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{{Influenza}} | {{Influenza}} | ||
{{CMG}} | {{CMG}} | ||
==Overview== | |||
==Cost-Effectiveness of Therapy== | ==Cost-Effectiveness of Therapy== | ||
Influenza produces [[variable cost|direct cost]]s due to lost [[productivity]] and associated medical treatment, as well as [[indirect costs]] of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. However, the economic impact of past pandemics have not been intensively studied, and some authors have suggested that the [[Spanish flu|Spanish influenza]] actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.<ref>Brainerd, E. and M. Siegler (2003), “The Economic Effects of the 1918 Influenza Epidemic”, ''CEPR Discussion Paper'', no. 3791.</ref> Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease [[gross domestic product]] by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.<ref>{{cite journal | author = Poland G | title = Vaccines against avian influenza—a race against time. | url=http://content.nejm.org/cgi/content/full/354/13/1411 | journal = N Engl J Med | volume = 354 | issue = 13 | pages = 1411–3 | year = 2006 | id = PMID 16571885}}</ref> | Influenza produces [[variable cost|direct cost]]s due to lost [[productivity]] and associated medical treatment, as well as [[indirect costs]] of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. However, the economic impact of past pandemics have not been intensively studied, and some authors have suggested that the [[Spanish flu|Spanish influenza]] actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.<ref>Brainerd, E. and M. Siegler (2003), “The Economic Effects of the 1918 Influenza Epidemic”, ''CEPR Discussion Paper'', no. 3791.</ref> Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease [[gross domestic product]] by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.<ref>{{cite journal | author = Poland G | title = Vaccines against avian influenza—a race against time. | url=http://content.nejm.org/cgi/content/full/354/13/1411 | journal = N Engl J Med | volume = 354 | issue = 13 | pages = 1411–3 | year = 2006 | id = PMID 16571885}}</ref> | ||
===Antiviral Drugs=== | |||
Randomized, controlled trials conducted primarily among persons with mild illness in outpatient settings have demonstrated that zanamivir or oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day when administered within 48 hours of illness onset compared with placebo<ref name="pmid9302301">{{cite journal| author=Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG et al.| title=Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. | journal=N Engl J Med | year= 1997 | volume= 337 | issue= 13 | pages= 874-80 | pmid=9302301 | doi=10.1056/NEJM199709253371302 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9302301 }} </ref><ref name="pmid10395837">{{cite journal| author=Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T et al.| title=Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections. | journal=J Infect Dis | year= 1999 | volume= 180 | issue= 2 | pages= 254-61 | pmid=10395837 | doi=10.1086/314904 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10395837 }} </ref><ref name="pmid10866439">{{cite journal| author=Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH et al.| title=Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group. | journal=Lancet | year= 2000 | volume= 355 | issue= 9218 | pages= 1845-50 | pmid=10866439 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10866439 }} </ref><ref name="pmid11224828">{{cite journal| author=Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D et al.| title=Oral oseltamivir treatment of influenza in children. | journal=Pediatr Infect Dis J | year= 2001 | volume= 20 | issue= 2 | pages= 127-33 | pmid=11224828 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11224828 }} </ref> | |||
*One randomized, controlled trial of oseltamivir treatment among 408 children aged 1--3 years reported that when oseltamivir was started within 24 hours of illness onset, the median time to illness resolution was shortened by 3.5 days compared with placebo [143]. | |||
*Minimal or no benefit was reported in healthy children and adults when antiviral treatment was initiated more than 2 days after onset of uncomplicated influenza. | |||
