Podcast: Play in new window | Download

Subscribe: RSS

Date: February 27, 2023

Reference: Walsh PS, Schnadower D, Zhang Y, Ramgopal S, Shah SS, Wilson PM. Association of early oseltamivir with improved outcomes in hospitalized children with influenza, 2007-2020. JAMA Pediatr. 2022.

Guest Skeptic: Dr. Marisu Rueda-Altez is a pediatric infectious disease fellow at Children’s National Hospital in Washington, DC. She is also the President of the Junior Section of the Society for Pediatric Research.

Dr. Marisu Rueda-Altez

Case: A 5-year-old child presents to the emergency department in the midst of flu season with three days of fever, upper respiratory symptoms, and malaise. His parents also report that he has lost his appetite and refusing to drink liquids. Nasopharyngeal PCR testing is positive for Influenza A. On physical exam, he is tired appearing and showing signs of respiratory distress with tachypnea and accessory muscle use. His lips look dry and cracked. His oxygen saturation is hovering around 88-90%. His chest radiograph does not demonstrate any focal opacities. After a discussion with his parents, you all agree that it is best for him to be admitted to the for IV hydration and close monitoring. His parents ask you, “A few years ago when we had the flu, we took a medication that helped reduce the length of our symptoms. Would he benefit from that too?”

Background: Oseltamivir is recommended by the American Academy of Pediatrics, Infectious Diseases Society of America and Center for Disease Control and Prevention for the treatment of influenza in both adults and children. [1-3] Possible benefits include reduction in duration of symptoms and improvement of outcomes in hospitalized patients. Most of these recommendations are based on data from adult studies during the H1N1 pandemic with limited pediatric data.

The SGEM has covered the use of oseltamivir for influenza on SGEM #98 and SGEM #312. Despite the recommendations from these various organizations, there remains some controversy (and skepticism) about the use of oseltamivir due to unpublished trial data, lack of access to the research data by the authors, and ghost-written papers. The BMJ was involved in a long legal battle with the manufacturer that you can read about here. Suffice it to say, that there were more harms than originally reported (including nausea and vomiting, neuropsychiatric events, headaches), and it is possible that the potential benefits were exaggerated.[4]

Clinical Question: Will early administration of oseltamivir reduce length of hospitalization and complications of influenza infection?

Reference: Walsh PS, Schnadower D, Zhang Y, Ramgopal S, Shah SS, Wilson PM. Association of early oseltamivir with improved outcomes in hospitalized children with influenza, 2007-2020. JAMA Pediatr. 2022.

  • Population: Children <18 year from Pediatric Health Information System (PHIS) database hospitalized with Influenza from 2007-2020.
    • Excluded: Transfers to other hospitals, repeated encounters (if >7 days between encounters, picked one at random; if <7 days, picked the first one), death/ECMO on day 0 or 1 to avoid immortal time bias.
  • Exposure: Early administration of oseltamivir (HD 0 or 1)
  • Comparison: Late administration of oseltamivir (HD 2 or later) or none.
  • Outcome:
    • Primary Outcome: Hospital length of stay (LOS)
    • Secondary Outcomes: 7-day hospital readmission, late ICU transfer (on or after hospital day 2 after being admitted to general ward), composite outcome of in-hospital death or ECMO use.

Authors’ Conclusions: “Early use of oseltamivir is associated with shorter hospital stay and lower odds of 7-day readmission, ICU transfer, ECMO use and death.”

Quality Checklist for Observational Study:

  1. Did the study address a clearly focused issue? Yes
  2. Did the authors use an appropriate method to answer their question? Unsure.
  3. Was the cohort recruited in an acceptable way? Unsure
  4. Was the exposure accurately measured to minimize bias? Unsure
  5. Was the outcome accurately measured to minimize bias? Yes
  6. Have the authors identified all-important confounding factors? Unsure
  7. Was the follow up of subjects complete enough? Unsure
  8. How precise are the results? Unsure
  9. Do you believe the results? Yes
  10. Can the results be applied to the local population? Yes
  11. Do the results of this study fit with other available evidence? Yes
  12. Funding of the Study: None

Results: There were 55,799 patients were included, who were diagnosed with influenza by ICD 9/10 coding. Of those, 56% were male, and mean age was 3.6 years. 33,207 (59.5%) received early oseltamivir. 4,098 (7%) received oseltamivir on day 2 or later, and 18,494 (33%) were untreated.

Key Result: Children treated with early oseltamivir was associated with a shorter length of stays and lower odds of 7-day readmission, late ICU transfer, ECMO use, and death.

