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Trans Am Clin Climatol Assoc. 2010; 121: 128–140.
PMCID: PMC2917128

The 2009 Influenza A (H1N1) Pandemic: What Have We Learned in the Past 6 Months

Carlos del Rio, M.D. (by invitation) and Jeannette Guarner, M.D.

Abstract

The present review describes how the first influenza pandemic of the XXI century occurred, the characteristics of the virus that produced it, its epidemiology, clinical and pathological presentation, and the treatment and prevention methods that have been instituted. The lessons that have been learned in the first 6 months of the pandemic include: 1) predictions were not fulfilled (it was not an avian virus but a swine virus that caused the pandemic, it started in the American continent not in Asia), 2) international cooperation was critical, 3) mass media played a key role communicating to the public and health care professionals about this evolving, and 4) preparedness plans were very important to confront the pandemic.

In late April 2009, Mexico became the epicenter of the current influenza pandemic. International cooperation between Mexican, Canadian, and American public health authorities and scientists led to the rapid identification of a novel influenza A (H1N1) virus strain. On April 24th, Mexican authorities instituted aggressive social distancing interventions and began the deployment of antiviral drugs to treat cases and contacts. Within a few days, the virus that was causing the epidemic in Mexico was identified in many other countries worldwide, and on June 11, 2009, the World Health Organization raised the status from epidemic to pandemic. Thus, the first influenza pandemic of the new millennium was officially declared. Since then, and through December 5, 2009, 208 countries have reported cases and over 10,000 deaths have occurred as a consequence of the pandemic. In the first six months of the pandemic, we have learned many important lessons: To begin with, and contrary to what many believed, the first influenza pandemic of the XXI Century started in North America and not in South East Asia and was of swine rather than avian in origin.

INFLUENZA PANDEMICS

Influenza pandemics are unpredictable but recurring events that can have severe consequences on human health and economic development. Three criteria must be met for an influenza pandemic to occur. First, a new virus strain to which the vast majority of the population lacks immunity has to appear. Second, the new virus has to cause severe disease in humans, and third, the virus has to be able to easily infect and to be efficiently transmitted between humans. During the past century, there were three major influenza pandemics: in 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2). The most serious influenza pandemic in recent history is the 1918 Spanish flu that killed over 50 million people worldwide (1). The latter two pandemics were milder than the 1918 one but still resulted in significant mortality, with close to 2 million people dying from the 1957 virus and 1 million from the 1968 virus.

Because of the real threat of a new influenza pandemic, international public health agencies called for the development of preparedness plans that would ensure the strengthening of national and global response capacity. As a result, countries began developing pandemic influenza plans in the late 1990's, and many countries had plans in place by 2005. In the United States, the National Strategic Plan for Pandemic Influenza was published in November of 2005 (http://www.hhs.gov/pandemicflu/plan/pdf/HHSPandemicInfluenzaPlan.pdf). The plan outlined how the US intended to prepare for, detect and respond to a pandemic. It also outlined the roles to be played not only by the Federal government, but also by State and local governments, private industry, international partners and individual citizens. The pillars of the National Strategy included preparedness and communication, surveillance and detection, and response and containment. As a result of the National Strategic Plan, pandemic response plans were developed and exercised, a national stockpile of antiviral drugs was procured, surveillance for respiratory viruses was strengthened, and vaccine production surge capacity was addressed. In addition, on a global scale, the response to outbreaks of avian influenza A (H5N1) in poultry and humans, and SARS in humans has allowed for practical experience to be gained.

THE CURRENT PANDEMIC

The current influenza pandemic began in the spring of 2009, when cases in both the United States and Mexico were diagnosed with a novel, swine (H1N1) influenza A virus. On April 15–17, 2009, the Centers for Disease Control and Prevention (CDC) confirmed the first two cases of human infection with the pandemic H1N1 virus in San Diego, California. The cases were diagnosed among two children who did not appear to have exposure to swine, suggesting the possibility of human-to-human transmission (2). Between April 15–17, the Mexico Ministry of Health received informal notification of clusters of rapidly progressive severe pneumonia occurring mostly in Mexico City (3, 4) and San Luis Potosi (5). In response, on April 17, Mexico intensified national surveillance for acute respiratory illness and pneumonia, and on April 22, alerted the world to a rising epidemic of severe respiratory disease associated with a recently discovered influenza A virus that was identical to that described in the two cases in California.

