.
Abstract/Text
A 13-year-old previously healthy girl developed rhabdomyolysis and acute renal failure during influenza A infection. The patient recovered renal function completely with supportive therapy. This complication has been described in adult patients, but progression to acute renal failure in this context has not been reported previously in children. This diagnosis should be considered in the differential diagnosis of a pediatric patient presenting with acute renal failure and viral symptomatology.
Cunningham E, Kohli R, Venuto RC.
Influenza-associated myoglobinuric renal failure.
JAMA. 1979 Nov 30;242(22):2428-9.
Abstract/Text
Acute myoglobinuric renal failure developed in three patients during the course of influenza virus infection. Muscle enzyme levels were elevated in all patients. Myoglobin was detected in the urine or serum by immunodiffusion. Recent influenza infection was documented by elevated hemagglutination inhibition titers. One patient died, whereas the remaining two patients completely recovered renal function. These patients with influenza infection represented more than half of the cases of myoglobinuric renal failure seen on the medical services of the study institutions during ths same period. These observations suggest that the association between influenza infection and myoglobinuric renal failure may be more common than previously suspected.
Salonen O, Koshkiniemi M, Saari A, Myllylä V, Pyhälä R, Airaksinen L, Vaheri A.
Myelitis associated with influenza A virus infection.
J Neurovirol. 1997 Feb;3(1):83-5. doi: 10.3109/13550289709015797.
Abstract/Text
We report a patient presenting with myelitis after respiratory symptoms. A high level of antibodies to influenza A virus was measured in serum and cerebrospinal fluid (CSF), and the serum/CSF antibody ratio was 1.7, suggesting specific antibody production in the central nervous system. Magnetic resonance imaging of the spinal canal showed a contrast-enhanced swelling on the cervical medulla. Such a case would have warranted the use of antiviral therapy and calls to mind the neurotropic potential of influenza A viruses.
Rotbart HA.
Viral meningitis.
Semin Neurol. 2000;20(3):277-92. doi: 10.1055/s-2000-9427.
Abstract/Text
Enteroviruses account for 85 to 95% of all cases of aseptic meningitis, but the arboviruses and herpes simplex virus are also important etiologic agents. Mumps, lymphocytic choriomeningitis virus, herpes zoster, human herpesvirus type 6, and influenza viruses are rare causes of meningitis. The virology, pathogenesis, epidemiology, clinical manifestations, diagnostic studies, and established and potential antiviral therapies for viral meningitis are discussed. A differential diagnosis of the aseptic meningitis syndrome is provided.
Mamas MA, Fraser D, Neyses L.
Cardiovascular manifestations associated with influenza virus infection.
Int J Cardiol. 2008 Nov 28;130(3):304-9. doi: 10.1016/j.ijcard.2008.04.044. Epub 2008 Jul 14.
Abstract/Text
Influenza accounts for 3 to 5 million cases of severe illness and up to 300,000 deaths annually. Cardiovascular involvement in acute influenza infection can occur through direct effects of the virus on the myocardium or through exacerbation of existing cardiovascular disease. Epidemiological studies have demonstrated an association between influenza epidemics and cardiovascular mortality and a decrease in cardiovascular mortality in high risk patients has been demonstrated following vaccination with influenza vaccine. Influenza is a recognised cause of myocarditis which can lead to significant impairment of cardiac function and mortality. With recent concerns regarding another potential global pandemic of influenza the huge potential for cardiovascular morbidity and mortality is discussed.
Levenson JE, Kaul DR, Saint S, Nallamothu BK, Gurm HS.
Clinical problem-solving. A shocking development.
N Engl J Med. 2013 Dec 5;369(23):2253-8. doi: 10.1056/NEJMcps1301587.
Abstract/Text
MacDonald KL, Osterholm MT, Hedberg CW, Schrock CG, Peterson GF, Jentzen JM, Leonard SA, Schlievert PM.
Toxic shock syndrome. A newly recognized complication of influenza and influenzalike illness.
JAMA. 1987 Feb 27;257(8):1053-8. doi: 10.1001/jama.257.8.1053.
Abstract/Text
Nine cases of severe hypotension or death compatible with toxic shock syndrome (TSS) as a complication of influenza and influenzalike illness were identified in Minnesota with onsets between Jan 2, 1986, and Feb 23, 1986, in which five of the patients died. During this time, an influenza outbreak was occurring in the state. Cultures of respiratory secretions were performed in eight patients; Staphylococcus aureus was isolated from all of them. Seven S aureus isolates were available for determination of exotoxin production; five isolates produced toxic shock syndrome toxin-1, one produced enterotoxin B, and one produced both. Acute influenza B infection was confirmed in three of four patients for whom throat cultures or acute and convalescent serum samples were available. Two patients fulfilled the Centers for Disease Control-confirmed case definition for TSS. Four additional patients fulfilled the CDC criteria for a probable case of TSS, and TSS was a likely diagnosis in the remaining three patients. The initial presentation was suggestive of nonsuppurative tracheitis or viral pneumonia in eight patients. In the remaining patient, the initial clinical presentation was compatible with staphylococcal pneumonia. This report demonstrates that TSS can occur as a complication of influenza and influenzalike illness.
Tolan RW Jr.
Toxic shock syndrome complicating influenza A in a child: case report and review.
Clin Infect Dis. 1993 Jul;17(1):43-5. doi: 10.1093/clinids/17.1.43.
Abstract/Text
Despite extensive literature on toxic shock syndrome, reports of its manifestations in children remain relatively uncommon. Similarly, toxic shock syndrome in association with influenza B or influenza-like illness has been reported in 12 patients, but it has been reported to occur following influenza A in only two patients to date. We report a third case of toxic shock syndrome in a child with influenza A and review the association between epidemic influenza and toxic shock syndrome ("the Thucydides syndrome").
Warren-Gash C, Bhaskaran K, Hayward A, Leung GM, Lo SV, Wong CM, Ellis J, Pebody R, Smeeth L, Cowling BJ.
Circulating influenza virus, climatic factors, and acute myocardial infarction: a time series study in England and Wales and Hong Kong.
J Infect Dis. 2011 Jun 15;203(12):1710-8. doi: 10.1093/infdis/jir171.
Abstract/Text
BACKGROUND: Previous studies identifying associations between influenza and acute cardiac events may have been confounded by climatic factors. Differing seasonal patterns of influenza activity in Hong Kong and England and Wales provide a natural experiment to examine associations with myocardial infarction (MI) independent of cold weather effects.
METHODS: Weekly clinical and laboratory influenza surveillance data, environmental temperature and humidity data, and counts of MI-associated hospitalizations and deaths were obtained for England and Wales and for Hong Kong for the period 1998-2008. We used Poisson regression models that included environmental and seasonal variables to investigate the relationship between influenza and MI.
RESULTS: There were ≥1.2 million MI-associated hospitalizations and 410,204 MI-associated deaths in England and Wales, with a marked peak in the winter season. In Hong Kong, the incidence of MI, on the basis of 65,108 hospitalizations and 18,780 deaths, had a large winter and smaller summer peak, mirroring patterns of influenza activity. There was strong evidence for a link between influenza and MI both in England and Wales, where 3.1%-3.4% of MI-associated deaths (P < .001) and 0.7%-1.2% of MI-associated hospitalizations (P < .001) were attributable to influenza, and in Hong Kong, where the corresponding figures were 3.9%-5.6% (P = .018) and 3.0%-3.3% (P = .002).
CONCLUSIONS: Influenza was associated with an increase in MI-associated deaths and hospitalizations in 2 contrasting settings.
Lichenstein R, Magder LS, King RE, King JC Jr.
The relationship between influenza outbreaks and acute ischemic heart disease in Maryland residents over a 7-year period.
J Infect Dis. 2012 Sep 15;206(6):821-7. doi: 10.1093/infdis/jis435. Epub 2012 Jul 12.
Abstract/Text
BACKGROUND: We sought to expand the understanding of relationships of influenza outbreaks to ischemic heart disease (IHD)-related events.
METHODS: Retrospective data sources were used to examine relationships of intense influenza outbreak periods (intense-IOP) to rates of IHD-related hospitalizations and deaths for Maryland residents aged ≥ 50 years. Rate ratios (RRs) were calculated for medical outcomes during intense-IOP compared to non-IOP for 7 years.
