Infectious Disease, Pediatric EM

Tamiflu: To Use or Not to Use?

One of the worst flu seasons in recent years sent patients to the ED in droves. It also focused attention on oseltamivir's efficacy and safety in various populations. Is it safe for children? Adults? Immunocompromised patients? 

With the CDC reporting a 36% efficacy rate in the 2017-2018 flu vaccine, an increasing number of both adult and pediatric populations sought care in the ED for influenza-related symptoms and complications.1 CDC reports cite a total of 84 influenza associated pediatric deaths, and a rate of 67.9 influenza related hospitalizations per 100,000 people this 2017-2018 season.1 Currently, the CDC recommends the use of antiviral treatment in children under the age of 2, adults age 65 or older, residents of nursing homes and other chronic care facilities, Native Americans or Alaskan Natives, children younger than age 19 who are receiving long-term aspirin therapy, individuals with a body mass index > 40, women who are pregnant or postpartum (within 2 weeks after delivery), persons with immunosuppression, including that caused by medications or by HIV infection, and individuals with chronic pulmonary (including asthma), cardiovascular (excluding hypertension), renal, hepatic, hematologic (including sickle cell disease), or metabolic disorders (including diabetes mellitus) or neurologic and neurodevelopmental conditions.1

However, with increased morbidity and mortality rates of this season’s influenza viral strains, providers are more likely to prescribe antiviral treatments to previously healthy patients outside of the CDC recommended populations, leading to a nationwide shortage in medications and risk of drug resistance. As contraindications to antiviral therapy are limited to hypersensitivity reactions, the real questions become: who benefits from it and what evidence is necessary to administer treatment?

Children
In addition to CDC recommendations, the American Academy of Pediatrics recommends the consideration of treatment with antiviral therapy for any healthy child with presumed influenza.2 The efficacy and benefit of antiviral therapy in children is widely debated. The latest 2014 Cochrane review reports that in healthy children antiviral therapy reduced the time to first alleviation of symptoms by 29 hours (95% CI, 12-47 hours). However, no effect was seen in asthmatic children. In addition, the review found no evidence of a reduction in hospitalization or serious influenza complications including pneumonia, bronchitis, sinusitis, or ear infection in either healthy or asthmatic children.3

On the other hand, a 2017 systematic review of 5 randomized control trials of 2,561 patients comparing oseltamivir to placebo in children found antiviral therapy reduced duration of illness by 17.6 hours. When excluding patients with asthma, antiviral therapy was shown to reduce duration by 29.2 hours.4 In addition, the risk of subsequent development of otitis media was 34% lower in the antiviral group.4 Similar results were also seen in a large randomized control trial of 695 healthy children, in which duration of illness was reduced by 36 hours, and subsequent development of otitis media was reduced by 44%.5

Studies also have also suggested that early antiviral treatment may reduce the rate of influenza related morbidity. One retrospective trial of 4,447 previously healthy children with physician diagnosed influenza found that children who received oseltamivir were 51.7% less likely to have a subsequent diagnosis of pneumonia.6 This reduction was also associated with a statistically significant decrease in antibiotic use, as well as outpatient and emergency room visits.6

In children with chronic medical conditions (including those with asthma treated with bronchodilators or steroids, and diabetes treated with medication) antiviral therapy was associated with a reduction in hospitalizations 14 days after influenza diagnosis.7 The study, however, did not find any significant reduction in hospitalizations attributable to pneumonia or otitis media.7

The most common statistically significant reductions in hospitalizations 14 days after influenza were found to be related to hypovolemia (30%), other manifestations of influenza (18%), gastrointestinal tract- related causes (15%), and infections (9%), all of which could be influenced by these patients’ chronic medical conditions.7

In children, the use of antiviral therapy has also been associated with a few side effects, with the most common relating to gastrointestinal issues. These issues are typically limited to vomiting, diarrhea, poor appetite, and nausea.4,8 While case reports predominantly from Japan have suggested a relationship between oseltamivir in children and neuropsychiatric events (including delirium, convulsions, and encephalitis),9 this has not been proven in controlled studies or preclinical research.10,11