There was rapid spread of this new influenza virus within Mexico to other neighboring countries and, within 2 months, to other continents led the World Health Organization to raise the worldwide pandemic alert level to phase 6 and to officially declare, on June 11, 2009, that the first influenza pandemic of the XXI century had begun.

Genomic analysis of the 2009 influenza A (H1N1) virus indicates that it is closely related to common swine and avian influenza A viruses isolated in North America, Europe and Asia. The 2009 Influenza A (H1N1) virus reasortment contains three classical swine genes (H1, NP, and NS), one human gene (H3N2 PB1), two North American avian genes (PB2 and PA), and two Eurasian avian-like swine genes (N1 and M) (6, 7).

EPIDEMIOLOGY AND CLINICAL CHARACTERISTICS

In the outbreak that occurred at a New York City school, the incubation period of 2009 influenza A(H1N1) virus was estimated to be in the order of 1.4 days, with symptoms developing in 95% of cases by 2.2 days (8). In addition, and contrary to seasonal influenza, most cases have occurred in young individuals with approximately 60% of the reported cases in the United States having occurred in persons 18 years of age or younger (7). The reason for the increased attack rate among younger individuals is not entirely clear, but it has been shown that adults, especially those born before 1957, have low levels of cross-reacting neutralizing antibodies, likely due to repeated exposures to seasonal H1N1 viruses (9). Studies in household contacts support this hypothesis, as household contacts 18 years of age or younger appear to be twice as susceptible as those 19 to 50 years of age, and household contacts older than 50 years of age were less susceptible than those who were 19 to 50 years of age (10). That same household contact study suggests that the infectivity does not vary with the age of the infected case and that the mean time between the onset of symptoms in a case patient and the onset of symptoms in the household contacts infected by that patient is 2.6 days (10).

The clinical characteristics of cases infected with the pandemic 2009 influenza A(H1N1) virus is similar to the signs and symptoms of seasonal influenza and include fever, cough, headache, sore throat, rhinorrea, chills and muscle aches (11). In addition, it has been suggested that patients infected with pandemic 2009 influenza A (H1N1) virus are more likely to also have gastrointestinal symptoms such as nausea, vomiting and diarrhea. Approximately one out of every 10 patients infected with pandemic 2009 influenza A(H1N1) virus has required hospitalization. The great majority of patients who have been hospitalized have an underlying condition, such as asthma, diabetes, heart, lung, and neurologic diseases and pregnancy (12). In addition, obesity also has been noted as a risk factor for severe disease (13). Among hospitalized patients in the United States, 25% were admitted to intensive care units (ICU) and 7% died. Hypoxia is the most common cause of admission to an ICU, and chest roentgenograms usually show changes consistent with acute respiratory distress syndrome (14). Early use of antivirals (within 2 days after the onset of illness) was associated with deceased likelihood of admission to the ICU and death (12, 13). Leucopenia, anemia and thrombocitypenia accompany the previously described signs and symptoms in about 20–30% of patients.

Complications seen in patients infected with the pandemic 2009 influenza A(H1N1) virus have been similar to those of seasonal influenza and have included bacterial pneumonia, encephalopathy, pericarditis and myocarditis, and rhabdomyolisis. People at high risk for developing complications, such as death, include individuals under the age of 2 years or over 65, pregnant women, persons younger than 19 years who are receiving long-term aspirin therapy and people with underlying medical conditions (http://www.cdc.gov/h1n1flu/risks.htm).

Bacterial pneumonias caused by common upper respiratory tract bacteria, such as Streptococcus pneumoniae, were an important cause of mortality during the 1918 influenza pandemic (15). During the current outbreak, a study conducted by the CDC showed that 29% of patients who died had evidence of bacterial superinfection with pneumococci as the predominant pathogen (16) This finding suggests that the administration of pneumococcal vaccine and early antibiotic therapy may be important in reducing the mortality from influenza (17).