RESULTS: RRs for IHD-related hospitalizations (RR=1.06), deaths (RR=1.16), and combined hospitalizations for IHD- and medically attended acute respiratory illness (MAARI) (RR=1.42) were significantly elevated during intense-IOP over the 7 years (P< .01). RRs for IHD-related hospitalizations increased significantly with age (P= .0007). Also, RRs for IHD-related hospitalizations each year were significantly correlated to proportions of circulating A/H3N2 viruses in that year (correlation coefficient [CC] =0.83, P= .02). Finally, for residents aged ≥ 65 years, RRs for IHD-related hospitalizations each year were significantly correlated with magnitude of the intense-IOPs in that year as measured by RRs for MAARI-related emergency department (ED) visits (CC=0.77, P= .04).
CONCLUSIONS: These data suggest that influenza infections, particularly by A/H3N2 viruses, are directly associated with acute IHD-related events in older individuals.
Metersky ML, Masterton RG, Lode H, File TM Jr, Babinchak T.
Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza.
Int J Infect Dis. 2012 May;16(5):e321-31. doi: 10.1016/j.ijid.2012.01.003. Epub 2012 Mar 2.
Abstract/Text
Post-influenza bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. However, despite much interest in influenza and its complications in recent years, good clinical trial data to inform clinicians in their assessment of treatment options are scant. This paucity of evidence needs to be addressed urgently in order to improve guidance on the management of post-influenza bacterial pneumonia. The objectives of the current article are to evaluate the emergence of the 2009 H1N1 influenza pandemic and use this information as background for an in-depth review of the epidemiology of bacterial pneumonia complicating influenza, to review the bacterial pathogens most likely to be associated with post-influenza bacterial pneumonia, and to discuss treatment considerations in these patients. When determining optimal management approaches, both antiviral and antibacterial agents should be considered, and their selection should be based upon a clear understanding of how their mechanisms of action intervene in the pathogenesis of post-influenza acute bacterial pneumonia.
Copyright © 2012 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F.
Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations.
Arch Intern Med. 2003 Jul 28;163(14):1667-72. doi: 10.1001/archinte.163.14.1667.
Abstract/Text
BACKGROUND: Influenza causes lower respiratory tract complications (LRTCs), particularly bronchitis and pneumonia, in both otherwise healthy adults and those with underlying conditions. The aim of this study was to assess the effect of oseltamivir treatment on the incidence of LRTCs leading to antibiotic treatment and hospitalizations following influenza illness.
METHODS: We analyzed prospectively collected data on LRTCs and antibiotic use from 3564 subjects (age range, 13-97 years) with influenzalike illness enrolled in 10 placebo-controlled, double-blind trials of oseltamivir treatment.
RESULTS: In adults and adolescents with a proven influenza illness, oseltamivir treatment reduced overall antibiotic use for any reason by 26.7% (14.0% vs 19.1% with placebo; P<.001) and the incidence of influenza-related LRTCs resulting in antibiotic therapy by 55% (4.6% vs 10.3% with placebo; P<.001). In those subjects considered at increased risk of complications, 74 (18.5%) of 401 placebo recipients developed an LRTC leading to antibiotic use compared with 45 (12.2%) of 368 oseltamivir recipients (34.0% reduction; P =.02). Hospitalization for any cause occurred in 18 (1.7%) of 1063 placebo recipients compared with 9 (0.7%) of 1350 oseltamivir-treated patients (59% reduction; P =.02). In contrast, among subjects with an influenzalike illness but without a confirmed influenza infection, the incidence of LRTCs (6.7% vs 5.3%), overall antibiotic use (19.7% vs 19.3%), or hospitalizations (1.7% vs 1.9%) was similar between placebo and oseltamivir recipients, respectively.
CONCLUSION: Oseltamivir treatment of influenza illness reduces LRTCs, antibiotic use, and hospitalization in both healthy and "at-risk" adults.
Podewils LJ, Liedtke LA, McDonald LC, Hageman JC, Strausbaugh LJ, Fischer TK, Jernigan DB, Uyeki TM, Kuehnert MJ; Infectious Diseases Society of America Emerging Infections Network.
A national survey of severe influenza-associated complications among children and adults, 2003-2004.
Clin Infect Dis. 2005 Jun 1;40(11):1693-6. doi: 10.1086/430424. Epub 2005 Apr 25.
Abstract/Text
This report summarizes findings of a national survey conducted among infectious diseases consultants to assess complications associated with influenza during the 2003-2004 influenza season. The survey identified severe complications, including secondary infection with Staphylococcus aureus and deaths among children and adults, as well as perceived shortages in rapid diagnostic tests and influenza vaccine.
Song JY, Cheong HJ, Heo JY, Noh JY, Yong HS, Kim YK, Kang EY, Choi WS, Jo YM, Kim WJ.
Clinical, laboratory and radiologic characteristics of 2009 pandemic influenza A/H1N1 pneumonia: primary influenza pneumonia versus concomitant/secondary bacterial pneumonia.
Influenza Other Respir Viruses. 2011 Nov;5(6):e535-43. doi: 10.1111/j.1750-2659.2011.00269.x. Epub 2011 Jun 20.
Abstract/Text
BACKGROUND: Although influenza virus usually involves the upper respiratory tract, pneumonia was seen more frequently with the 2009 pandemic influenza A/H1N1 than with seasonal influenza.
METHODS: From September 1, 2009, to January 31, 2010, a specialized clinic for patients (aged ≥15 years) with ILI was operated in Korea University Guro Hospital. RT-PCR assay was performed to diagnose 2009 pandemic influenza A/H1N1. A retrospective case-case-control study was performed to determine the predictive factors for influenza pneumonia and to discriminate concomitant/secondary bacterial pneumonia from primary influenza pneumonia during the 2009-2010 pandemic.
RESULTS: During the study period, the proportions of fatal cases and pneumonia development were 0·12% and 1·59%, respectively. Patients with pneumonic influenza were less likely to have nasal symptoms and extra-pulmonary symptoms (myalgia, headache, and diarrhea) compared to patients with non-pneumonic influenza. Crackle was audible in just about half of the patients with pneumonic influenza (38·5% of patients with primary influenza pneumonia and 53·3% of patients with concomitant/secondary bacterial pneumonia). Procalcitonin, C-reactive protein (CRP), and lactate dehydrogenase were markedly increased in patients with influenza pneumonia. Furthermore, procalcitonin (cutoff value 0·35 ng/ml, sensitivity 81·8%, and specificity 66·7%) and CRP (cutoff value 86·5 mg/IU, sensitivity 81·8%, and specificity 59·3%) were discriminative between patients with concomitant/secondary bacterial pneumonia and patients with primary influenza pneumonia.
CONCLUSIONS: Considering the subtle manifestations of 2009 pandemic influenza A/H1N1 pneumonia in the early stage, high clinical suspicion is required to detect this condition. Both procalcitonin and CRP would be helpful to differentiate primary influenza pneumonia from concomitant/secondary bacterial pneumonia.
© 2011 Blackwell Publishing Ltd.
Muscedere J, Ofner M, Kumar A, Long J, Lamontagne F, Cook D, McGeer A, Chant C, Marshall J, Jouvet P, Fowler R; ICU-FLU Group and the Canadian Critical Care Trials Group.
The occurrence and impact of bacterial organisms complicating critical care illness associated with 2009 influenza A(H1N1) infection.
Chest. 2013 Jul;144(1):39-47. doi: 10.1378/chest.12-1861.
Abstract/Text
BACKGROUND: Although secondary infections are recognized as a cause of morbidity and mortality in seasonal influenza, their frequency, characteristics, and associated clinical outcomes in 2009 influenza A(H1N1) (A[H1N1])-related critical illness are unknown.
METHODS: In a prospective cohort of adult patients admitted to Canadian ICUs with influenza A(H1N1) infection, the frequency and associated clinical outcomes of prevalent (culture taken within 72 h of ICU admission) and ICU-acquired (culture taken after 72 h from ICU admission) positive bacterial cultures were determined.