While there seems to be conflicting data in the literature for the benefits of antiviral therapy in healthy children, most of the data in favor of antiviral therapy cite around a 24 hour reduction in symptom duration, but also an increased risk of gastrointestinal side effects such as nausea, vomiting, and diarrhea.4,5,8 Putting this data into a clinical context, a shortened duration of influenza-related symptoms may be negated by the medication side effects, which are similar to the symptoms themselves. Thus while the evidence does suggest some modest decrease in duration, it may not be clinically relevant.

In addition, in terms of the efficacy of antiviral therapy in preventing complications of influenza, most of the data suggest a decrease risk of otitis media with the use of antiviral therapy;4,5 however, the most serious risk of superimposed bacterial pneumonia is one that was not well quantified. In the Cochrane review trial, of the 107 clinical trials obtained, there were inconsistent definitions of pneumonia: some trials defined pneumonia as a radiologically confirmed consolidation while other trials a more clinical diagnostic criteria was used.3

While the Cochrane trial found that antiviral therapy reduced self- reported unverified pneumonia, in the 5 trials that used a detailed radiological diagnostic definition no reduction was seen.3 Barr et al. found that antiviral use was associated with a decrease in subsequent development of pneumonia, but again this end point was not well- defined. It was also a clinical diagnosis, which may differ between providers.6

In the Pedtro et al study, pneumonia was defined using hospital ICD 10 codes with no strict definitions as to clinically versus radiologically diagnosed disease.7 Thus assessing the efficacy of antivirals in preventing influenza associated pneumonia has been complicated by inconsistencies in diagnostic definitions.

Lastly, when reviewing the literature, there seems to be a gap between the CDC recommendations and the literature evidence on the efficacy of antivirals in asthmatic children. While Cochrane review trial found a modest reduction in symptom duration among healthy children, no effect was evident on asthmatic children.3 In addition, antiviral therapy was not associated with any reduction in influenza complications such as pneumonia or otitis media among children with asthma.3,7 When excluding children with asthma, Malosh et al. found a twofold increase in symptom reduction time in children given antiviral therapy.4

Adults
The recommendation for use of antivirals in previously healthy adults is mostly based on clinical judgment. A meta-analysis of randomized control trials from 2001-2007 of antiviral treatment in outpatient adult population found that in four trials with a total of 1410 participants comparing oseltamivir to placebo in healthy adults; the mean reduction time of symptom resolution to be 0.55 days. At-risk individuals had shortened time to symptom resolution by a mean of 0.74 days for oseltamivir (based on four trials with a total of 1472 participants).12

While results of this study suggest some efficacy in the use of antivirals in not only high risk or healthy adult populations, a meta-analysis of unpublished manufacturer data conducted by the AAFP found that in terms of healthy adults, oseltamivir reduced the time to alleviation of symptoms by 0.7 days, with no differences in hospitalization rates between oseltamivir and placebo. In addition, the study found that vomiting and nausea were increased with treatment and the needed number to harm (NNTH) being 28 in the placebo group and 22 in the oseltamivir group.13 Similarly, a 2014 systematic review of randomized control trials comparing oseltamivir to placebo found that antiviral therapy reduced time to symptom alleviation by 16.8 hours in healthy adults but did not find any difference in hospital admissions. The use of oseltamivir was also associated with an increased risk of psychiatric adverse events (NNTH 94 in placebo vs. 36 in antiviral group), headaches (NNTH 32 in placebo vs. 18 in antiviral group), and nausea (NNTH 25 in placebo vs. 11 in antiviral group).14

The results of these studies suggest that in terms of healthy adults, the benefits of antiviral therapy is limited to reduction in symptoms for less than one day, but may also be associated with adverse effects such as vomiting, nausea, headaches, and psychiatric symptoms.