PATHOGENESIS AND PATHOLOGY

Pathologic descriptions from specimens of at least 22 fatal cases infected with the pandemic 2009 influenza A(H1N1) virus have been published (3, 5, 18). In general, the trachea and major bronchi have shown necrosis and desquamation of infected mucosal epithelium, and edema and mixed inflammatory infiltrate in the surrounding submucosa. The glands in these airways show loss of infected goblet cells and necrosis of surrounding submucosa. The lung parenchyma in these patients has shown changes consistent with the different stages of diffuse alveolar damage. If the death occurred close to the onset of symptoms, the changes may consist of extensive hyaline membrane formation, intraalveolar edema, thrombosis of capillaries with accompanying necrosis of the alveolar walls, and varying degrees of mixed inflammatory infiltrate in the alveolar walls. Infected pneumocytes have shown reactive changes and may desquamate into the alveolar spaces and appear together with infected intralaveolar macrophages. Intraalveolar hemorrhage and erythrophagocytosis have also been observed. If the death occurred weeks after the onset of symptoms, prominent proliferation of fibroblasts has been observed. Bacterial pneumonias, defined as accumulation of neutrophils in the alveoli, have been observed in approximately 29% of cases (16).

Pathogenesis studies that compared a seasonal H1N1 virus strain and pandemic 2009 influenza A(H1N1) virus in a ferret animal model demonstrated that the pandemic 2009 H1N1 strain produced larger lung consolidation than the consolidation produced by the seasonal strain (19). In addition, ferrets infected with the pandemic 2009 strain showed multifocal mild to moderate necrotizing rhinitis, tracheitis, bronchitis and bronchiolitis, and viral antigens were observed from the nasal turbinates to the bronchioles. Those ferrets infected with the seasonal strain primarily showed viral antigens in the nasal turbinates with minimal viral antigens in the trachea and bronchioles. The pandemic 2009 A(H1N1) influenza viruses replicate to higher titers in lung tissue and have been recovered from the upper and lower airways as well as the intestinal tract (20).

DIAGNOSIS

Reverse-transcriptase PCR is the recommended test for diagnosis and confirmation of infections due to pandemic 2009 influenza A(H1N1) virus. Approved PCR tests for hospital laboratories determine that the sample is positive for influenza A but negative for seasonal H1 and H3 viruses. The sample then needs to be confirmed as pandemic 2009 influenza A(H1N1) virus by State Health Laboratories or the CDC. The currently available rapid tests for the diagnosis of influenza, as well as immunofluorescence tests, have low to moderate sensitivity for diagnosing pandemic 2009 influenza A(H1N1) virus (21, 22) and the sensitivity declines substantially with lower viral titers (23). Thus, a negative result by any of these tests should not be used to rule out pandemic 2009 influenza A(H1N1) in the appropriate clinical setting. Viral cultures can be performed in hospital laboratories using adequate precautions. Here again, the virus will react positively with influenza A virus reagents and confirmation of the pandemic 2009 H1N1 strain will require referral to specialized laboratories.

TREATMENT

Since it was first isolated, the 2009 H1N1 virus has been susceptible to neuraminidase inhibitors (oseltamivir, zanamivir and peramivir) but resistant to the adamantanes (amantadine and rimantadine). Emergence of oseltamivir-resistant 2009 H1N1 virus during or following treatment or prophylaxis have been described (24, 25) but remains rare. Oseltamivir resistance has been associated with replacement of histidine for tyrosine at position 275 (H275Y) of the neuraminidase gene, a mutation that has also been responsible for oseltamivir resistance in seasonal H1N1 and avian H5N1 viruses (26, 27). Viruses that have the oseltamivir-resistant H275Y mutation continue to be susceptible to zanamivir.