RESULTS: Among 681 patients, the mean age was 47.9 years (SD, 15.1), APACHE (Acute Physiology and Chronic Health Examination) II score was 21.0 (9.9), and 573 patients (84.0%) were invasively mechanically ventilated. Positive cultures were obtained in 259 patients (38.0%): 77 (29.7%) had prevalent, 115 (44.4%) had ICU-acquired, and 40 (15.4%) had both; culture date was unavailable in 27 (10.4%). The most common bacterial organisms isolated were coagulase-negative staphylococci, Staphylococcus aureus, Pseudomonas species, and Streptococcus pneumoniae. Antibiotics were prescribed in 661 (97.1%), with 3.8 (1.9) prescriptions per patient. Patients with any positive culture had longer days of mechanical ventilation (mean [SD], 15.2 [10.7] vs 10.7 [9.0]; P<.0001), ICU stay (median [interquartile range (IQR)], 18.2 [12.5] days vs 10.8 [9.0] days, P<.0001), and hospitalization (median [IQR], 30.7 [20.7] days vs 19.2 [17.4] days, P<.0001) and a trend toward increased hospital mortality (25.1% vs 19.9%, P=.15). Patients with ICU-acquired positive cultures had worse outcomes compared with those with positive prevalent cultures or who were culture-negative.
CONCLUSION: Culture-based evidence of secondary infections commonly complicates A(H1N1)-related critical illness and is associated with worse clinical outcomes despite nearly ubiquitous antibiotic administration.
Kawai N, Ikematsu H, Iwaki N, Maeda T, Satoh I, Hirotsu N, Kashiwagi S.
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.
Clin Infect Dis. 2006 Aug 15;43(4):439-44. doi: 10.1086/505868. Epub 2006 Jun 26.
Abstract/Text
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.
Stephenson I, Democratis J, Lackenby A, McNally T, Smith J, Pareek M, Ellis J, Bermingham A, Nicholson K, Zambon M.
Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children.
Clin Infect Dis. 2009 Feb 15;48(4):389-96. doi: 10.1086/596311.
Abstract/Text
BACKGROUND: Oseltamivir, a specific influenza neuraminidase inhibitor, is an effective treatment for seasonal influenza. Emergence of drug-resistant influenza viruses after treatment has been reported, particularly in children in Japan, where the dosing schedule is different from that used throughout the rest of the world. We investigated the emergence of drug-resistant infection in children treated with a tiered weight-based dosing regimen.
METHODS: We analyzed sequential clinical nasopharyngeal samples, obtained before and after tiered weight-based oseltamivir therapy, from children with acute influenza during 2005-2007. We isolated viruses, tested for drug resistance with use of a fluorescence-based neuraminidase inhibition assay, performed neuraminidase gene sequencing, and determined quantitative viral loads.
RESULTS: Sixty-four children (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, and 19 with influenza B virus) aged 1-12 years (median age, 3 years, 1 month) were enrolled. By days 4-7 after initiation of treatment, of 64 samples tested, 47 (73.4%) and 26 (40.6%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. By days 8-12 after initiation of treatment, of 53 samples tested, 18 (33.9%) and 1 (1.8%) had virus detectable by reverse-transcriptase polymerase chain reaction and culture, respectively. We found no statistically significant differences in the reduction of viral shedding or time to clearance of virus between viral subtypes. Antiviral-resistant viruses were recovered from 3 (27.3%) of 11 children with influenza A subtype H1N1, 1 (2.9%) of 34 children with influenza A subtype H3N2, and 0 (0%) of 19 children with influenza B virus, all of whom were treated with oseltamivir (P = .004). There was no evidence of prolonged illness in children infected with drug-resistant virus.
CONCLUSIONS: Drug resistance emerges at a higher rate in influenza A subtype H1N1 virus than in influenza A subtype H3N2 or influenza B virus after tiered weight-based oseltamivir therapy. Virological surveillance for patterns of drug resistance is essential for determination of antiviral treatment strategies and for composition of pandemic preparedness stockpiles.
Koseki N, Kaiho M, Kikuta H, Oba K, Togashi T, Ariga T, Ishiguro N.
Comparison of the clinical effectiveness of zanamivir and laninamivir octanoate for children with influenza A(H3N2) and B in the 2011-2012 season.
Influenza Other Respir Viruses. 2014 Mar;8(2):151-8. doi: 10.1111/irv.12147. Epub 2013 Aug 19.
Abstract/Text
OBJECTIVES: To evaluate the clinical effectiveness of the two inhaled neuraminidase inhibitors (NAIs), zanamivir (ZN) and laninamivir octate (LO), for influenza A(H3N2) and B virus infections.
DESIGN: A prospective, multicenter observational study was conducted from January to April in 2012.
SETTING: Outpatients aged 5-18 years who had a temperature of 37.5°C or higher and were diagnosed as having influenza based on an immunochromatographic assay were enrolled.
SAMPLE: A total of 338 patients treated with ZN and 314 patients treated with LO were compared.
MAIN OUTCOME MEASURES: The duration of fever after administration of the first dose of each NAI was evaluated as a primary endpoint. The secondary endpoint was episodes of biphasic fever.
RESULTS: No statistically significant difference in the duration of fever was found between the ZN and LO groups (log-rank test, P = 0.117). A logistic regression model showed that episodes of biphasic fever increased by 1.19 times for every decrease of 1 year of age (P = 0.016) and that the number of biphasic fever episodes in patients treated with LO was 5.80-times greater than that in patients treated with ZN (P < 0.001).
CONCLUSIONS: Although the duration of fever in the LO group was comparable to that in the ZN group, episodes of biphasic fever were more frequent in younger children and in the LO group than in the ZN group.
© 2013 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.
Suzuki E, Ichihara K.
The course of fever following influenza virus infection in children treated with oseltamivir.
J Med Virol. 2008 Jun;80(6):1065-71. doi: 10.1002/jmv.21144.
Abstract/Text
Although the effectiveness of oseltamivir against influenza virus infection is well known, there has been no report analyzing the detailed time course of fever following the drug treatment in children. Oseltamivir was prescribed for 4 days to every child with a positive result for rapid immunological test for influenza virus during 2002--2003, 2003--2004, and 2004--2005 epidemics. Only those who were 1-12 years of age and prescribed oseltamivir within 24 hr after the onset of fever were included in the analysis. The numbers of children with type A/H3N2 disease for the three seasons were 64, 77, and 33, and those with type B disease were 102, 4, and 86, for the respective seasons. The period until normalization of temperature was obtained from six-hourly recordings of body temperature. By multiple regression analysis, temperature periods were longer in type B than in type A/H3N2 disease, negatively associated with age, and positively with maximal body temperature (all: P < 0.001). The effectiveness of oseltamivir on body temperature in type B disease was less apparent in the 2004--2005 than in the 2002--2003 season, irrespective of age. No such between-season difference was observed for Type A/H3N2 disease. Frequencies of ineffective cases with biphasic fever (19.6% and 43.0% during 2002--2003 and 2004--2005 seasons) were significantly higher in type B than in type A/H3N disease (12.0% and 11.8%, respectively). The effectiveness of oseltamivir depends on a child's age, maximal body temperature and the virus type. This study confirmed recent reports indicating decreased effectiveness of oseltamivir against type B disease.
Centers for Disease Control and Prevention (CDC).
Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices--United States, 2013-2014.
MMWR Recomm Rep. 2013 Sep 20;62(RR-07):1-43.
Abstract/Text
This report updates the 2012 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccines for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2012;61:613-8). Routine annual influenza vaccination is recommended for all persons aged ≥ 6 months. For the 2013-14 influenza season, it is expected that trivalent live attenuated influenza vaccine (LAIV3) will be replaced by a quadrivalent LAIV formulation (LAIV4). Inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Vaccine virus strains included in the 2013-14 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1)-like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012-like virus. Quadrivalent vaccines will include an additional influenza B virus strain, a B/Brisbane/60/2008-like virus, intended to ensure that both influenza B virus antigenic lineages (Victoria and Yamagata) are included in the vaccine. This report describes recently approved vaccines, including LAIV4, IIV4, trivalent cell culture-based inactivated influenza vaccine (ccIIV3), and trivalent recombinant influenza vaccine (RIV3). No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one product is otherwise appropriate. This information is intended for vaccination providers, immunization program personnel, and public health personnel. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates also will be found at this website. Vaccination and health-care providers should check the CDC influenza website periodically for additional information.