Immunocompromised
Various studies have reported higher rates of hospital admission and influenza associated complications in immunosuppressed patients, including HIV/AIDS patients, solid organ and bone marrow transplant recipients, chemotherapy and hemodialysis patients, as well as those on chronic systemic corticosteroids.15 In addition, immunocompromised patients exhibited longer lengths of viral shedding with a mean of 19 days vs. 6.4 in healthy patients.16 Initiation of oseltamivir was shown to reduce the progression to pneumonia as well as decreased duration of viral shedding in patients undergoing hematopoietic stem cell transplantations.17,18

Similar results were found in HIV infected patients. A 2009 study of 15 HIV infected school age children with CD4 counts >350, reported decreased viral shedding duration from three to six days as measured by viral culture, potentially reducing transmission rates.19 In addition, a study of 126 HIV infected patients in Mexico City showed that absence of administration of oseltamivir was associated with increased mortality.20 The literature on antiviral treatment among the immunocompromised population is limited with small sample sizes and mostly retrospective studies. While the increased risk of influenza associated complications is well-established in these populations, more evidence is needed to determine the benefit of antivirals in reducing these complications.

Timing of Treatment
Considering efficacy of antiviral therapy among different population subsets, the timing of symptoms also plays a key role in the determination of treatment initiation. A randomized control trial of 1,190 previously healthy individuals in Bangladesh showed that in participants enrolled greater than 48 hours since illness onset there was no difference in duration of symptoms between placebo and treatment groups, while the duration in symptoms was reduced by one day in treated patients who enrolled less than 48 hours since symptoms onset.21 In patients presenting at or before 48 hours of onset, treatment within the first 12 hours reduced median illness duration by 75.4 hours.22 However, in patients with compromised immunity or severely ill requiring hospitalization, treatment up to 5 days after symptom onset was associated with improved survival.23 Timing of treatment not only affects disease course, morbidity, mortality, but also can reduce viral shedding time and thus decrease risk of transmission.24

Antiviral Resistance
While the initiation of antiviral therapy improved disease prognosis and severity in immunocompromised patients, it has also been linked to the development of antiviral resistance. Viral resistance to neuraminidase inhibitors has been reported in multiple immunocompromised patients after prolonged (ranging from 23-75 days) use of antiviral therapy.25,26 While resistance was identified using viral genetic sequencing, it is unknown if such resistance is clinically relevant.

Recommendation Discrepancies
The CDC recommends the use of antiviral therapy in high-risk populations, and advises antiviral therapy can be considered for any previously healthy, symptomatic individual on a basis of clinical judgement. CDC states that “clinical trials and observational data show that early antiviral treatment can shorten the duration of fever and illness symptoms, and may reduce the risk of complications from influenza (ie, otitis media in young children, pneumonia, and respiratory failure).”1

This statement contrasts sharply with that of the FDA, which states that “oseltamivir phosphate does not prevent bacterial infections that may happen with the flu.”27 In addition, the most recent 2017 World Health Organization list of essential medicines has downgraded oseltamivir from a “core” drug to a “complementary” drug, citing that the use of antivirals should be limited to “severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients.”28

In light of the Cochrane review trial and other literature suggesting only modest benefits of antiviral therapy, especially among healthy individuals, there seems to be a shift toward more conservative policies towards the use of these medications. The conflicting recommendations, as well as inconsistency among the literature as to the real benefit of antivirals, has made the practice of prescribing antivirals one that is widely variable and difficult to establish a firm evidence-based approach.