Most people ill with influenza will recover without complications with only supportive therapy. Prompt empiric treatment with antivirals is recommended by the CDC for persons with suspected or confirmed influenza illness that requires hospitalization, for patients with progressive, severe or complicated illness, and patients at risk for severe disease or complications as described above (http://www.cdc.gov/H1N1flu/recommendations.htm). The treatment benefit is greatest if antivirals are started within two days of onset of symptoms, but hospitalized patients may benefit from treatment even if started later (28).

Pre- and post-exposure prophylaxis with antivirals should be considered for patients in high-risk groups, health care providers, public health workers and first responders.

The recommended doses of the neuraminidase inhibitors oseltamivir and zanamivir for treatment and prophylaxis of adults are shown in Table 1.

TABLE 1
Antiviral Medication Dosing Recommendations for 2009 Influenza A(H1N1) Infection

A third neuraminidase inhibitor, peramivir, formulated for intravenous (IV) administration is an investigational product currently being evaluated in clinical trials. As of October, 2009, safety and/or efficacy data from 1,891 patients with acute uncomplicated seasonal influenza A has been submitted to the Food and Drug Administration (FDA), and the FDA issued an emergency use authorization for treatment with peramivir of hospitalized patients infected with 2009 influenza A(H1N1) virus who have not responded to either oral or inhaled antiviral therapy or who need the drug delivered by intravenous route.

VACCINATION

On September 15, 2009, the FDA granted marketing licenses for 2009 (H1N1) influenza vaccines to 4 pharmaceutical companies: CSL Limited, MedImmune LLC, Novartis Vaccines and Diagnostics Limited, and Sanofi Pasteur, Inc. Since the manufacturing process was based on the same standards as the seasonal influenza vaccines, the licensure was viewed as a strain change and no efficacy results were required. A fifth manufacturing company, GSK, received FDA approval of their vaccine on November 10th, 2009. The vaccine is based on the A/California/07/2009 (H1N1) strain and is available both in live-attenuated and inactivated formulations. The live-attenuated intranasal vaccine should only be administered to persons 2–49 years-old who are healthy and non-pregnant. The inactivated vaccine is administered intramuscularly and is approved for adults and children 6 months and older.

Because vaccine availability was anticipated to be initially limited, the ACIP established five population groups that should be given the highest priority for initial vaccination, including pregnant women, persons who live with or provide care for infants aged <6 months, health care and emergency medical services personnel who have direct contact with patients or infectious material, children aged 6 months– 4 years, and children and adolescents aged 5–18 years who have medical conditions that put them at high risk for influenza-related complications (29). It was calculated that these five target groups comprise approximately 159 million persons in the United States. The ACIP also advised that extension of vaccination beyond these groups should be made based on vaccine availability at a local level. With the availability of over 60 million doses of vaccine as of December 1st, 2009, most health departments have expanded H1N1 influenza vaccine eligibility to the general public.

Safety and immunogenicity studies conducted with the 2009 pandemic influenza A(H1N1) vaccine have shown similar results to seasonal vaccine (30). A single dose of the vaccine has proven to be highly immunogenic in adults but not in children younger than 9 years of age (31, 32). Based on the result of these studies, it is recommended that clinicians immunize adults with a single dose, and children 6 months–9 years with two doses separated by 4 weeks (http://www.cdc.gov/h1n1flu/vaccination/public/vaccination_qa_pub.htm).

Concerns about vaccine safety were based on the post-vaccination Guillain-Barre syndrome (GBS) that occurred during the 1976 swine influenza A vaccine campaign. In 1976, the influenza A/New Jersey/1976/H1N1 vaccine, also known as the “swine flu” vaccine, was found to be associated with the development of GBS and the program was suspended on December 16, 1976. Studies conducted to assess the risk of GBS following influenza immunization in 1976 estimated the attributable risk of vaccine-related GBS in the adult population at just under one case per 100,000 vaccinations (33). As a precaution during the current pandemic influenza immunization program, the CDC, FDA and other federal agencies will be tracking GBS through the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) project.