Burch J, Corbett M, Stock C, Nicholson K, Elliot AJ, Duffy S, Westwood M, Palmer S, Stewart L.
Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis.
Lancet Infect Dis. 2009 Sep;9(9):537-45. doi: 10.1016/S1473-3099(09)70199-9. Epub 2009 Aug 7.
Abstract/Text
In publicly funded health systems with finite resources, management decisions are based on assessments of clinical effectiveness and cost-effectiveness. The UK National Institute for Health and Clinical Excellence commissioned a systematic review to inform their 2009 update to guidance on the use of antiviral drugs for the treatment of influenza. We searched databases for studies of the use of neuraminidase inhibitors for the treatment of seasonal influenza. We present the results for healthy adults (ie, adults without known comorbidities) and people at-risk of influenza-related complications. There was an overall reduction in the median time to symptom alleviation in healthy adults by 0.57 days (95% CI -1.07 to -0.08; p=0.02; 2701 individuals) with zanamivir, and 0.55 days (95% CI -0.96 to -0.14; p=0.008; 1410 individuals) with oseltamivir. In those at risk, the median time to symptom alleviation was reduced by 0.98 days (95% CI -1.84 to -0.11; p=0.03; 1252 individuals) with zanamivir, and 0.74 days (95% CI -1.51 to 0.02; p=0.06; 1472 individuals) with oseltamivir. Little information was available on the incidence of complications. In view of the advantages and disadvantages of different management strategies for controlling seasonal influenza in healthy adults recommending the use of antiviral drugs for the treatment of people presenting with symptoms is unlikely to be the most appropriate course of action.
Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, Ades AE, Sutton A, Cooper N, Elliot AJ, Nicholson K, Duffy S, McKenna C, Stewart L, Westwood M, Palmer S.
Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation.
Health Technol Assess. 2009 Nov;13(58):1-265, iii-iv. doi: 10.3310/hta13580.
Abstract/Text
OBJECTIVES: To evaluate the clinical effectiveness (including adverse events) and cost-effectiveness of antivirals for the treatment of naturally acquired influenza for 'at-risk' and otherwise healthy populations.
DATA SOURCES: Eleven electronic databases (MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Pascal, Science Citation Index, BIOSIS, Latin American and Caribbean Health Sciences, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, and Health Technology Assessment Database) were searched from October 2001 to November 2007. A supplementary search was undertaken in June 2008 for information relating to drug resistance during the 2007-8 influenza season.
REVIEW METHODS: Systematic reviews of the evidence on the clinical effectiveness and cost-effectiveness of antivirals for the treatment of influenza were undertaken. Twenty-nine randomised controlled trials comparing antivirals with each other, placebo, or best symptomatic care were included in the evaluation of clinical effectiveness in patients presenting with an influenza-like illness (ILI). Primary outcomes were measures of symptom duration (median time to alleviation of symptoms and median time to return to normal activity). Incidence of complications, mortality, hospitalisations, antibiotic use (as a surrogate for complications) and adverse events was also assessed. In addition, an independent decision model was developed to evaluate the cost-effectiveness of antiviral treatment from the perspective of the UK NHS.
RESULTS: Amantadine was excluded at an early stage, owing to a lack of any new trials that met the inclusion criteria and the limitations of the existing evidence. The review therefore focused on the neuraminidase inhibitors (NIs) oseltamivir and zanamivir, both of which were found to be effective in reducing symptom duration (zanamavir by 0.5-1.0 days and oseltamivir by 0.5-1.5 days). However, the effect sizes were often small and unlikely to be clinically significant in many cases, particularly in healthy adults. For the at-risk subgroups, effect sizes for differences in symptom duration were generally larger, and potentially more clinically significant, than those seen in healthy adults (median duration of symptoms reduced by 1-2 days with zanamivir and 0.50-0.75 days with oseltamivir). However, there was greater uncertainty around these results, with estimates often failing to reach statistical significance. The most consistent data and strongest evidence related to antibiotic use, with both zanamivir and oseltamivir resulting in statistically significant reductions in antibiotic use. In general, the estimates from the cost-effectiveness model were more favourable in at-risk populations (including adults and children with comorbid conditions and the elderly) compared with otherwise healthy populations. Zanamivir was the optimal NI treatment in each of the at-risk populations considered, and oseltamivir was optimal for healthy populations (both adults and children).
CONCLUSIONS: The clinical effectiveness data for population subgroups used to inform the multiparameter evidence synthesis and cost-effectiveness modelling were, in places, limited and this should be borne in mind when interpreting the findings of this review. Trials were often not designed to determine clinical effectiveness in population subgroups and hence, although the direction of effect was clear, estimates of differences in symptom duration tended to be subject to greater uncertainty in subgroups. Despite some concerns, the use of NIs in at-risk populations appeared to be a cost-effective approach for the treatment of influenza. Well-designed observational studies might also be considered to evaluate the clinical course of influenza in terms of complications, hospitalisation, mortality and quality of life, as well as the impact of NIs.
Matheson NJ, Harnden AR, Perera R, Sheikh A, Symmonds-Abrahams M.
Neuraminidase inhibitors for preventing and treating influenza in children.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002744. doi: 10.1002/14651858.CD002744.pub2. Epub 2007 Jan 24.
Abstract/Text
BACKGROUND: During epidemic years, influenza attack rates in children exceed 40%. Options for prevention and treatment include the neuraminidase inhibitors: zanamivir and oseltamivir.
OBJECTIVES: To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza infection in children.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005); MEDLINE (1966 to April 2005); EMBASE (January 1980 to December 2004); the on-line GlaxoSmithKline Clinical Trials Register; the on-line Roche Clinical Trial Protocol Registry and Clinical Trial Results Database (August 2005); and reference lists of articles. We also scrutinised web sites of European and US regulatory bodies and contacted manufacturers and authors.
SELECTION CRITERIA: Double-blind, randomised, controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs in children less than 12 years of age. Additional safety and tolerability data from other sources were also included.
DATA COLLECTION AND ANALYSIS: Four authors applied the inclusion criteria to the retrieved studies, assessed trial quality and extracted data. Data were analysed separately for oseltamivir and zanamivir.
MAIN RESULTS: Three trials involving 1500 children with a clinical case definition of influenza were included, of whom 977 had laboratory-confirmed influenza. Overall, trial quality was good. Oseltamivir reduced the median duration of illness by 26% (36 hours) in healthy children with laboratory-confirmed influenza (P value less than 0.0001). The reduction was only 7.7% (10 hours) in 'at risk' (asthmatic) children, and this did not reach statistical significance (P value = 0.54). Zanamivir reduced the median duration of illness by 24% (1.25 days) in healthy children with laboratory-confirmed influenza (P value less than 0.001). No data in 'at risk' children were available. Only oseltamivir produced a significant reduction in the complications of influenza (particularly otitis media), although there was a trend to benefit for zanamivir. We identified one randomised, controlled trial of oseltamivir for the prevention of influenza transmission in households, reporting data from 222 paediatric contacts. Where index cases had laboratory-confirmed influenza, a protective efficacy of 55% was observed, but this did not reach statistical significance (P value = 0.089). The adverse events profile of zanamivir was no worse than placebo, but vomiting was more common in children treated with oseltamivir.
AUTHORS' CONCLUSIONS: Neuraminidase inhibitors are effective in shortening illness duration in healthy children with influenza, but efficacy in 'at risk' children remains to be proven. Oseltamivir is also effective in reducing the incidence of secondary complications, and may be effective for influenza prophylaxis.
Shun-Shin M, Thompson M, Heneghan C, Perera R, Harnden A, Mant D.
Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials.
BMJ. 2009 Aug 10;339:b3172. doi: 10.1136/bmj.b3172. Epub 2009 Aug 10.
Abstract/Text
OBJECTIVE: To assess the effects of the neuraminidase inhibitors oseltamivir and zanamivir in treatment of children with seasonal influenza and prevention of transmission to children in households.
