Question
What are the clinical indications to initiate antiviral treatment for patients with suspected H1N1 influenza?
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Response from James Wilde, MD Associate Professor of Emergency Medicine & Pediatrics, Department of Emergency Medicine; Faculty, Pediatric Emergency Medicine, Medical College of Georgia, Augusta, Georgia |
When novel H1N1 "swine flu" was first detected on April 22, 2009, little information was available about the virus. Soon after the Centers for Disease Control and Prevention (CDC) notified the public that a new subtype of influenza A had appeared in the US Southwest, reports came in from Mexico indicating that the virus may be highly lethal. Initial estimates of mortality rates from H1N1 infection in Mexico ranged as high as 8%. This is a remarkably high mortality rate when viewed in the context of the 2% mortality rate observed during the 1918 Spanish Flu pandemic, the most deadly single-season pandemic in world history, which killed as many as 50-100 million people worldwide.
The CDC and other public health authorities responded quickly to what appeared to be the start of a new and deadly pandemic. The initial strategy was to treat anyone who had confirmed or suspected swine flu with the neuraminidase inhibitors oseltamivir (Tamiflu®) or zanamivir (Relenza®). Although the literature in general shows only modest benefit from the use of antiviral medications for influenza infections, some recent studies showed a reduction in influenza mortality in high-risk hospitalized patients after the use of neuraminidase inhibitors. In an effort to stop the spread of the virus and reduce the mortality rate, treatment was recommended without regard for the severity of the illness or underlying health problems.
It soon became apparent that there was a mismatch between the information coming from Mexico and the experience with H1N1 in the United States and the rest of the world. Data from the United States and World Health Organization (WHO) indicated that the mortality rate from H1N1 infection outside of Mexico was very low, probably even lower than the mortality rate expected from seasonal flu, which kills an estimated 36,000 Americans each year. Data over the ensuing months have confirmed that overall mortality from H1N1 infection is less than 1% and may be less than 0.1%.
Resistance to antiviral medications has been well documented in influenza viruses. In 2006, resistance to adamantanes (amantadine, rimantadine) was detected in A/H3N2 seasonal flu viruses in the United States. By the next year, resistance was nearly 100%. Similarly, resistance to oseltamivir was noted in A/H1N1 seasonal flu isolates in 2008, and by 2009, the resistance rate was almost 100%. Given this history, public health authorities have reason to be concerned about the overuse of neuraminidase inhibitors and the development of resistance in the treatment of H1N1 infection.
New information about low mortality rates coupled with concerns about the development of resistant strains led to revised CDC guidelines on May 6, 2009. As of that date, treatment was recommended for hospitalized patients with proven or likely flu and all other patients with an influenza-like illness who are members of groups known to be at higher risk for seasonal flu complications. Those guidelines also contained recommendations for the prophylactic use of oseltamivir or zanamivir in certain populations, such as healthcare workers and others who had close contact with a person known or suspected to have an active H1N1 infection. Treatment with antiviral medications was not recommended for otherwise healthy patients who were not members of high-risk groups.
The May 6, 2009, guidelines remained in effect throughout much of the summer in the United States, during which time H1N1 remained in low-level circulation. In August, rates of infection increased dramatically, first in the Southeast United States and then in most of the rest of the country. By September, the May 6 recommendations became somewhat impractical, particularly in regard to prophylaxis. In response, the CDC published revised guidelines on September 8, 2009. Those guidelines removed the recommendation for prophylaxis in all but a handful of cases.
The September 8, 2009, guidelines still had some problems. The most significant was the inclusion of children younger than 5 years on the list of high-risk groups. Children younger than age 5 can be expected to have 4-8 upper respiratory infections each year, many associated with fever. Because the clinical features of influenza and other upper respiratory tract infections overlap, including all children younger than age 5 on the list of high-risk patients meant that many of these children could be prescribed multiple courses of oseltamivir over the course of a 3- to 6-month fall and winter season. This could potentially deplete the supply of oseltamivir and accelerate the development of resistance.
In response to these concerns, the CDC published another revision to the treatment guidelines on September 22. In this revision, children between 2 and 5 years of age were noted to be at only a slightly increased risk for hospitalization due to influenza and were, therefore, removed from the list of high-risk groups. Children younger than 2 years remained on the list because the data do show a substantially increased risk for hospitalization due to influenza in this age group.
Conclusion
Current recommendations by the CDC are to treat all hospitalized patients with likely or proven H1N1 infection with oseltamivir or zanamivir. Treatment of outpatients is recommended if the patient has an influenza-like illness and more severe symptoms, such as evidence of lower respiratory tract infection or clinical deterioration.
Treatment is recommended for all outpatients with confirmed or suspected influenza if they belong to groups known to be at higher risk for complications. These groups include:
Children younger than 2 years;
Persons aged 65 years or older;
Pregnant females;
Persons of any age with chronic medical or immunosuppressive conditions; and
Persons younger than 19 years who are on chronic aspirin therapy.
Available rapid assays for influenza have shown very poor sensitivity in the detection of H1N1. Antiviral therapy should be started as soon as possible after the onset of symptoms, ideally within 48 hours. Treatment decisions should not be based on the results of assays performed for detection of influenza, due to poor sensitivity of detection of H1N1.