CONCLUSIONS

Contrary to what had been predicted, North America, and not South East Asia, was the epicenter of the first influenza pandemic of the XXI century. Concerted international collaboration among Mexican, Canadian and American scientists led to the rapid identification of a novel influenza A (H1N1) virus strain leading to the early institution of aggressive social distancing interventions and deployment of antiviral drugs to treat cases and contacts. Despite these interventions, and in a matter of a few weeks, the virus had spread to other countries, and WHO declared the official start of a pandemic. In the first six months of the pandemic, the virus was identified, and a vaccine has been produced which will undoubtedly limit the morbidity and mortality of the pandemic. Some of the clinical characteristics of the disease are similar to those observed with seasonal influenza infections; however, others remain to be explained, for example, the higher attack rate in children, and the higher mortality in pregnant and obese persons. The pathogenesis of novel H1N1 seems to be similar to that described for avian H5N1, and both viruses produce almost identical pathology in human fatal cases. In the U.S., as in other countries, we have seen a “second wave” of disease, and it is possible that pandemic influenza will continue throughout the winter of 2010 and could be more severe than during the first wave of the spring of 2009. Through this pandemic, the world has learned the importance of preparedness, communication and collaboration between countries, and how to detect and respond to an influenza pandemic; however, what we cannot forget is that complacency is dangerous and not acceptable when confronting the threat of an influenza pandemic or a potentially severe new emerging respiratory infection.

Footnotes

Potential Conflicts of Interest: Dr. del Rio is an investigator with the N.I.H. and founded the Emory Vaccine Trials Evaluation Unit.

DISCUSSION

Mackowiak, Baltimore: Is there any evidence that the age-adjusted case fatality rate is increasing as the epidemic progresses?

del Rio, Atlanta: There is a little bit of evidence of that and as I said, patients with lung disease tend to also have severe disease so it may be that the impact of age is due to co-morbidities. There's a lot of mathematical modeling being done to try to better understand that - but it still looks like the biggest burden of disease is in young people and the biggest case-fatality happens to be among pregnant women.

Duma, Daytona Beach: The Australians, in their recent epidemic, have described, particularly in some of the patients that have been pregnant and severely ill, a deficiency in IgG subclass 2 in about 60 or 70% of these individuals. They were looking to see if there might be any sort of cause-and-affect relationship or what that relationship might be. Any comments on that? We are seeing a number of patients who are pregnant who have been on the intensive care unit and are pretty impressed with the virulence of this organism in terms of pregnant individuals.

del Rio, Atlanta: Yes. I read that paper. That's really an interesting observation and I don't know of anybody who has followed up on that, but I know that some people in our vaccine center are actually trying to look into understanding what's happening to pregnant patients.

Lange, San Antonio: Carlos, as you alluded to, the age of the individuals dying has a mean of about 30, 32 years of age, but the recommendations for treatment are for individuals over the age of 65. It sounds like the recommendations are really at odds with what the current data are showing. Will you clarify?

del Rio, Atlanta: Yes, I know and I agree. I think most of us, if we saw somebody ill with influenza today we would have a problem deciding to treat or not. You know that most people are going to get better on their own, but if you wait and they get sick, then the use of an antiviral agent is not as useful since you've got to use them right away. So, I think that we probably need to be a little more liberal in the use of antivirals. I am not necessarily in agreement with holding them. I think that until we understand what really are the risk factors for this severe disease, I think we really need to think that if somebody has developed the disease, we need to go ahead and treat them if we have the antivirals available. I can tell you though, coming from San Antonio as you mentioned, I had a call from somebody in San Antonio who had their kid fairly ill, and they were telling me that they couldn't find any Tamiflu in any pharmacy, because they had run out of it, I think that's one of the risks that we are potentially having, and the national stockpile is probably going to have to be opened for this.