DESIGN: Systematic review and meta-analysis of data from published and unpublished randomised controlled trials.
DATA SOURCES: Medline and Embase to June 2009, trial registries, and manufacturers and authors of relevant studies. Review methods Eligible studies were randomised controlled trials of neuraminidase inhibitors in children aged RESULTS: We identified four randomised trials of treatment of influenza (two with oseltamivir, two with zanamivir) involving 1766 children (1243 with confirmed influenza, of whom 55-69% had influenza A), and three randomised trials for postexposure prophylaxis (one with oseltamivir, two with zanamivir) involving 863 children; none of these trials tested efficacy with the current pandemic strain. Treatment trials showed reductions in median time to resolution of symptoms or return to normal activities, or both, of 0.5-1.5 days, which were significant in only two trials. A 10 day course of postexposure prophylaxis with zanamivir or oseltamivir resulted in an 8% (95% confidence interval 5% to 12%) decrease in the incidence of symptomatic influenza. Based on only one trial, oseltamivir did not reduce asthma exacerbations or improve peak flow in children with asthma. Treatment was not associated with reduction in overall use of antibiotics (risk difference -0.30, -0.13 to 0.01). Zanamivir was well tolerated, but oseltamivir was associated with an increased risk of vomiting (0.05, 0.02 to 0.09, number needed to harm=20).
CONCLUSIONS: Neuraminidase inhibitors provide a small benefit by shortening the duration of illness in children with seasonal influenza and reducing household transmission. They have little effect on asthma exacerbations or the use of antibiotics. Their effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.
Jefferson T, Jones M, Doshi P, Del Mar C, Dooley L, Foxlee R.
Neuraminidase inhibitors for preventing and treating influenza in healthy adults.
Cochrane Database Syst Rev. 2010 Feb 17;2011(2):CD001265. doi: 10.1002/14651858.CD001265.pub3. Epub 2010 Feb 17.
Abstract/Text
BACKGROUND: Neuraminidase inhibitors (NI) are recommended for use against influenza and its complications in inter-pandemic years and during pandemics.
OBJECTIVES: To assess the effects of NIs in preventing and treating influenza, its transmission, and its complications in otherwise healthy adults, and to estimate the frequency of adverse effects.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 3) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to August 2009) and EMBASE (1980 to August 2009).
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-randomised placebo-controlled trials of NIs in healthy adults exposed to naturally occurring influenza.
DATA COLLECTION AND ANALYSIS: Two review authors independently applied inclusion criteria, assessed trial quality, and extracted data. We structured the comparisons into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose.
MAIN RESULTS: We identified four prophylaxis, 12 treatment and four post-exposure prophylaxis trials. In prophylaxis compared to placebo, NIs had no effect against influenza-like illnesses (ILI) (risk ratio (RR) ranging from 1.28 for oral oseltamivir 75 mg daily to 0.76 for inhaled zanamivir 10 mg daily). The efficacy of oral oseltamivir against symptomatic influenza was 76% (at 75 mg daily), and 73% (at 150 mg daily). Inhaled zanamivir 10 mg daily performed similarly. Neither NI had a significant effect on asymptomatic influenza. Oseltamivir induced nausea (odds ratio (OR) 1.79, 95% CI 1.10 to 2.93). Oseltamivir for post-exposure prophylaxis had an efficacy of 58% and 84% in two trials for households. Zanamivir performed similarly. The hazard ratios for time to alleviation of symptoms were in favour of the treated group 1.20 (1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Because of the exclusion of a review of mainly unpublished trials of oseltamivir, insufficient evidence remained to reach a conclusion on the prevention of complications requiring antibiotics in influenza cases (RR 0.57, 95% CI 0.23 to 1.37). Analysis of the US FDA and Japan's PMDA regulators' pharmacovigilance dataset, revealed incomplete reporting and description of harms preventing us from reaching firm conclusions on the central nervous system toxicity of neuraminidase inhibitors.
AUTHORS' CONCLUSIONS: Numerous inconsistencies detected in the available evidence, followed by an inability to adequately access the data, has undermined confidence in our previous conclusions for oseltamivir. Independent RCTs to resolve these uncertainties are needed.
McGeer A, Green KA, Plevneshi A, Shigayeva A, Siddiqi N, Raboud J, Low DE; Toronto Invasive Bacterial Diseases Network.
Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada.
Clin Infect Dis. 2007 Dec 15;45(12):1568-75. doi: 10.1086/523584.
Abstract/Text
BACKGROUND: We conducted a prospective cohort study to assess the impact of antiviral therapy on outcomes of patients hospitalized with influenza in southern Ontario, Canada.
METHODS: Patients admitted to Toronto Invasive Bacterial Diseases Network hospitals with laboratory-confirmed influenza from 1 January 2005 through 31 May 2006 were enrolled in the study. Demographic and medical data were collected by patient and physician interview and chart review. The main outcome evaluated was death within 15 days after symptom onset.
RESULTS: Data were available for 512 of 541 eligible patients. There were 185 children (<15 years of age), none of whom died and none of whom were treated with antiviral drugs. The median age of the 327 adults was 77 years (range, 15-98 years), 166 (51%) were male, 245 (75%) had a chronic underlying illness, and 216 (71%) had been vaccinated against influenza. Of the 327 adult patients, 184 (59%) presented to the emergency department within 48 h after symptom onset, 52 (16%) required intensive care unit admission, and 27 (8.3%) died within 15 days after symptom onset. Most patients (292 patients; 89%) received antibacterial therapy; 106 (32%) were prescribed antiviral drugs. Treatment with antiviral drugs active against influenza was associated with a significant reduction in mortality (odds ratio, 0.21; 95% confidence interval, 0.06-0.80; n=100, 260). There was no apparent impact of antiviral therapy on length of stay in survivors.
CONCLUSIONS: There is a significant burden of illness attributable to influenza in this highly vaccinated population. Treatment with antiviral drugs was associated with a significant reduction in mortality.
Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, Ishida T, Sekino H, Yamada K, Portsmouth S, Kawaguchi K, Shishido T, Arai M, Tsuchiya K, Uehara T, Watanabe A; Baloxavir Marboxil Investigators Group.
Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents.
N Engl J Med. 2018 Sep 6;379(10):913-923. doi: 10.1056/NEJMoa1716197.
Abstract/Text
BACKGROUND: Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.
METHODS: We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016-2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.
RESULTS: In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.
CONCLUSIONS: Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354 .).
Ison MG, Portsmouth S, Yoshida Y, Shishido T, Mitchener M, Tsuchiya K, Uehara T, Hayden FG.
Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial.
Lancet Infect Dis. 2020 Oct;20(10):1204-1214. doi: 10.1016/S1473-3099(20)30004-9. Epub 2020 Jun 8.
Abstract/Text
BACKGROUND: Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.
METHODS: We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.
FINDINGS: 2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (-7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.
INTERPRETATION: Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.
FUNDING: Shionogi.
Copyright © 2020 Elsevier Ltd. All rights reserved.
Kuo YC, Lai CC, Wang YH, Chen CH, Wang CY.
Clinical efficacy and safety of baloxavir marboxil in the treatment of influenza: A systematic review and meta-analysis of randomized controlled trials.
J Microbiol Immunol Infect. 2021 Oct;54(5):865-875. doi: 10.1016/j.jmii.2021.04.002. Epub 2021 Apr 29.
Abstract/Text
PURPOSE: The aim of this meta-analysis is to compare the clinical efficacy and safety of baloxavir with other anti-influenza agents or placebo in the treatment of influenza.
METHODS: PubMed, Embase, Web of Science, Google Scholar, Scopus, CINAHL, Cochrane databases and clinical registration were searched from inception until February 15 2021 for relevant randomized controlled trials (RCTs). Only phase 3 RCTs evaluating the usefulness of baloxavir in the treatment of influenza were included.
