Serious respiratory syndrome, emerging resistance make H1N1 formidable foe even after vaccine
'You will see cases of young, healthy people requiring critical care support.'
With a vaccine on the way, it may be tempting to downplay the threat of pandemic H1N1 influenza A as it moves out of the Southern Hemisphere to spread in more favorable fall and winter conditions in the United States. That would be a mistake for at least two reasons, both of them intensive care patients at Emory University Hospital in Atlanta, as this issue went to press.
There are two relatively young, healthy adults in our ICU on ventilators as a consequence of this H1N1 virus," says Alexander Isakov, MD, MPH, executive director of the Emory University's Office of Critical Event Preparedness and Response in Atlanta. "This virus is not just your run-of-the-mill seasonal flu. You see serious illness and death among young individuals that are otherwise healthy. The vast majority of people who contract this will have mild illness and won't require any medical treatment, but you will see cases of young healthy people requiring critical care support."
Indeed, while the vast majority of H1N1 infections have cleared without complication, the World Health Organization is warning of severe, sometimes fatal infections in young, healthy people. A recent WHO update on the situation said "clinicians from around the world are reporting a very severe form of [H1N1] disease . . . which is rarely seen during seasonal influenza infections. In these patients, the virus directly infects the lung, causing severe respiratory failure. Saving these lives depends on highly specialized and demanding care in intensive care units, usually with long and costly stays."
In addition to a severe respiratory failure syndrome that is striking otherwise healthy patients, there are continuing, sporadic reports of H1N1 strains resistant to oseltamivir (Tamiflu). Last year, seasonal influenza A strains developed virtually complete resistance to the antiviral, one of the two available treatments. If either of these troubling trends manifest in a significant way as H1N1 resurges, there could be dire clinical consequences before vaccine can be widely administered — and for some people — even after.
"No vaccine is 100% effective; you hope it will be at least 70%," says Richard Wenzel, MD, chairman of the department of internal medicine at Virginia Commonwealth University in Richmond. "Then there are people who won't take the vaccine, and there are people that are going to get sick between now and the availability of the vaccine. We should not be complacent. I know what [H1N1] is capable of doing, having seen 20-, 30-, 40-year-olds on respirators in countries in Latin America."
Wenzel did rounds with international colleagues to assess the H1N1 situation, observing seriously infected, ventilated patients in Mexico, Brazil, Chile, and Columbia. "A third to a half have no obvious underlying conditions," he says. "Up to a quarter are pregnant women, maybe 15% to 20% are obese patients."
During the winter season in the Southern Hemisphere, several countries reported that about 15% of hospitalized cases were in ICUs. U.S. hospitals and other Northern nations should be aware that ICUs could be overwhelmed by a sudden surge in the number of severe cases, the WHO advised. The reasons for the severe respiratory syndrome are not completely understood, though there was some speculation initially that it seemed similar to the hyperimmune response — the so-called cytokine story — that was reported in the 1918 H1N1 pandemic.
"I haven't seen anything to suggest that the 'cytokine storm' is contributing to these patients respiratory failure," Isakov says. "What I have seen broadly described is that it is affecting the lower respiratory tract in those cases, causing injury to the alveoli and causing a noncardiogenic pulmonary edema that requires ventilation. It is just difficult to oxygenate these patients because the virus is affecting the structures of the lower airways as opposed to just the upper airways."
Certain medical conditions increase the risk of severe and fatal H1N1 illness, including pregnancy, asthma, cardiovascular disease, diabetes, immunosuppression and obesity. "Conditions such as asthma and diabetes are not usually considered killer diseases, especially in children and young adults," the WHO noted. "Young deaths from such conditions, precipitated by infection with the H1N1 virus, [may] be another dimension of the pandemic's impact."
The Centers for Disease Control and Prevention recently reported that 36 pediatric deaths associated with H1N1 infection had been reported from 15 state and local health authorities through Aug. 8.1 The median age of the patients was 9 years (range: 2 months-17 years). Among 24 children who had high-risk medical conditions, 22 (92%) had neurodevelopmental conditions (e.g., developmental delay or cerebral palsy).
Raising the specter of a multidrug-resistant pandemic flu strain, the CDC recently reported what appears to be the first documented case of human-to-human transmission of oseltamivir-resistant novel influenza A (H1N1).2
The transmission occurred between two girls who were roommates at a summer camp in North Carolina where oseltamivir was given to most campers and staff to prevent influenza. The CDC detected the H275Y mutation in neuraminidase from both specimens by pyrosequencing. The H275Y mutation is associated with resistance to oseltamivir, though zanamivir (Relenza) susceptibility is retained. A second mutation (I223V) in neuraminidase also was detected in both specimens.
"There is no way to tell how [transmission occurred] with 100% certainty," says Zack Moore, MD, respiratory epidemiologist at the North Carolina state department of health. "But the fact that there was not only this H275Y mutation, but also a second mutation in the virus from both girls is pretty strong evidence that it was not a de novo mutation in each of them."