*The amount of influenza viral shedding was reduced among those treated, but studies on whether the duration of viral shedding is reduced have been inconsistent <ref name="pmid18230677">{{cite journal| author=Carrat F, Vergu E, Ferguson NM, Lemaitre M, Cauchemez S, Leach S et al.| title=Time lines of infection and disease in human influenza: a review of volunteer challenge studies. | journal=Am J Epidemiol | year= 2008 | volume= 167 | issue= 7 | pages= 775-85 | pmid=18230677 | doi=10.1093/aje/kwm375 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18230677 }} </ref><ref name="pmid20558368">{{cite journal| author=Cowling BJ, Chan KH, Fang VJ, Lau LL, So HC, Fung RO et al.| title=Comparative epidemiology of pandemic and seasonal influenza A in households. | journal=N Engl J Med | year= 2010 | volume= 362 | issue= 23 | pages= 2175-84 | pmid=20558368 | doi=10.1056/NEJMoa0911530 | pmc=PMC4070281 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20558368 }} </ref><ref name="pmid9449698">{{cite journal| author=Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE| title=Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. | journal=J Clin Invest | year= 1998 | volume= 101 | issue= 3 | pages= 643-9 | pmid=9449698 | doi=10.1172/JCI1355 | pmc=PMC508608 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9449698 }} </ref><ref name="pmid10517426">{{cite journal| author=Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M et al.| title=Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. | journal=JAMA | year= 1999 | volume= 282 | issue= 13 | pages= 1240-6 | pmid=10517426 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10517426 }} </ref><ref name="pmid16220098">{{cite journal| author=Sato M, Hosoya M, Kato K, Suzuki H| title=Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors. | journal=Pediatr Infect Dis J | year= 2005 | volume= 24 | issue= 10 | pages= 931-2 | pmid=16220098 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16220098 }} </ref> and the temporal and causal relationships between changes in influenza viral shedding and clinical outcomes have not been well-established. | |||
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*One evidence review concluded that neuraminidase inhibitors were not effective in reducing the severity or duration of ILI (defined as acute respiratory infection with fever and cough). | |||
*However, a variety of pathogens can cause ILI besides influenza viruses, and this review did not conclude that neuraminidase inhibitors were ineffective in reducing laboratory-confirmed influenza among adults [146, 147]. | |||
*Data are limited about the effectiveness of zanamivir and oseltamivir treatment in preventing serious influenza-related complications (e.g., bacterial or viral pneumonia or exacerbation of chronic diseases). | |||
*In a study that combined data from 10 clinical trials, the risk for pneumonia among those participants with laboratory-confirmed influenza receiving oseltamivir treatment was approximately 50% lower than among those persons receiving a placebo and 34% lower among patients at risk for complications (p is less than 0.05 for both comparisons) [22]. | |||
*Although a similar significant reduction also was determined for hospital admissions among the overall group, the 50% reduction in hospitalizations reported in the small subset of high-risk participants was not statistically significant [22]. | |||
One randomized, controlled trial found a decreased incidence of otitis media among children treated with oseltamivir [21]. | |||
*A randomized, controlled trial among children aged 1--3 years found an 85% reduction in acute otitis media when oseltamivir treatment was started within 12 hours of illness onset, but no reduction when treatment was started more than 24 hours from symptom onset [143]. | |||
*Another randomized, controlled study conducted among influenza virus-infected children with asthma reported greater improvement in lung function and fewer asthma exacerbations among oseltamivir-treated children compared with those who received placebo but did not determine a difference in symptom duration [148]. | |||
*Insufficient data exist regarding the effectiveness of any of the influenza antiviral drugs for use among children aged younger than 1 year. | |||
Observational studies have determined that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza. A large prospective observational study assessed clinical outcomes among 327 hospitalized adults with laboratory-confirmed influenza whose health-care provider chose to use oseltamivir treatment compared with untreated influenza patients. The average age of adults in this study was 77 years, and 71% began treatment more than 48 hours after illness onset. In a multivariate analysis, oseltamivir treatment was associated with a significantly decreased risk for death within 15 days of hospitalization (odds ratio [OR] = 0.2; 95% CI = 0.1--0.8). Benefit was observed even among those starting treatment more than 48 hours after symptom onset. However, oseltamivir treatment did not reduce either the duration of hospitalization or 30-day mortality after hospitalization significantly. An additional 185 hospitalized children with laboratory-confirmed influenza were identified during this study, but none received antiviral treatment, and no assessment of outcomes based on receipt of antiviral treatment of