RESULTS: Three RCTs enrolling 3771 patients (baloxavir group, n = 1451; oseltamivir group, n = 1288; placebo group, n = 1032) were included. Compared with oseltamivir, baloxavir had an insignificantly shorter time to the alleviation of symptoms (mean difference [MD], -1.29 h; 95% CI, -6.80 to 4.21; I2 = 0%). In contrast, baloxavir had a significantly shorter time to the alleviation of symptoms than placebo (MD, -26.32 h; 95% CI, -33.78 to -18.86; I2 = 0%). Baloxavir was associated with a significant decline in influenza virus titers and viral RNA load compared to oseltamivir and placebo. Baloxavir was associated with a lower risk of any adverse events than oseltamivir (OR, 0.82; 95% CI, 0.69-0.98; I2 = 0%) and placebo (OR, 0.79; 95% CI, 0.66-0.96; I2 = 0%).
CONCLUSIONS: The findings of this meta-analysis suggested that baloxavir is superior to placebo in the treatment of influenza in both clinical outcome and virological response. Moreover, baloxavir was found to have a better virological response than oseltamivir and to be as effective as oseltamivir clinically. Compared with oseltamivir and placebo, baloxavir appears to be a relatively safe anti-influenza agent.
Copyright © 2021. Published by Elsevier B.V.
Baker J, Block SL, Matharu B, Burleigh Macutkiewicz L, Wildum S, Dimonaco S, Collinson N, Clinch B, Piedra PA.
Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2).
Pediatr Infect Dis J. 2020 Aug;39(8):700-705. doi: 10.1097/INF.0000000000002747.
Abstract/Text
BACKGROUND: Baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. We assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza.
METHODS: MiniSTONE-2 (Clinicaltrials.gov: NCT03629184) was a double-blind, randomized, active controlled trial enrolling children 1-<12 years old with a clinical diagnosis of influenza. Children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. The primary endpoint was incidence, severity and timing of adverse events (AEs); efficacy was a secondary endpoint.
RESULTS: In total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. Characteristics of participants were similar between treatment groups. Overall, 122 AEs were reported in 84 (48.6%) children. Incidence of AEs was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). The most common AEs were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. No deaths, serious AEs or hospitalizations were reported. Median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6-163.2) hours with baloxavir versus 150.0 (115.0-165.7) hours with oseltamivir.
CONCLUSIONS: Oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. Baloxavir provides a new therapeutic option with a simple oral dosing regimen.
Sugaya N, Ohashi Y.
Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection.
Antimicrob Agents Chemother. 2010 Jun;54(6):2575-82. doi: 10.1128/AAC.01755-09. Epub 2010 Apr 5.
Abstract/Text
We conducted a double-blind, randomized controlled trial to compare a long-acting neuraminidase inhibitor, laninamivir octanoate, with oseltamivir. Eligible patients were children 9 years of age and under who had febrile influenza symptoms of no more than 36-h duration. Patients were randomized to 1 of 3 treatment groups: a group given 40 mg laninamivir (40-mg group), a group given 20 mg laninamivir (20-mg group), and an oseltamivir group. Laninamivir octanoate was administered as a single inhalation. Oseltamivir (2 mg/kg of body weight) was administered orally twice daily for 5 days. The primary end point was the time to alleviation of influenza illness. The primary analysis included 184 patients (61, 61, and 62 in the 40-mg group, 20-mg group, and oseltamivir group, respectively). Laninamivir octanoate markedly reduced the median time to illness alleviation in comparison with oseltamivir in patients infected with oseltamivir-resistant influenza A (H1N1) virus, and the reductions were 60.9 h for the 40-mg group and 66.2 h for the 20-mg group. On the other hand, there were no significant differences in the times to alleviation of illness between the laninamivir groups and oseltamivir group for patients with influenza A (H3N2) or B virus infection. Laninamivir octanoate was well tolerated. The most common adverse events were gastrointestinal events. Laninamivir octanoate was an effective and well-tolerated treatment for children with oseltamivir-resistant influenza A (H1N1) virus infection. Further study will be needed to confirm clinical efficacy against influenza A (H3N2) or B virus infection. Its ease of administration is noteworthy, because a single inhalation is required during the course of illness.
Watanabe A, Chang SC, Kim MJ, Chu DW, Ohashi Y; MARVEL Study Group.
Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial.
Clin Infect Dis. 2010 Nov 15;51(10):1167-75. doi: 10.1086/656802. Epub 2010 Oct 11.
Abstract/Text
BACKGROUND: A single administration of laninamivir octanoate, a long-acting neuraminidase inhibitor, against influenza infection has been proven effective in nonclinical studies. This study evaluated the clinical efficacy of laninamivir octanoate for the treatment of adult influenza patients.
METHODS: A double-blind, randomized controlled trial examined whether laninamivir octanoate was noninferior to oseltamivir. A total of 1003 patients aged ≥ 20 years with febrile influenza symptoms for no more than 36 h were randomized to receive either 40 mg of laninamivir octanoate, 20 mg of laninamivir octanoate, or oseltamivir. Laninamivir octanoate was inhaled once on day 1, and oseltamivir (75 mg) was administered orally twice daily for 5 days. The primary end point was the time to illness alleviation.
RESULTS: A total of 996 patients were included in the primary analysis (40-mg laninamivir octanoate, n = 334; 20-mg laninamivir octanoate, n = 326; and oseltamivir, n = 336). The median time to illness alleviation in the 40-mg laninamivir octanoate, 20-mg laninamivir octanoate, and oseltamivir groups was 73.0, 85.8, and 73.6 h, respectively. The difference between laninamivir octanoate and oseltamivir was -0.6 h (95% confidence interval, -9.9 to 6.9 h) for the 40-mg group and 12.2 h (95% confidence interval, -1.5 to 17.2 h) for the 20-mg group. The upper limits of the 95% confidence intervals were less than the prespecified noninferiority margin (18 h). The proportion of patients shedding virus at day 3 was significantly lower in the 40-mg laninamivir octanoate group than in the oseltamivir group (P = .006).
CONCLUSIONS: A single inhalation of laninamivir octanoate is effective for the treatment of seasonal influenza, including that caused by oseltamivir-resistant virus, in adults.
CLINICAL TRIALS REGISTRATION: NCT00803595.
Kohno S, Kida H, Mizuguchi M, Shimada J; S-021812 Clinical Study Group.
Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection.
Antimicrob Agents Chemother. 2010 Nov;54(11):4568-74. doi: 10.1128/AAC.00474-10. Epub 2010 Aug 16.
Abstract/Text
Peramivir, a sialic acid analogue, is a selective inhibitor of neuraminidases produced by influenza A and B viruses. We evaluated the efficacy and safety of a single intravenous dose of peramivir in outpatients with uncomplicated seasonal influenza virus infection. A total of 300 previously healthy adult subjects aged 20 to 64 years with a positive influenza virus rapid antigen test were recruited within 48 h of the onset of influenza symptoms and randomized to three groups: single intravenous infusion of either 300 mg peramivir per kg of body weight, 600 mg peramivir, or matching placebo on study day 1. Influenza symptoms and body temperature were self-assessed for 14 days. Nasal and pharyngeal swabs were collected to determine the viral titer. The primary endpoint was the time to alleviation of symptoms. Of the 300 subjects, 296 were included in the intent-to-treat infected population (300 mg peramivir, n = 99; 600 mg peramivir, n = 97; and placebo, n = 100). Peramivir significantly reduced the time to alleviation of symptoms at both 300 mg (hazard ratio, 0.681) and 600 mg (hazard ratio, 0.666) compared with placebo (adjusted P value, 0.0092 for both comparisons). No serious adverse events were reported. Peramivir was well tolerated, and its adverse-event profile was similar to that of placebo. A single intravenous dose of peramivir is effective and well tolerated in subjects with uncomplicated seasonal influenza virus infection.
Kohno S, Kida H, Mizuguchi M, Hirotsu N, Ishida T, Kadota J, Shimada J; S-021812 Clinical Study Group.
Intravenous peramivir for treatment of influenza A and B virus infection in high-risk patients.
Antimicrob Agents Chemother. 2011 Jun;55(6):2803-12. doi: 10.1128/AAC.01718-10. Epub 2011 Apr 4.