References
1. Centers for Disease Control and Prevention. Estimating Seasonal Influenza-Associated Deaths in the United States.
2. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2017 – 2018. Pediatrics. 2017. 140(4):e20172550.
3. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst Rev. 2014;10(4):CD008965. 
4. Malosh RE, Martin ET, Heikkinen T, Brooks WA, Whitley RJ, Monto AS. Efficacy and safety of oseltamivir in children: systematic review and individual patient data meta-analysis of randomized controlled trials. Clin Infect Dis. 2018;66(10):1492-1500.
5. Whitley RJ, Hayden FG, Reisinger KS, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20(2):127–133.
6. Barr CE, Schulman K, Iacuzio D, et al. Effect of oseltamivir on the risk of pneumonia and use of health care services in children with clinically diagnosed influenza. Curr Med Res Opin. 2007;23(3):523–531.
7. Piedra P, Schulman K, Blumentals W. Effects of oseltamivir on influenza-related complications in children with chronic medical conditions. Pediatrics. 2009;124(1):170–178.
8. Dalvi PS, Singh A, Trivedi HR, Mistry SD, Vyas BR. Adverse drug reaction profile of oseltamivir in children. J Pharmacol Pharmacother. 2011;2(2):100–103.
9. Maxwell SRJ. Tamiflu and neuropsychiatric disturbance in adolescents. BMJ. 2007;334(7606):1232–1233.
10. Urushihara H, Doi Y, Arai M, et al. Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database. PLoS ONE. 2011;6(12):e28483.
11. Toovey S, Rayner C, Prinssen E, et al. Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf. 2008;31(12):1097-1114.
12. Burch J, Corbett M, Stock C, et al. Prescription of anti-influenza drugs for healthy adults: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9(9):537-545.
13. Shaughnessy AF. Oseltamivir Slightly Decreases Influenza Symptom Duration but Not Hospitalizations. Am Fam Physician. 2014;90(7):497.
14. Jefferson Tom, Jones Mark, Doshi Peter, Spencer Elizabeth A, Onakpoya Igho, Heneghan Carl J et al. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ. 2014; 348:g2545.
15. Kunisaki KM, Janoff EN. Influenza in Immunosuppressed Populations: A Review of Infection Frequency, Morbidity, Mortality, and Vaccine Responses. Lancet Infect Dis. 2009;9(8):493–504.
16. Memoli MJ, Athota R, Reed S, et al. The Natural History of Influenza Infection in the Severely Immunocompromised vs Nonimmunocompromised Hosts. Clin Infect Dis. 2014;58(2):214–224.
17. Nichols WG, Guthrie KA, Corey L, Boeckh M. 2004. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39(9):1300–1306.
18. Machado CM, Boas LS, Mendes AV, et al. Use of Oseltamivir to control influenza complications after bone marrow transplantation. Bone Marrow Transplant. 2004;34(2):111-114.
19. Feiterna-Sperling C, Edelmann A, Nickel R, et al. Pandemic Influenza A (H1N1) Outbreak among 15 School-Aged HIV-1-Infected Children. Clin Infect Dis. 2010;51(11):e90-e94.
20. Ormsby CE, de la Rosa-Zamboni D, Vazquez-Perez J, et al. Severe 2009 pandemic influenza A (H1N1) infection and increased mortality in patients with late and advanced HIV disease. AIDS. 2011;25(4):435-439.
21. Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2014;14(2):109–118.
22. Aoki FY, Macleod MD, Paggiaro P, et al. Early administration of oral oseltamivir increases the benefits of influenza treatment. J Antimicrob Chemother. 2003;51(1):123–129.
23. Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012;55(9):1198–1204.
24. Leung YH, et al. Delayed oseltamivir treatment is associated with longer viral shedding of pandemic (H1N1) 2009 virus. Epidemiol Infect. 2012;140(5):814–817.
25. Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of Drug-Resistant Influenza Virus from Immunocompromised Patients: A Case Series. J Infect Dis. 2006;193(6):760-764.
26. Tamura D, DeBiasi RL, Okomo-Adhiambo M, et al. Emergence of Multidrug-Resistant Influenza A(H1N1)pdm09 Virus Variants in an Immunocompromised Child Treated With Oseltamivir and Zanamivir. J Infect Dis. 2015;212(8):1209-1213.
27. Tamiflu (oseltamivir phosphate) Information. Published August 2016.
28. WHO Model Lists of Essential Medicines. March 2017.

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