In another recently reported case, the virus similarly mutated after prolonged exposure to oseltamivir in two Seattle leukemia patients who had undergone hematopoietic stem cell transplant.3 Those two patients were not epidemiologically linked and were treated at different hospitals. Clinicians caring for immunosuppressed patients with H1N1 infection should be aware of the potential for development of antiviral drug resistance during therapy and prolonged viral shedding.
"Remember these were immune-suppressed patients; so by definition, they are not going to get rid of the virus inside of seven days like healthy hosts," Wenzel says. "The virus is hanging out, the patients aren't well, and if they keep giving them more doses, the exposure selects out resistant strains. If it starts transmitting, then it's a big deal. It looks as though in that hospital it didn't transmit to health care workers."
In that regard, no evidence was found that health care workers or other patients developed influenza caused by the oseltamivir-resistant novel strain, the CDC reports. Strict adherence to recommended personal protective equipment and infection-control measures is advised until an immunosuppressed patient with influenza virus infection has several respiratory specimens that remain negative when tested by both PCR and viral culture, the CDC recommended. Similarly, no evidence of additional transmission was found in North Carolina, but the two girls in that case were out in public while symptomatic.
"When we found out that we had resistant virus in these girls and that they had been out in the community we sent [the CDC] a lot of the other [circulating] virus that we had at our state lab," Moore says. "None of that was found to have the resistance mutation."
The H275Y mutation — which rendered the 2008-2009 seasonal influenza A completely Tamiflu-resistant — is the same mechanism of resistance in the Seattle patients and North Carolina campers.
"It's the most common mutation that is identified in association with Tamiflu resistance," Moore says. "In the cases of this pandemic H1N1 the majority have been after Tamiflu exposure. What happened last year with our seasonal H1N1 is that [the resistant mutation] just became part of the dominant circulating strain. It was just out there, but most of these cases are linked to drug exposure."
An exception to that occurred on July 3, when the Hong Kong Department of Health reported a resistant H1N1 virus was isolated from a 16-year-old girl who had a fever upon arrival from San Francisco. Her symptoms began prior to boarding the plane. The patient had not taken antiviral agents and reported no illness among close contacts. The compelling question is whether such cases represent anomalies or foreshadow widespread resistance to come.
"There is not a formula [to answer] that," Moore says. "What we saw with the seasonal H1N1, was that the previous year — 2007-2008 — we had about 12% or 13% Tamiflu resistance. That was new; it hadn't really been seen before. No one knew what was going to happen, and then this past season; sure enough, it was virtually 100% resistance for those seasonal H1N1 [strains]. Whether that means that same pattern will happen here — or that it is going to happen this flu season, next flu season, or never — is impossible to predict. "
As a result of the cases, the CDC updated its antiviral guidance on Sept. 8, emphasizing that use of antiviral medications for postexposure chemoprophylaxis should be reserved for people at higher risk for influenza-related complications who have had contact with someone likely to have been infected with influenza. An emphasis on early treatment once a patient has developed symptoms, rather than chemoprophylaxis, should reduce opportunities for development of oseltamivir resistance, the CDC noted. Chemoprophylaxis remains an option for exposed health care workers, but should not be used for prevention of illness among healthy people after exposures in community settings. People who are taking antiviral medications for prevention should be instructed to contact a health care provider if illness develops. Indeed, an alert physician in the North Carolina case noticed the girls were ill despite receiving Tamiflu.
Chemoprophylaxis failure is known to occur even without antiviral resistance, so testing for resistance should be considered in consultation with the state health department, the CDC advises. However, if symptoms develop during chemoprophylaxis, providers should consider the possibility of antiviral resistance and consider alternate treatment options. Because the H1N1 virus is resistant to adamantanes, limited treatment options will be available if widespread oseltamivir resistance develops. Zanamivir — the other effective antiviral — is not licensed for treatment of children under age 7 years and is contraindicated for people with underlying airway disease, the CDC notes.
"It wasn't an issue for these particular kids [in North Carolina] because these are healthy people with uncomplicated illness," Moore says. "But if you have patients like the cases in Seattle, you run out of treatment options very quickly. The only other treatment commercially available being zanamivir — and that is only available as an inhaled powder. So, you run out of treatment options. And for situations where you really do need prophylaxis — such as someone at high risk has a close exposure — you run out of options for that, too, if you have a resistant virus circulating."
References
- Centers for Disease Control and Prevention. Surveillance for Pediatric Deaths Associated with 2009 Pandemic Influenza A (H1N1) Virus Infection —- United States, April — August 2009. MMWR 2009; 58(34):941-947.
- CDC. Oseltamivir-Resistant 2009 Pandemic Influenza A (H1N1) Virus Infection in Two Summer Campers Receiving Prophylaxis — North Carolina, 2009. MMWR 2009; 58(35):969-972.
- CDC. Oseltamivir-Resistant Novel Influenza A (H1N1) Virus Infection in Two Immunosuppressed Patients —- Seattle, Washington, 2009. MMWR 2009; 58(32):893-896.
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