The Medical Grand Rounds lecture on October 6, 2010 titled “Influenza 2010: Update after the 2009 Pandemic was presented by Dr. Alicia Fry, M.D., MPH an epidemiologist from the United States Centers for Disease Control and Prevention. I’m sure that those of us who were fortunate enough to be on the wards at that time recall the wonder of seeing a small piece of history unfold firsthand. Now, let’s take the journey again with Dr. Fry, from reports of the first US case through the CDC/WHO responses to the current vaccine status of this very interesting disease.
To review, the influenza virus is a single-stranded RNA virus comprised of eight gene segments, with a relatively high error rate of 1×105, which explains the small variations between different flu seasons known as antigenic drift. The two surface proteins hemagglutinin and neuraminidase have a number of variations—the neuraminidase (NA) protein is a common target of antiviral therapy. Influenza virus strains are most commonly found in birds, pigs, and humans, with some interspecies variation; when two or more of these strains combine, this is called antigenic shift and produces a dramatically novel flu, which is what happened with the novel A/H1N1 influenza virus.
The first documented flu pandemic was in 1918, the infamous Spanish influenza. Other notable pandemics include the 1957 H2N2 Asian flu, the 1968 H3N2 Hong Kong flu, and the 1977 H1N1 Russian flu. Serologic studies from individuals who lived during the 1918 pandemic compared to those who were born after this virus stopped circulating indicated that there is some cross-reactivity between the 1918 H1N1 pandemic virus and this new 2009 pandemic H1N1, as illustrated by Dr. Fry—these data predicted the epidemiology of the pandemic. The genomic content of H1N1 shows that it was an influenza virus comprised of genes from four different strains of swine flu viruses, all of which originated in birds and spread to pigs. Many viruses are easily transmitted between birds/pigs and humans/pigs, but not between birds/humans. The combination of these swine virus genes, including two from Eurasian swine, has never before been reported in humans or animals.
Clinically, the H1N1 pandemic was first recognized in America in mid-April, when southern California identified two adolescents who presented with typical flu-like symptoms (cough, fevers, myalgias) and were found to be infected with a swine-like virus; neither had a history of direct contact with swine. These US cases were reported to the CDC ILI Net Sentinel Provider surveillance system. By April 24, the virus was sequenced, found to be novel, and matched to cases from a large outbreak in Mexico, and by April 28, there were a significant number of cases in Texas and California as well as a cluster of cases in New York City. By the last week in April, collective data showed a spike of more than 35,000 cases in one week, about eight times as many as the regular seasonal flu, leading the WHO to declare a Pandemic level 4, then 5.
The CDC turnaround was quick. They began investigating the first case on April 15 and reported them in the MMWR by April 21—the viral sequence of this flu was complete two days later. By April 28, a PCR protocol was in place, and diagnostic kits were shipped out on May 1. The first report describing 624 affected patients was published in the New England Journal of Medicine on May 7, 2009. Amazingly, vaccine strains were ready for shipment to manufacturers by May 23, only one month after the virus was initially sequenced. Though it reads now as an orderly process, in reality Dr. Fry described this time as “chaos,” showing photographs of stacks of boxes in the offices of the CDC, all of which arrived daily and were marked urgent.
Obviously, one must wonder, what was so special about this particular strain of influenza? Several factors merit further attention. For one, epidemiologists noted that the H1N1 pandemic season was not a regular flu season, as it reached its prime in the fall months as opposed to the usual winter months. Also, and more importantly, it had a significantly larger impact on children and young adults as compared to the seasonal flu, the latter of which typically affects the elderly. The current theory here is that the elderly had cross reactive antibodies from exposure to the 1918 viruses as children…thus , were less likely to get infected than those who previously had no exposure
In July 2009, young adults and children made up the largest population of patients infected with the novel A/H1N1 virus, with the highest hospitalization rate seen in children younger than five. Hospital rates of seasonal flu viruses are typically bimodal, affecting primarily the very young and very old. Many of the fatalities from this virus were in young adults and persons 50-64 years of age—still, the number of deaths within the pediatric population was estimated to be 4-5 times that from previous flu seasons. Overall, there were an estimated 61 million cases of people with symptomatic illness due to the 2009 pandemic virus. Older patients overall were still more likely to die from this flu than their younger counterparts, but the sheer numbers of young people affected were staggering.