DuPont, Houston: Carlos, the two most infectious transmissible agents that exist are pandemic flu and measles. Pandemic flu, we've learned, really occurs when there's a change in the hemagglutinin; H1 Spanish, H2 Asian, H3 Hong Kong flu. This one comes out of nowhere. How does a H1N1 that has been around, I mean not this particular virus, but H1N1 viruses have been around for a long time, and how can it be so uniquely different to produce pandemic flu? That is the first question I am having trouble relating to. The second one has to do with the unusual mortality pattern. It's easy to say those of us 60 years of age and more were exposed to a virus 50 years ago, but I didn't think immunity lasted 50 years for a serotype-specific influenza. We're lucky to get four months out of the vaccine for protectiveness, and the fact that no elderly people are dying from this disease and its all young people, I can't understand.

del Rio, Atlanta: No, those are very good questions, With the first one, related to the hemagglutinin, the hemagglutinin of this virus has about a 72% homology with a hemagglutinin of previous H1s in circulation, and so, not a lot of homology. That is the reason why the vaccine is necessary. There's a lot of argument of whether or not you do get cross-immunity or you don't. I tend to believe that there is no cross-immunity. There was a paper from Mexico published in the British Medical Journal using a case-control study design, suggesting that there was some protection from seasonal vaccine. I don't think so. I mean from data in the lab it doesn't look like those patients developed antibodies against this virus. The mortality is fascinating, and I think it has to do with the fact that as hemagglutinin attaches to a different receptor and also the activation of a gene, the MP-1 gene, in the virus is a potent inducer of interleukin-1, It may be that that's what is going on, that you have a lot of basically cytokine storms induced by this virus.

Karchmer, Boston: I just wanted to make two quick comments and then ask a question. One comment is on the insensitivity of the rapid test, at least in our hands. As published recently in CID, it depends on the sample that you submit and if you have adequate columnar respiratory cells, indeed, the test can be sensitive and specific. The second comment was, and this is to the audience really rather and hopefully that will go beyond this room: medicine and physicians around the country are balking at administering to their patients the H1N1 vaccine. I personally think this is a travesty and that we should return to our communities and really promote vaccine utilization. We have had multiple calls from people whose pediatricians are not providing their patients with the vaccine. The question I wanted to get your response to is are we going to see a perfect storm between this infection and the body-mass-index epidemic that is currently going on in the country, and is that another vulnerable population that we should be addressing specifically with vaccine?

del Rio, Atlanta: Yes, I was so surprised when the ACIP did not include BMIs over 30 as one of the clear populations to immunize, and you know, if you talk to some people, they say, “Well you know we did some further analysis and it doesn't pan out;” but I haven't seen that published, and I have seen the other papers published saying that that's an increased risk. So I was wondering whether we were politically correct by not recommending immunization to people that were obese. It's unfortunate but that's public health being done that way. As far as you comments, I agree with you 100 percent. I think we really need to promote vaccination as physicians – populations primarily to, you know, the high-risk populations, such as healthcare workers, young individuals, et cetera. We need to do a good job doing that. With pregnant women, we've never done a good job, even with seasonal influenza, and we really need to use this opportunity as a way to do that. As far as a test, I am aware of your paper in CID. I think what happens with the test is that it is very dependent on getting the right cells, but also it is very dependent on how much virus shedding there is. So, in kids that have a lot of virus shedding, you may have a better sensitivity than in an older population and young adolescents who don't have as much viral shedding.

Markel, Ann Arbor: Carlos, that was superb. I have more of, really, a philosophical questions related to the waves seen in influenza pandemics. You know some people say there are three waves with the 1918 pandemic. Others include the 1920 wave. That's the American story. If you're in Australia, they talk about two waves, and if you're in Russia, they talk about one long wave. Similarly, with '57 you see that concept as well but in a globalized world where everyone travels everywhere else in under 24 hours. Isn't the wave concept really antiquated, if not Americano-centric, and does that really help us from an epidemiological standpoint?

del Rio, Atlanta: No, I agree, and I think in this globalized world, we have seen a continuous wave of this disease that has never gone away. I think what we've learned also with this disease is our classic concept that influenza is a winter disease and in summer it goes away. We learned very clearly that it didn't go away in the summer and that a continued transmission happened in the summer. So I think it is challenging a lot of our previous thoughts about what influenza epidemiology was like, and I think there's a lot of lessons to be learned in understanding this epidemic. I think it will help us better understand the way we really approach influenza in the future.

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