hospitalized children could be made [23]. A study in Thailand of patients with laboratory-confirmed influenza also found a significant (OR = 0.13 (95% CI = 0.04--0.40) reduction in mortality among patients who received oseltamivir treatment [149]. A retrospective cohort study of 99 hospitalized persons (median age: 70 years) with laboratory-confirmed influenza who received oseltamivir indicated that persons who received oseltamivir treatment more than 48 hours from illness onset had a median length of stay of 6 days, compared with 4 days for persons who received oseltamivir within 48 hours of symptom onset (p is less than 0.0001) [26], and a subsequent analysis of these data showed benefit for patients who received oseltamivir up to 96 hours after illness onset [27]. A prospective study of 754 hospitalized adults (mean age: 70 years) with laboratory-confirmed seasonal influenza reported that oseltamivir treatment initiated within 2 days was associated with earlier hospital discharge, and improved survival was observed when oseltamivir was administered within 4 days from illness onset [150]. One small observational study found that treatment of persons with leukemia who acquired influenza was associated with a decreased risk for death [151]. | |||
In one observational study, oseltamivir treatment of young adults with mild illness from 2009 H1N1 virus infection was reported to reduce the development of radiographically confirmed pneumonia, and initiation of treatment within 2 days of onset reduced the duration of fever and viral RNA shedding [152]. Earlier neuraminidase inhibitor treatment was associated with less severe disease, and any neuraminidase inhibitor treatment had a survival benefit in observational studies of patients hospitalized with 2009 H1N1 virus infection [6, 12, 65, 153, 154]. However, additional data on the impact of antiviral treatment on severe outcomes are needed. | |||
More clinical data are available concerning the efficacy of zanamivir and oseltamivir for treatment of influenza A virus infection than for treatment of influenza B virus infection. Data from human clinical studies have indicated that zanamivir and oseltamivir have activity against influenza B viruses [21, 116, 145, 155, 156]. However, an observational study among Japanese children with culture-confirmed influenza and treated with oseltamivir demonstrated that children with influenza A virus infection resolved fever and stopped shedding virus more quickly than children with influenza B, suggesting that oseltamivir might be less effective for the treatment of influenza B [157]. | |||
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===Vaccination=== | |||
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Because live attenuated influenza vaccine (LAIV) (nasal spray) vaccine was licensed more recently than inactivated vaccines, there are more data available on its effects from large randomized trials. For example, a RCT conducted among 1,602 healthy children initially aged 15–71 months assessed the efficacy of trivalent LAIV against culture-confirmed influenza during two seasons (Belshe et al., 1998; 2000). In season one, when vaccine and circulating virus strains were well-matched, efficacy in preventing laboratory-confirmed illness from influenza was 93% for participants who received two doses of LAIV. In season two, when the A (H3N2) component was not well-matched between vaccine and circulating virus strains, efficacy was 86% overall. | |||
A randomized, double-blind, placebo-controlled trial among 4,561 healthy working adults aged 18–64 years assessed multiple endpoints (i.e., targeted outcome measures), including reductions in self-reported respiratory tract illness without laboratory confirmation, absenteeism, health care visits, use of antibiotics, and use of over-the-counter medications for illness symptoms during peak and total influenza outbreak periods (Nichol et al., 1999). The study was conducted during the 1997-1998 influenza season, when the influenza vaccine and circulating A (H3N2) viruses were poorly matched. Vaccination was associated with reductions in severe febrile illnesses of 19%, and febrile upper respiratory tract illnesses of 24%. | |||
Vaccination was also associated with fewer days of illness, fewer days of work lost, fewer days with health care provider visits, and reduced use of prescription antibiotics and over-the-counter medications. Among a subset of 3,637 healthy adults aged 18–49 years, LAIV recipients (n = 2,411) had 26% fewer febrile upper-respiratory illness episodes; 27% fewer lost work days as a result of febrile upper respiratory illness; and 18%–37% fewer days of health care provider visits caused by febrile illness, compared with placebo recipients (n = 1,226). Days of antibiotic use were reduced by 41%–45% in this age subset. | |||