Many of the patients severely affected by the H1N1 pandemic, like seasonal flu, had underlying conditions: asthma, COPD, DM, cardiovascular disease, pregnancy, neuro-cognitive deficits, and morbid obesity. This last risk factor was newly reported with this pandemic and remains unexplained. Sixty-six percent of hospitalized patients with pandemic H1N1 infection had pneumonia by X-ray, much higher than that typically seen in seasonal flu. Almost a quarter of hospitalized patients required ICU care—estimates of ventilatory support ranged from 15-25%. Several reports from other countries reported a high proportion of patients placed on ECMO for adequate oxygenation. There were 39 documented cases of pulmonary hemorrhage. Pregnant women merit special commentary—five percent of them died from pandemic H1N1 (as compared to making up 1% of the general population), and the relative risk of hospitalization for a pregnant woman was 4.3 (versus those not pregnant).
Initial strains of pandemic H1N1 were susceptible to NA inhibitors like oseltamivir but almost 100% resistant to adamantanes. Recommendations were made for early, empiric treatment with NA inhibitors, even for pregnant women (oseltamivir is category C) and children under one, given the high risk of adverse events from untreated flu. NIH experimental trials regarding dosing in children under one were shared with the CDC, which allowed this medication to be properly administered. There was also some use of experimental NA inhibitors, like IV peramivir and zanamivir, both of which are now only available in clinical trials and via eIND. Several studies demonstrated the effectiveness of early antiviral therapy to prevent ICU admission and death. The bottom line, similar to seasonal flu, is that earlier therapy was better.
Patients infected with this virus with resistance to oseltamivir were rare—all had the H275Y mutation. Surveillance data from April 2009 to July 2010 found an oseltamivir resistance prevalence of 0.6%, ninety percent of which occurred in individuals exposed to the drug for either chemoprophylaxis and/or treatment. The majority of these patients also had a history of an immunocompromised status—for instance, 82% had a hematologic malignancy and had recently undergone chemotherapy or stem cell transplant. There were only four cases of reported resistance with no history of oseltamivir exposure, these cases may have arisen from spontaneous viral mutations.
So, where do we go from here? The H1N1 pandemic appears to be over. Vaccines were broadly available by November 2009, but the number of cases at this point had severely declined, so the true efficacy could not be tested. Data from other countries indicates 60-70% effectiveness. Early surveillance data from the U.S and Southern Hemisphere suggest that the pandemic H1N1 virus will continue to circulate, and that influenza A H3N2 viruses and influenza B viruses will circulate this coming season as well. There has been no evidence of circulation of seasonal H1N1 viruses (these viruses circulated before the pandemic and have 100% oseltamivir resistance). All 2010-2011 circulating influenza viruses are susceptible to oseltamivir and zanamivir and resistant to the adamantanes. The ACIP (Advisory Committee on Immunization Practices) antiviral use guidelines recommend early empiric therapy with a neuramindase inhibitor for all patients with suspected/confirmed influenza who are hospitalized or severely ill, and for those with a chronic underlying medical condition as previously detailed which puts them at high risk for complications, no matter what their illness severity is. Early antiviral therapy is important, but antivirals should still be used for hospitalized patients even if started more than 48 hours after illness onset.
Dr. Fry lastly reviewed the history of the ACIP influenza vaccine recommendations and how they have evolved over time. This year, the ACIP recommends the influenza trivalent vaccine for everyone, even those who received the pandemic H1N1 vaccine last year. The H3N2 strain mentioned above is new—previous vaccines will not offer cross protection. There is a new, higher antigen level, trivalent vaccine licensed for people greater than or equal to 65 years of age, which results in higher antibody titers, though whether or not this definitely translates into greater protection is unclear. If IV peramivir or zanamivir is desired, you can try to directly appeal to the parent company for compassionate use.
Dr. Tummala is a second year internal medicine resident at NYU Langone Medical Center
Peer reviewed by Alicia Fry, M.D., MPH, epidemiologist from the United States Centers for Disease Control and Prevention