  • Primary Outcome

Length of Stay

  • Secondary Outcomes

  1. The Diagnosis of Influenza: The diagnosis of influenza for this study was determined by review of ICD-9 and 10 codes. The authors do cite previous research that administrative databases have high specificity (99%) and positive predictive value (60-88%) for laboratory-confirmed influenza, these two studies only looked at records from one or three institutions respectively. [5-6] The data set used in this study is significantly larger and encompasses 36 hospitals where there may be much more variation in diagnosis and coding. The gold standard for diagnosis of influenza infection is a positive nasopharyngeal PCR test. Patients could have been missed if positive and not coded as such. Also, patients who were not tested but had symptoms suggestive of influenza could have been coded as having influenza. Using ICD codes is an imperfect gold standard or copper standard. There is also possible confusion from lingering positivity of respiratory viral PCR testing as well. There was a study showed that influenza can remained positive for at least a week after symptom onset. [7] If a patient who had influenza a week ago presents now with new respiratory distress, still influenza positive, but now had a bacterial superinfection with S. pneumoniae or S. aureus. Those patients would not benefit from oseltamivir, but may still have erroneously have been coded as influenza positive, and included in the study.
  2. Duration of Illness and Timing of Oseltamivir: We had mentioned a big limitation of the PHIS database before on SGEM #384 was that it lacks clinical information. With influenza, the recommendations state that the greatest benefit in the administration of antivirals is within the first 48 hours of symptoms. However, there may still be some benefit in hospitalized patients after that period. There’s a possibility that a portion of the providers that did not treat those 33% of patients with oseltamivir may have been influenced by the duration of illness prior to presentation. Not only do we not know when the illness started, but we also don’t know when the child got started on oseltamivir prior to their presentation at the hospital. This may be the reason for why they did not receive it again during the admission. This also raises the possibility that there was a portion of patients were classified into the “early oseltamivir” group inappropriately.
  3. Exclusion due to Immortal Time Bias: The authors chose to exclude encounters with discharge, in-hospital death, or ECMO use on hospital day 0 or 1 due to immortal time bias (there is a period of time before researchers are able to classify participants as being treated). This excluded 13,641(19.2%) of eligible patients. Given the limitations mentioned prior, another interpretation of this is that there were potentially 13,641 patients for which oseltamivir had no impact on their hospital length of stay, death or ECMO.
  4. Adverse Effects: Another thing missing from this study is that it did not report any adverse effects from oseltamivir administration. The Cochrane review from 2014 that included clinical study reports from drug manufacturers demonstrated that the use of oseltamivir increases risk of nausea, vomiting (NNH of 19 in children), and psychiatric effects. Adverse effects are important when weighing the potential risks and benefits of any treatment or intervention.
  5. Future Research: The authors write “it would likely be unethical to perform a RCT of oseltamivir given the current recommendations, so observational studies such as this one are the most practical way to evaluate its use.” Observational trials allow us to establish associations and can only control for known confounding factors. I think it is fair to say that the evidence for oseltamivir is mixed at best and still very limited in the pediatric population. We should not shy away from questioning clinical guidelines or standards of care. This is important for driving progress and striving to provide the best care for our patients based on the best evidence. I do not find the idea of a randomized controlled trial unethical and would love to see a multi-center, placebo-controlled, blinded randomized controlled trial to assess the effectiveness of oseltamivir in the pediatric population.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: Early oseltamivir use in hospitalized children with influenza may be associated with shorter hospital LOS, and lower odds of 7-day readmission, ICU transfers, ECMO use and death but these findings should be interpreted within the limitations of study.

SGEM Bottom Line: We do not have high-quality evidence to support the routine use of oseltamivir in the treatment of children admitted to hospital with suspected influenza.

Case Resolution: You tell the parents that there is an option to start their child on a medication called oseltamivir. You discuss the potential benefits and potential harms with the family and the admitting team and come to the shared decision. The child is admitted to the hospital and started on oral oseltamivir.

Clinical Application:

Dr. Rueda-Altez and I had differing opinions on how this study would affect our practice.

Dr. Rueda-Altez concluded:

Oseltamivir should be administered as early as possible after the diagnosis of influenza in hospitalized children, especially for patients at high risk for complications. Although the evidence for children is not as strong as for adults, given the low rates of severe complications in pediatrics, the low risk of the intervention, and additional benefits (reduction in duration of symptoms) justify initiation.

I offered another perspective:

I do not find the evidence for the efficacy of oseltamivir as strong or convincing as others may. This was a retrospective observation study with many excluded patients, a fuzzy diagnosis, unblinded, unmeasured confounders. In circumstances where we may be uncertain of the exact benefits and risks of a treatment, we should be candid with our patients and families and admit that uncertainty. It can actually help build rapport and trust and lead to much richer shared-decision making.

The literature is only one pillar of EBM. We still must consider clinical judgement and the patient/family’s values and preference. So even though we might not agree on everything, we both enjoyed our conversation and learned from one another.

What Do I Tell My Patient? There is a medication called oseltamivir that has some data to show that it may decreases symptom duration in influenza. It may also reduce the time you have to stay in the hospital and other complications, but we really are not certain. On the other hand, it can cause side effects like vomiting, headache, and neuropsychiatric effects like confusion or abnormal behavior. We can discuss what you all would prefer to do.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.

References:

  1. COMMITTEE ON INFECTIOUS DISEASES. Recommendations for prevention and control of influenza in children, 2022-2023. Pediatrics. 2022;150(4):e2022059275.
  2. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Infect Dis. 2019;68(6):895-902.
  3. Influenza Antiviral Medications: Summary for Clinicians. Centers for Disease Control and Prevention. Updated Sept 9, 2022. Accessed Feb 10, 2023. https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm
  4. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst Rev. 2014;2014(4):CD008965.
  5. Keren R, Wheeler A, Coffin SE, Zaoutis T, Hodinka R, Heydon K. Icd-9 codes for identifying influenza hospitalizations in children. Emerg Infect Dis. 2006;12(10):1603-1604.
  6. Feemster KA, Leckerman KH, Middleton M, et al. Use of administrative data for the identificationof laboratory-confirmed influenza infection: the validity ofinfluenza-specific icd-9 codes. J Pediatric Infect Dis Soc. 2013;2(1):63-66.
  7. Leekha S, Zitterkopf NL, Espy MJ, Smith TF, Thompson RL, Sampathkumar P. Duration of influenza A virus shedding in hospitalized patients and implications for infection control. Infect Control Hosp Epidemiol. 2007;28(9):1071-1076.