Abstract/Text
Influenza virus infections are known to persist longer in patients with underlying diseases, including respiratory tract diseases, and tend to become complicated by secondary influenza-associated infections, such as pneumonia. To assess the efficacy and safety of the novel anti-influenza virus drug peramivir in high-risk patients, we conducted a clinical trial of patients with diabetes or chronic respiratory tract diseases and patients being treated with drugs that suppress immune function. In this multicenter, uncontrolled, randomized, double-blind study, peramivir was intravenously administered at 300 or 600 mg/day for 1 to 5 days, as needed. Efficacy was investigated in 37 patients (300 mg, n = 18 patients; 600 mg, n = 19 patients). The median durations of influenza illness were 68.6 h (90% confidence interval, 41.5 to 113.4 h) overall, 114.4 h (90% confidence interval, 40.2 to 235.3 h) in the 300-mg group, and 42.3 h (90% confidence interval, 30.0 to 82.7 h) in the 600-mg group. The hazard ratio for the 600-mg group compared to the 300-mg group was 0.497 (90% confidence interval, 0.251 to 0.984), and the duration of influenza illness was significantly shorter in the 600-mg group than in the 300-mg group. Among the 42 patients in the safety analysis set, adverse events occurred in 73.8% and adverse drug reactions in 33.3%. No adverse events were particularly problematic clinically, and all patients recovered quickly from all events. The measured blood drug concentrations showed no tendency toward accumulation. Drug accumulation with repeated doses was thus considered to be of little concern. Intravenous peramivir appears to offer a potentially useful treatment for high-risk patients in the future.
Kubo T, Nishimura H.
Antipyretic effect of Mao-to, a Japanese herbal medicine, for treatment of type A influenza infection in children.
Phytomedicine. 2007 Feb;14(2-3):96-101. doi: 10.1016/j.phymed.2006.09.015. Epub 2006 Dec 1.
Abstract/Text
Mao-to is a Japanese traditional herbal medicine which has been used since ancient times for the treatment of influenza-like illness. This study was conducted to evaluate the effect of oral Mao-to administration in children with type A influenza, in comparison to Oseltamivir. We performed a controlled trial of 60 children, from 5 months through 13 years of age, with fever and influenza-like symptom of up to 48 h duration. Diagnosis of influenza type A was performed by virus isolation or detection of a viral gene by RT-PCR. Patients assigned into the following 3 groups: oral Mao-to powder (TJ-27) 0.06 g/kg body wt./dose three times daily (n=17), Oseltamivir 2 mg/kg body wt./dose twice daily (n=18) or both oral Mao-to plus Oseltamivir (n=14). The median duration of fever after treatment was significantly shorter in the Mao-to and Mao-to plus Oseltamivir groups, compared with the Oseltamivir only group (15 h [95%CI 13.2-22.1] p<0.01; 18 h[15.2-27.7] p<0.05; 24 h[23.5-43.0], respectively). Oral Mao-to administration was effective in the control of fever due to type A influenza infection in children.
Chen XY, Wu TX, Liu GJ, Wang Q, Zheng J, Wei J, Ni J, Zhou LK, Duan X, Qiao JQ.
Chinese medicinal herbs for influenza.
Cochrane Database Syst Rev. 2007 Oct 17;(4):CD004559. doi: 10.1002/14651858.CD004559.pub3. Epub 2007 Oct 17.
Abstract/Text
BACKGROUND: Influenza is an acute respiratory communicable disease which, during epidemics, can cause high morbidity and mortality. Traditional Chinese medicinal herbs, often administered following a particular theory, may be a potential medicine of choice.
OBJECTIVES: To assess the effect of Chinese medicinal herbs in preventing and treating influenza, and to estimate the frequency of adverse effects.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2007), which includes the Cochrane Acute Respiratory Infections Review Group specialised register; MEDLINE (January 1966 to January 2007); EMBASE (January 1988 to January 2007); CBM (Chinese Biomedical Database) (January 1980 to January 2007); and the Chinese Cochrane Center's Controlled Trials Register (up to January 2007). We also searched Current Controlled Trials (www.controlled-trials.com) and the National Research Register (http://www.update-software.com/National/) for ongoing trials and reference lists of articles. For more information we telephoned and wrote to researchers in the field, as well as trial authors of studies evaluated in the review
SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing traditional Chinese medicinal herbs with placebo, no treatment, or chemical drugs normally used in preventing and treating uncomplicated influenza patients.
DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality.
MAIN RESULTS: Two studies involving 1012 participants were reviewed. The methodological quality of both studies was 'poor'. Included RCTs separately compared two medicinal herbs with two different antiviral drugs, precluding any pooling of results. 'Ganmao' capsules were found to be more effective than amantadine in decreasing influenza symptoms and speeding recovery in one study, (in which adverse reactions were mentioned in the amantadine group although no data were reported). There were no significant differences between 'E Shu You' and ribavirin in treating influenza, nor in the occurrence of adverse reaction.
AUTHORS' CONCLUSIONS: The present evidence is too weak to support or reject the use of Chinese medicinal herbs for preventing and treating influenza. More RCTs with good methodological quality, larger numbers of participants and clear reporting are needed in the future. We recommend that all the clinical trials registered in the Chinese Clinical Trial Register and Chinese journals join in the Joint Statement of Establishing Chinese Clinical Trial Registration and Publishing System.
Wang C, Cao B, Liu QQ, Zou ZQ, Liang ZA, Gu L, Dong JP, Liang LR, Li XW, Hu K, He XS, Sun YH, An Y, Yang T, Cao ZX, Guo YM, Wen XM, Wang YG, Liu YL, Jiang LD.
Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial.
Ann Intern Med. 2011 Aug 16;155(4):217-25. doi: 10.7326/0003-4819-155-4-201108160-00005.
Abstract/Text
BACKGROUND: Observational studies from Asia suggest that maxingshigan-yinqiaosan may be effective in the treatment of acute H1N1 influenza.
OBJECTIVE: To compare the efficacy and safety of oseltamivir and maxingshigan-yinqiaosan in treating uncomplicated H1N1 influenza.
DESIGN: Prospective, nonblinded, randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00935194)
SETTING: Eleven hospitals from 4 provinces in China.
PATIENTS: 410 persons [corrected] aged 15 to 69 [corrected] years with laboratory-confirmed H1N1 influenza.
INTERVENTION: Oseltamivir, 75 mg twice daily; maxingshigan-yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan-yinqiaosan; or no intervention (control). Interventions and control were given for 5 days.
MEASUREMENTS: Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction.
RESULTS: Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan-yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan-yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan-yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan-yinqiaosan reported nausea and vomiting.
LIMITATIONS: Participants were young and had mild H1N1 influenza virus infection. Missing viral data precluded definitive conclusions about viral shedding.
CONCLUSION: Oseltamivir and maxingshigan-yinqiaosan, alone and in combination, reduced time to fever resolution in patients with H1N1 influenza virus infection. These data suggest that maxingshigan-yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection.
PRIMARY FUNDING SOURCE: Beijing Science and Technology Project and Beijing Nova Program.
Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB.
Reye's syndrome in the United States from 1981 through 1997.
N Engl J Med. 1999 May 6;340(18):1377-82. doi: 10.1056/NEJM199905063401801.
Abstract/Text
BACKGROUND: Reye's syndrome is characterized by encephalopathy and fatty degeneration of the liver, usually after influenza or varicella. Beginning in 1980, warnings were issued about the use of salicylates in children with those viral infections because of the risk of Reye's syndrome.
METHODS: To describe the pattern of Reye's syndrome in the United States, characteristics of the patients, and risk factors for poor outcomes, we analyzed national surveillance data collected from December 1980 through November 1997. The surveillance system is based on voluntary reporting with the use of a standard case-report form.
RESULTS: From December 1980 through November 1997 (surveillance years 1981 through 1997), 1207 cases of Reye's syndrome were reported in patients less than 18 years of age. Among those for whom data on race and sex were available, 93 percent were white and 52 percent were girls. The number of reported cases of Reye's syndrome declined sharply after the association of Reye's syndrome with aspirin was reported. After a peak of 555 cases in children reported in 1980, there have been no more than 36 cases per year since 1987. Antecedent illnesses were reported in 93 percent of the children, and detectable blood salicylate levels in 82 percent. The overall case fatality rate was 31 percent. The case fatality rate was highest in children under five years of age (relative risk, 1.8; 95 percent confidence interval, 1.5 to 2.1) and in those with a serum ammonia level above 45 microg per deciliter (26 micromol per liter) (relative risk, 3.4; 95 percent confidence interval, 1.9 to 6.2).