Few studies that directly compare live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) have been conducted, and results appear to differ for adults and children. More data are available for children than for adults. Among children, each of three RCTs comparing inactivated and live vaccines demonstrated that live vaccine offered better protection than inactivated vaccine. However, none of the studies included a placebo group, so the absolute efficacies of the two vaccines could not be assessed. One study included 2,187 children aged 6–71 months who had recurrent respiratory tract infections (Ashkenazi et al., 2006) and found overall influenza rates of 2.3% among live vaccine recipients and 4.8% for TIV, for a 52.7% decrease in children receiving live vaccine compared to those receiving inactivated vaccine. In a randomized study of 2,229 children aged 6–17 years with asthma, 4.1% of live vaccine recipients and 6.2% of TIV recipients developed influenza, for a relative reduction of 34.7% (Fleming et al., 2006). Finally, in 2004-2005 a multinational RCT was conducted among 8,352 children aged 6–59 months (Belshe et al., 2007). For the primary endpoint in this trial, culture-confirmed influenza-like illness, there were 45% fewer cases of influenza for well-matched influenza strains and 58% fewer for mismatched strains among live versus inactivated vaccine recipients. | |||
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===Chemoprophylaxis=== | |||
In randomized, placebo-controlled trials, both oseltamivir and zanamivir were efficacious in the prevention of influenza illness among persons administered chemoprophylaxis after a household member or other close contact had laboratory-confirmed influenza (zanamivir: 72%--82%; oseltamivir: 68%--89%) [13, 14, 17, 18, 141, 178, 179]. Postexposure chemoprophylaxis with neuraminidase inhibitors generally should be reserved for those who have had recent close contact with a person with influenza. Persons who can be considered for antiviral chemoprophylaxis include family or other close contacts of a person with a suspected or confirmed case who are at higher risk for influenza complications but have not been vaccinated against the influenza virus strains circulating at the time of exposure [28, 105]. Unvaccinated health-care workers who have occupational exposures and who did not use adequate personal protective equipment at the time of exposure are also potential candidates for chemoprophylaxis [28]. Because of widespread resistance among currently circulating influenza A virus strains and inherent nonsusceptibility among influenza B viruses, adamantanes have limited use in the prevention of influenza. Persons who receive an antiviral medication for chemoprophylaxis might still acquire influenza virus infection and be potentially able to transmit influenza virus, even if clinical illness is prevented [180, 181]. Development of illness caused by oseltamivir resistant 2009 H1N1 virus infection has been reported among persons receiving oseltamivir chemoprophylaxis [115], and one report of a small community cluster indicates that person-to-person transmission is possible among healthy persons who are not receiving oseltamivir [112]. | |||
==References== | ==References== | ||
Revision as of 17:40, 29 October 2014
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Cost-Effectiveness of Therapy
Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. However, the economic impact of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[1] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease gross domestic product by 5%. Additional costs would come from medical treatment of 18 million to 45 million people, and total economic costs would be approximately $700 billion.[2]
Antiviral Drugs
Randomized, controlled trials conducted primarily among persons with mild illness in outpatient settings have demonstrated that zanamivir or oseltamivir can reduce the duration of uncomplicated influenza A and B illness by approximately 1 day when administered within 48 hours of illness onset compared with placebo[3][4][5][6]
- One randomized, controlled trial of oseltamivir treatment among 408 children aged 1--3 years reported that when oseltamivir was started within 24 hours of illness onset, the median time to illness resolution was shortened by 3.5 days compared with placebo [143].
- Minimal or no benefit was reported in healthy children and adults when antiviral treatment was initiated more than 2 days after onset of uncomplicated influenza.
- The amount of influenza viral shedding was reduced among those treated, but studies on whether the duration of viral shedding is reduced have been inconsistent [7][8][9][10][11] and the temporal and causal relationships between changes in influenza viral shedding and clinical outcomes have not been well-established.
