Influenza in Children: Is Treat Early, Treat Often the Best Strategy?

Weijen Chang, MD; Matthew Garber, MD; Ricardo A. Quinonez, MD

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February 25, 2015

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Editor's Note: This post originally appeared at the Society of Hospital Medicine's blog, The Hospital Leader.

Weijen Chang, MD: Recently, Thomas Frieden, MD, director, US Centers for Disease Control and Prevention (CDC), in response to criticism about the reduced efficacy of this season's influenza vaccination, has been prominently advocating use of antiviral medications (oseltamivir [Tamiflu®] and zanamivir [Relenza®]) for the treatment of influenza infections in adults and children. In short, his philosophy can be paraphrased as, "Treat early, treat late, treat often." This treatment recommendation, however, seems to be swimming upstream against a growing river of evidence that questions the efficacy of influenza antiviral medications, especially in light of an unfavorable adverse effect profile.[1]

The current CDC recommendations advocate treatment with antivirals for all children hospitalized with influenza infection, despite recent studies showing lack of efficacy in otherwise healthy children.

Based on my concerns as a pediatric hospitalist with the recommendations and the lack of evidence, I decided to touch base with two other pediatric hospitalists, Matthew Garber, MD, and Ricardo Quinonez, MD, and I asked them about the use of antiviral medications in the treatment of pediatric influenza infections.

Drs Garber and Quinonez, what do you think is driving Dr Frieden's strong, perhaps non-evidence-based, recommendations for antiviral treatments in influenza infection?

Matthew Garber, MD: This is a difficult question, especially because I don't know Dr Frieden and am unaware of his life experiences, general approach to medicine, how he understands and deals with risk, or various outside pressures he may be under.

I can speak to some underlying psychological biases that most of us share and other issues in evidence-based medicine that may be at play. First you have the original CDC,[2] World Health Organization (WHO),[3] and American Academy of Pediatrics (AAP)[4] recommendations that advocate use of antivirals pretty broadly. If you were to take those recommendations at face value, without critically looking at the evidence and the Cochrane review,[1] you could logically conclude that because this season is predicted to be severe, and the vaccine is not very effective, we need to rely even more heavily on these medicines.

As you know, the best evidence we have—systematic reviews and meta-analyses of randomized controlled trials—including data from methodologically sound, industry-sponsored trials that were withheld from the Cochrane respiratory group for 5 years[5] and tells us that these medications reduce symptoms by about 1 day if given very early in the course of infection. However, there is no evidence that they prevent complications, hospitalizations, or deaths from influenza. Furthermore, even though prophylaxis with antivirals can prevent symptomatic disease in a contact, prophylaxis has not been shown to decrease transmission of the virus (the main impetus for stockpiling these medicines in order to halt an epidemic).

So did the Cochrane review prove that antivirals do not prevent complications, hospitalizations, and death? That is the evidence-based medicine issue I'm talking about. It is very hard to prove a negative. Except in extreme extenuating circumstances, we generally require proof that a drug works before using it—we do not require proof that a drug does not work to avoid using it.

Then there are the psychological issues to take into consideration. People, and perhaps especially doctors, like to help other people. Doctors have been trained that when a patient is sick, we find out what is wrong with him/her and then find the best treatment and administer it. It is very hard for us to say, "Thank you for coming to see me and paying for this visit, but there is really no effective therapy for this condition other than symptomatic relief." We'd much prefer to say, "Aha! You have the flu, and here is the drug that will make you better." Then of course, especially in pediatrics, the patients do get better, which reinforces our behavior. The placebo effect is large, especially in children,[6] which also encourages this type of behavior.

Finally, unfairly, we treat errors of omission differently from errors of commission. If someone complains of nausea and vomiting after receiving oseltamivir, we say, "Well yes, that is a known side effect of that drug." Basically it is the cost of doing business. If we don't give an antiviral and the person becomes very sick, we are often faulted for failing to provide the right treatment and may even be sued. Even our language contributes to overtesting and overtreatment saying things like, "To be conservative you better get that chest x-ray. And just to be safe, let's start that antibiotic or antiviral." When in fact one could argue that the conservative path in the face of uncertainty would be to intervene less, not more. This is partly explained by our failure to consider the harms of our interventions (finding an innocent lesion on the chest x-ray that leads to an invasive procedure; Clostridium difficile infection following antibiotics).[7]

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