CONCLUSIONS: Since 1980, when the association between Reye's syndrome and the use of aspirin during varicella or influenza-like illness was first reported, there has been a sharp decline in the number of infants and children reported to have Reye's syndrome. Because Reye's syndrome is now very rare, any infant or child suspected of having this disorder should undergo extensive investigation to rule out the treatable inborn metabolic disorders that can mimic Reye's syndrome.
Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi M.
Acute encephalopathy associated with influenza and other viral infections.
Acta Neurol Scand. 2007 Apr;115(4 Suppl):45-56. doi: 10.1111/j.1600-0404.2007.00809.x.
Abstract/Text
Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthem subitum. It occurs worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy. This article reviews various syndromes of acute encephalopathy by classifying them into three major categories. The first group caused by metabolic derangement consists of various inherited metabolic disorders and the classical Reye syndrome. Salicylate is a risk factor of the latter condition. The second group, characterized by a systemic cytokine storm and vasogenic brain edema, includes Reye-like syndrome, hemorrhagic shock and encephalopathy syndrome, and acute necrotizing encephalopathy. Non-steroidal anti-inflammatory drugs, such as diclofenac sodium and mephenamic acid, may aggravate these syndromes. Severe cases are complicated by multiple organ failure and disseminated intravascular coagulation. Mortality is high, although methylprednisolone pulse therapy may be beneficial in some cases. The third group, characterized by localized edema of the cerebral cortex, has recently been termed acute encephalopathy with febrile convulsive status epilepticus, and includes hemiconvulsion-hemiplegia syndrome and acute infantile encephalopathy predominantly affecting the frontal lobes. Theophylline is a risk factor of these syndromes. The pathogenesis is yet to be clarified, but an increasing body of evidence points to excitotoxicity and delayed neuronal death.
Nagao T, Morishima T, Kimura H, Yokota S, Yamashita N, Ichiyama T, Kurihara M, Miyazaki C, Okabe N.
Prognostic factors in influenza-associated encephalopathy.
Pediatr Infect Dis J. 2008 May;27(5):384-9. doi: 10.1097/INF.0b013e318162a13b.
Abstract/Text
BACKGROUND: Recently, reports of influenza-associated encephalopathy have increased worldwide. Given the high mortality and morbidity rates attributable to this severe neurologic complication of influenza, we conducted a nationwide study in Japan to identify the prognostic factors.
METHODS: We retrospectively evaluated 442 cases of influenza-associated encephalopathy that were reported to the Collaborative Study Group on Influenza-Associated Encephalopathy, which was organized by the Japanese Ministry of Health, Labor, and Welfare in collaboration with hospitals, clinics, and local pediatric practices in Japan between 1998 and 2002. The outcome for each patient was classified as either survival or death. Predictors of death were identified using logistic regression analysis.
RESULTS: Four major prognostic factors for death were found to be significant by multivariate analysis (P < 0.05) in the 184 patients for whom we had complete data: elevation of aspartate aminotransferase, hyperglycemia, the presence of hematuria or proteinuria, and use of diclofenac sodium.
CONCLUSIONS: We identified patients who had factors associated with a poor prognosis, and these findings might be clinically useful for the management of this illness.
Khazeni N, Bravata DM, Holty JE, Uyeki TM, Stave CD, Gould MK.
Systematic review: safety and efficacy of extended-duration antiviral chemoprophylaxis against pandemic and seasonal influenza.
Ann Intern Med. 2009 Oct 6;151(7):464-73. doi: 10.7326/0003-4819-151-7-200910060-00143. Epub 2009 Aug 3.
Abstract/Text
BACKGROUND: Neuraminidase inhibitors (NAIs) are stockpiled internationally for extended use in an influenza pandemic.
PURPOSE: To evaluate the safety and efficacy of extended-duration (>4 weeks) NAI chemoprophylaxis against influenza.
DATA SOURCES: Studies published in any language through 11 June 2009 identified by searching 10 electronic databases and 3 trial registries.
STUDY SELECTION: Randomized, placebo-controlled, double-blind human trials of extended-duration NAI chemoprophylaxis that reported outcomes of laboratory-confirmed influenza or adverse events.
DATA EXTRACTION: 2 reviewers independently assessed study quality and abstracted information from eligible studies.
DATA SYNTHESIS: Of 1876 potentially relevant citations, 7 trials involving 7021 unique participants met inclusion criteria. Data were pooled by using random-effects models. Chemoprophylaxis with NAIs decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], -3.9 percentage points [CI, -5.8 to -1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, -0.4 percentage point [CI, -1.6 to 0.9 percentage point]). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, -0.2 to 0.4 percentage point]), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir.
LIMITATIONS: All trials were industry-sponsored. No study was powered to detect rare adverse events, and none included diverse racial groups, children, immunocompromised patients, or individuals who received live attenuated influenza virus vaccine.
CONCLUSION: Extended-duration zanamivir and oseltamivir chemoprophylaxis seems to be highly efficacious for preventing symptomatic influenza among immunocompetent white and Japanese adults. Extended-duration oseltamivir is associated with increased nausea and vomiting. Safety and efficacy in several subpopulations that might receive extended-duration influenza chemoprophylaxis are unknown.
Doll MK, Winters N, Boikos C, Kraicer-Melamed H, Gore G, Quach C.
Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses.
J Antimicrob Chemother. 2017 Nov 1;72(11):2990-3007. doi: 10.1093/jac/dkx271.
Abstract/Text
OBJECTIVES: To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness.
METHODS: We conducted an SR of SR/MAs of randomized control and/or observational studies. We searched eight electronic databases for SR/MAs that examined the effectiveness or safety of NIs administered for influenza (i.e. influenza-like illness or lab-confirmed) treatment or prophylaxis.
RESULTS: We identified 27 (0.7%) eligible SR/MAs of 3723 articles reviewed. NI (n = 2) or oseltamivir (n = 1) versus no treatment were consistently associated with a decrease in mortality odds among the hospitalized, general population (OR range 0.2 - 0.8). Oseltamivir versus no treatment was associated with a decrease in hospitalization and pneumonia risk/odds in 2/4 SR/MAs. Oseltamivir (n = 4) and zanamivir (n = 3) were consistently associated with a 0.5 - 1 day decrease in symptom duration. Oseltamivir (n = 4) or zanamivir (n = 4) versus no prophylaxis were consistently associated with a decrease in the odds/risk of symptomatic secondary transmission (OR/RR range 0.1 - 0.5). Oseltamivir versus no treatment was consistently associated with a 1.5- to 2.5-fold increase in the odds/risk of nausea (n = 4) and vomiting (n = 5).
CONCLUSIONS: NI treatment is likely to be effective at reducing mortality among hospitalized patients, and symptom duration by up to 1 day in the general population. Oseltamivir or zanamivir prophylaxis are likely to be effective at reducing secondary symptomatic influenza transmission. Increased nausea and vomiting are likely associated with oseltamivir use. We recommend that decisions regarding NI use are made in consideration of potential adverse events, particularly for the general population at low risk of complications. Among hospitalized patients, NI administration seems warranted to reduce mortality risk.
© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Ikematsu H, Hayden FG, Kawaguchi K, Kinoshita M, de Jong MD, Lee N, Takashima S, Noshi T, Tsuchiya K, Uehara T.
Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts.
N Engl J Med. 2020 Jul 23;383(4):309-320. doi: 10.1056/NEJMoa1915341. Epub 2020 Jul 8.
Abstract/Text
BACKGROUND: Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear.
METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018-2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed.
RESULTS: A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out.
CONCLUSIONS: Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.).
Copyright © 2020 Massachusetts Medical Society.
インフルエンザワクチンの効果に関する研究（主任研究者：神谷齊（国立療養所三重病院）.
予防接種実施規則；昭和33年9月17日厚生省令第27号（最終改正：平成25年3月30日厚生労働省令第50号）.
