In January, it was reported that 29 children had died from influenza nationwide1. More recently, the CDC reported that through February 2 pediatric deaths had increased to 59. Such numbers cause the public to cry out that the medical community do more to prevent these catastrophes. But can these cases be prevented? As awful as it sounds, I have to say that I doubt it.
It’s tragic to lose even one child. However, we have to take a hard look at the numbers and not allow emotions to dictate our medical response. The truth is that influenza is a nasty disease. And tragically, but rarely, for patients with very robust immune responses, systemic inflammatory response creates an unsurvivable cascade of inflammation and end organ injury. For the vast majority of cases, management strategies are fairly simple, but very limited. In fact, our approach to this disease hasn’t changed since the flu pandemic of 2009. It’s also true that from a cold, hard epidemiological perspective, 29 or even 59 pediatric deaths among the millions with influenza or influenza-like illnesses is actually a relatively small number.
We need to respond quickly and decisively to combat the flu, but we need to fight the temptation to use ineffective tools simply because they are the only pharmacological options available. Vaccination, surveillance and recognizing population subsets at risk for complications are tools that work.
I’m talking about Tamiflu (Oseltamivir), which is really the only treatment option beyond detection and identification of those at risk for complications. On one hand it would seem easy: The patient has the disease, we can treat it with a drug, so you prescribe it.
However, what have we learned from treating millions with this drug in 2009? First, we saw how difficult – and suspect – it was to gauge success. The original research indicated that Tamiflu had to be given within the first 48 hours of symptom onset to have even marginal benefit. But instead of using reduction of viral load as the measure of success, reduction of symptoms was the marker. Given the variability among patients in the time from exposure to the onset of symptoms, 48 hours becomes quite an arbitrary time period by which to judge success. Put it all together and it begins to look suspect: We judged the effectiveness of a medication by using reduction of symptoms as an end point, and found a marginal benefit only within a very narrow time, when symptom onset was highly variable.
This would all be a meaningless discussion if there was not a downside to giving Tamiflu. Side effects are admittedly uncommon, but they are much more common than originally thought before 2009. The most common side effect is nausea. Now, if oseltamivir is largely used for symptomatic treatment, one must question whether the risk of inducing nausea is worth the marginal benefit the drug may provide. The odds ratio (OR) of inducing nausea has been reported to be 1.79 for those taking Tamiflu2.
And then there is the issue of the expense. After Tamiflu’s release in 1999 it dominated the market. By 2009, $3 billion of Tamiflu was sold worldwide3. If the drug provides meaningful benefit, it’s probably worth every dollar spent. If not, it’s just another way to waste healthcare dollars. But the biggest downside may be neither side effects nor wasted healthcare dollars.
Just as we have seen antibiotic resistance from excessive and inappropriate antibiotic prescribing, influenza resistance to Tamiflu is being reported4. In addition, this early resistance may be resulting in more complications such as pneumonia. In a meta-analysis from McMaster University, 19 studies reported antiviral resistance, with a pooled incidence rate for Tamiflu resistance of 2.6%. A meta-analysis of 4 studies showed a statistically significant risk ratio of 4.2 for an association between Tamiflu resistance and pneumonia5.
So, are physicians being educated regarding Tamiflu’s appropriate use? If they are, I’m not seeing it. In response to anti-viral resistance, one study looked at combining antivirals. But this type of study fails to address whether the antivirals are needed in the first place6.
At least when antibiotics are prescribed with appropriate indication, there is usually real patient and public health benefit. Even the CDC admits “When used for treatment [of influenza], antiviral drugs can lessen symptoms and shorten the time you are sick by 1-2 days.” Is such a benefit worth the potential of the viral mutation fallout? I personally am not interested in seeing flu strains next year that are resistant to multiple antivirals, particularly when we barely nudge the natural course of this disease when we use them7.
To be fair, some have reported that in addition to Tamiflu’s ability to reduce symptoms, when treating index patients it may reduce disease transmission, similar to Pertussis. Unfortunately, the data is not so convincing. Prophylaxing close household contacts has only modest benefit.
Furthermore, the assumption that Tamiflu prevents severe complications such as pneumonia just hasn’t been proven. While there is evidence on both sides of the discussion, a Cochrane database review summarized their response to this question in this way: “Eight unpublished studies on complications were ineligible and therefore excluded. The remaining evidence suggests oseltamivir did not reduce influenza related lower respiratory tract complications (risk ratio 0.55, 95% confidence interval 0.22 to 1.35)8.
There are always two sides to any story. However, it seems that we have lost our objectivity in the widespread acceptance of this drug. It is available and provides us with the ability to do something that we all want, and which our patients often demand. However, what is the quality of evidence supporting its use? A systematic review and meta-analysis by Hsu reported that in 51 studies which compare oseltamivir to placebo, the quality of data is low to very low for the majority of outcomes measures9.
Tamiflu is indicated for influenza, but does it really make a difference? It may be just another expensive drug looking for a disease. I recognize that to a certain degree the train may have already left the station on this. But if we use this drug for high-risk cases only, thus reducing resistance rates and providing a marginal benefit to those who stand most to benefit, Tamiflu may make more sense.
At-risk populations (via the CDC):
- Children aged younger than 2 years
- Adults aged 65 years and older
- Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological (including sickle cell disease), metabolic disorders (including diabetes mellitus) or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury);
- Persons with immunosuppression, including that caused by medications or by HIV infection;
- Women who are pregnant or postpartum (within 2 weeks after delivery);
- Persons aged younger than 19 years who are receiving long-term aspirin therapy;
- American Indians/Alaska Natives;
- Persons who are morbidly obese (i.e., BMI is 40 or greater); and
- Residents of nursing homes and other chronic-care facilities.
A rational approach is necessary for the appropriate management of Influenza. We must learn from our history and respond to the evidence. Tamiflu isn’t for everyone, and it doesn’t make a difference for most. One to two days of symptomatic relief is probably not worth the cost of antiviral resistance. However, applying this drug to the right at-risk patients may help reduce severity of illness and will hopefully prevent deaths, where even a small therapeutic benefit might provide the right patients an added advantage.
Kevin Klauer, DO, EJD is Editor-in-chief of Emergency Physicians Monthly, CMO of Emergency Medicine Physicians, Vice Speaker of the ACEP Council.
1. Maggie Fox; January 18, 2013, NBCNews.com
2. Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2010 Feb 17;(2): CD001265.
3. medconsumers; January 24, 2012
4. Leang SK, et al. Influenza antiviral resistance in the Asia-Pacific region during 2011.Antiviral Res. 2013 Feb;97(2):206-10
5. Thorlund K, et al. Systematic review of influenza resistance to the neuraminidase inhibitors. BMC Infect Dis. 2011 May 19;11:134
6. Nguyen JT, et al. Efficacy of combined therapy with amantadine, oseltamivir, and ribavirin in vivo against susceptible and amantadine-resistant influenza A viruses.PLoS One. 2012;7(1)
7. CDC Seasonal Influenza(Flu);http://www.cdc.gov/flu/antivirals/whatyoushould.htm#benefits
8. Tom Jefferson, et al., Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ 2009;339:b5106.
9. Hsu, J., et al, Antivirals for the treatment of influenza: A systematic review and meta-analysis of observations studies. Ann Intern Med 156(7):512, April 3, 2012).