2009 H1N1 Influenza A: Clinical Details, Antiviral Resistance, and Other Mutations
By Amesh A. Adalja, MD, July 17, 2009
As more clinical and scientific facts are learned about illness caused by the novel 2009 H1N1 influenza virus, clinical policy will become more firmly rooted in scientific data, and optimal management strategies will emerge. To that end, several scientific papers have been published recently that shed light on both the spectrum of illness caused by this virus and its ability to evade antiviral drugs.
Clinical Characteristics of Severe Cases
Two recent papers in The New England Journal of Medicine detail the clinical characteristics of severe cases. One, from the National Institutes of Health’s Fogarty International Center, confirms that deaths in Mexico from severe pneumonia during the beginning stages of the outbreak did represent a shift in demographics from previous influenza seasons. In prior epidemics, patients aged 5 to 59 years accounted for 17% of deaths; in contrast, 87% of the 2009 deaths in Mexico occurred in patients in that age group. Similar shifts were seen in the age distribution of severe pneumonia cases.1
The other NEJM paper2 recounts the clinical course of 18 hospitalized patients in Mexico. All suffered from pneumonia and influenza. Eight of the 18 patients had pre-existing medical conditions, while 3 had received seasonal flu vaccine. Those 3 did not require mechanical ventilation. Several other important details emerged from the study:
The median time from symptom onset to hospital admission was 6 days, with a range of 4 to 25 days.
All patients presented with fever, cough, and dyspnea.
Twelve of 18 patients were treated with antibiotics.
Common laboratory abnormalities among these patients included elevated lactate dehydrogenase, creatine kinase, and lymphopenia. No co-pathogens (bacterial or viral) were identified within 24 hours of admission.
Statistically significant differences were found between those who survived (11) and those who died (7); specifically, among patients who died, the following features were more common:
development of renal failure
lower arterial blood pH
higher Apache II score
higher SOFA score
lower Pa02:FiO2 ratio.
Oseltamivir therapy was not initiated in any patient prior to hospitalization; however, 14 of 18 received it during hospitalization. Antibacterial therapy was administered to the majority of patients. Mechanical ventilation was initiated in 10 patients within 24 hours of hospitalization, while 2 others required it later in their hospital stay. Ventilator-associated pneumonia occurred in 4 patients. Before infection control measures were instituted, influenza-like illness developed in 22 healthcare workers who cared for the first 3 of these patients.2
Antiviral Resistance Has Emerged
Prior to the outbreak of 2009 H1N1, most isolates of the seasonal variety of H1N1 influenza A harbored a resistance mutation (H274Y) that renders oseltamivir ineffective; now this mutation has appeared in several 2009 H1N1 virus isolates. To date, 3 resistant cases have been identified in Asia and Europe among patients with uncomplicated influenza: 2 of the patients were being treated with oseltamivir, the third was a patient who had neither taken oseltamivir nor been exposed to anyone who had, suggesting acquisition of a resistant strain circulating in the community. All isolates retained susceptibility to zanamivir, a neuraminidase inhibitor. The CDC has not altered antiviral guidelines due to the current rarity of this phenomenon.3
Shanghai Mutation Renders Virus More Fit for Human Replication
Another important mutation that has been identified in some isolates from Shanghai is the E627K mutation in the PB2 gene. This mutation renders the virus more fit to replicate at 33°C, the temperature of the human nose during winter months. The PB2 gene of the 2009 H1N1 virus is derived from an avian source and, accordingly, contains a genetic sequence optimizing replication at 41°C, the normal temperature of avian species.4,5
2009 H1N1: The Future
As the 2009 H1N1 influenza A virus continues to spread, tracking the clinical and virologic attributes of this virus will be important as policy is developed to prepare for the possibility of a severe influenza season around the globe. Of the developments to date, antiviral resistance poses a major challenge given the extensive reliance on oseltamivir. Fortunately, inhaled zanamivir remains an option, albeit a limited one. Two possibilities in the pipeline include the investigational agent peramivir and an intravenous formulation of zanamivir. The emergence of the E627K mutation and its potential for worldwide progression could foster more efficient spread of the virus, increasing the proportion of persons expected to become ill, and stretching an already over-burdened healthcare system.
Chowell G, Bertozzi SM, Colchero MA, et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med 2009; Jun 29. [Epub ahead of print]. http://content.nejm.org/cgi/content/full/NEJMoa0904023. Accessed July 10, 2009.
Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al. Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico. N Engl J Med 2009; Jun 29. [Epub ahead of print]. http://content.nejm.org/cgi/content/full/NEJMoa0904252. Accessed July 10, 2009.
CDC. Three reports of oseltamivir resistant novel influenza A (H1N1) viruses. July 9, 2009. http://www.cdc.gov/h1n1flu/HAN/070909.htm. Accessed July 10, 2009.
MacKenzie D. “Swine flu sweeps the southern hemisphere.” New Scientist. July 9, 2009. http://www.newscientist.com/article/mg20327164.000-swine-flu-sweeps-the-southern-hemisphere.html. Accessed July 10, 2009.
Recombinomics. E627K acquisition in swine H1N1 raises pandemic concerns. June 18, 2009. http://www.recombinomics.com/News/06180901/H1N1_Swine_E627K.html. Accessed July 10, 2009.