Vaccination
Chemoprophylaxis
In randomized, placebo-controlled trials, both oseltamivir and zanamivir were efficacious in the prevention of influenza illness among persons administered chemoprophylaxis after a household member or other close contact had laboratory-confirmed influenza (zanamivir: 72%--82%; oseltamivir: 68%--89%) [13, 14, 17, 18, 141, 178, 179]. Postexposure chemoprophylaxis with neuraminidase inhibitors generally should be reserved for those who have had recent close contact with a person with influenza. Persons who can be considered for antiviral chemoprophylaxis include family or other close contacts of a person with a suspected or confirmed case who are at higher risk for influenza complications but have not been vaccinated against the influenza virus strains circulating at the time of exposure [28, 105]. Unvaccinated health-care workers who have occupational exposures and who did not use adequate personal protective equipment at the time of exposure are also potential candidates for chemoprophylaxis [28]. Because of widespread resistance among currently circulating influenza A virus strains and inherent nonsusceptibility among influenza B viruses, adamantanes have limited use in the prevention of influenza. Persons who receive an antiviral medication for chemoprophylaxis might still acquire influenza virus infection and be potentially able to transmit influenza virus, even if clinical illness is prevented [180, 181]. Development of illness caused by oseltamivir resistant 2009 H1N1 virus infection has been reported among persons receiving oseltamivir chemoprophylaxis [115], and one report of a small community cluster indicates that person-to-person transmission is possible among healthy persons who are not receiving oseltamivir [112].
References
- ↑ Brainerd, E. and M. Siegler (2003), “The Economic Effects of the 1918 Influenza Epidemic”, CEPR Discussion Paper, no. 3791.
- ↑ Poland G (2006). "Vaccines against avian influenza—a race against time". N Engl J Med. 354 (13): 1411–3. PMID 16571885.
- ↑ Hayden FG, Osterhaus AD, Treanor JJ, Fleming DM, Aoki FY, Nicholson KG; et al. (1997). "Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group". N Engl J Med. 337 (13): 874–80. doi:10.1056/NEJM199709253371302. PMID 9302301.
- ↑ Monto AS, Fleming DM, Henry D, de Groot R, Makela M, Klein T; et al. (1999). "Efficacy and safety of the neuraminidase inhibitor zanamivirin the treatment of influenza A and B virus infections". J Infect Dis. 180 (2): 254–61. doi:10.1086/314904. PMID 10395837.
- ↑ Nicholson KG, Aoki FY, Osterhaus AD, Trottier S, Carewicz O, Mercier CH; et al. (2000). "Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group". Lancet. 355 (9218): 1845–50. PMID 10866439.
- ↑ Whitley RJ, Hayden FG, Reisinger KS, Young N, Dutkowski R, Ipe D; et al. (2001). "Oral oseltamivir treatment of influenza in children". Pediatr Infect Dis J. 20 (2): 127–33. PMID 11224828.
- ↑ Carrat F, Vergu E, Ferguson NM, Lemaitre M, Cauchemez S, Leach S; et al. (2008). "Time lines of infection and disease in human influenza: a review of volunteer challenge studies". Am J Epidemiol. 167 (7): 775–85. doi:10.1093/aje/kwm375. PMID 18230677.
- ↑ Cowling BJ, Chan KH, Fang VJ, Lau LL, So HC, Fung RO; et al. (2010). "Comparative epidemiology of pandemic and seasonal influenza A in households". N Engl J Med. 362 (23): 2175–84. doi:10.1056/NEJMoa0911530. PMC 4070281. PMID 20558368.
- ↑ Hayden FG, Fritz R, Lobo MC, Alvord W, Strober W, Straus SE (1998). "Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense". J Clin Invest. 101 (3): 643–9. doi:10.1172/JCI1355. PMC 508608. PMID 9449698.
- ↑ Hayden FG, Treanor JJ, Fritz RS, Lobo M, Betts RF, Miller M; et al. (1999). "Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment". JAMA. 282 (13): 1240–6. PMID 10517426.
- ↑ Sato M, Hosoya M, Kato K, Suzuki H (2005). "Viral shedding in children with influenza virus infections treated with neuraminidase inhibitors". Pediatr Infect Dis J. 24 (10): 931–2. PMID 16220098.