As H5N1 Virus Continues to Spread, the World Awaits the Next Flu Pandemic

Internal Medicine World ReportNovember 2005

As H5N1 Virus Continues to Spread, the World Awaits the Next Flu Pandemic

By Rebekah McCallister

The world has entered into a tense “waiting game” as experts agree it is no longer a question of whether an influenza pandemic will occur, it is when. Avian flu virus (H5N1) is thus far the most likely candidate. Over the last several weeks, the first human deaths associated with the virus in 2005 were reported in Thailand and Indonesia (Table), scientists reconstructed the full genome sequence of the 1918 human influenza virus, H5N1 was discovered for the first time in Europe, and world leaders did their best to calm public fears in the midst of a massive media blitz.

H5N1—The Leading Pandemic Candidate

Only one condition is missing before the H5N1 virus can set off the feared pandemic—the ability to be “rapidly transmitted from person to person,” said Director-General of the World Health Organization (WHO), Lee Jong-wook, MD, MPH.

The financial impact of such a pandemic will be “huge,” according to Dr Lee. “The economic cost of SARS has been estimated at $30 billion. Remember, there were fewer than 800 deaths from SARS throughout the whole outbreak,” he emphasized.

An influenza pandemic is most likely to begin in Asia, where sustained outbreaks of avian flu have occurred over the past 3 years. “We think that the pandemic flu virus in humans is most likely to be a mutation of avian flu virus H5N1,” Dr Lee said.

A natural reservoir for the avian flu virus is migratory waterfowl. Infected birds have recently been found in Mongolia, Kazakhstan, Russia, Romania, and Turkey, raising concerns in the United States as the disease moves west.

One expert in the United States watching the progress of the H5N1 virus is Alfonso Torres, DVM, PhD, director of the Animal Health Diagnostic Center and associate dean for veterinary public policy at Cornell University’s College of Veterinary Medicine, Ithaca, NY.

Dr Torres stresses a crucial difference between the Asian avian flu and the one spreading through Eastern Europe. “When experts look at the maps of the areas affected by avian influenza in Asia and they look at the flying pathways of migratory waterfowl, there is not an overlap,” Dr Torres explained. “Waterfowl, at this point in time, are not the culprit for what is happening in Asia.”

Michael Ryan, MD, director, WHO Department of Epidemic and Pandemic Alert and Response, agreed, saying, “it is mainly the migratory bird species of geese and ducks—birds like that have the potential to carry these particular strains.”

There are, however, many reasons for bird die-off, and any over-association of a particular bird species with avian flu could produce “scare mongering,” Dr Ryan warned. “It is important that people limit their contact with dead or sick birds, but that doesn’t mean that every death of a bird was caused by avian influenza.”

In fact, in Asia, the disease has spread in backyard and low-tech poultry and duck production areas, where infected chickens are transported on top of cars or on motorbikes to the market. There, sick birds can infect other birds that are then returned home unsold. In addition, people who handle uncooked meat, and infected birds can spread the virus from bird to bird.

As long as the disease stays primarily in birds, health officials have some control, Dr Torres explained. International policymakers are debating whether to routinely vaccinate poultry with H5 or H7 avian flu viruses and whether to include H5N1 in regular human flu vaccines.

“The fear is that if the virus changes or recombines with a regular human flu, the virus may acquire the ability to be effectively transmitted from human to human. Then it could become the big pandemic that everyone is very concerned about,” Dr Torres said.

Recreating the 1918 Flu Virus

In an effort to better understand the H5N1 virus, scientists have reconstructed the full genome sequence of the 1918 “Spanish flu” virus that is thought to have killed more than 50 million people. This led to the chilling revelation that the avian flu virus has acquired 5 of the 10 gene sequences associated with human-to-human transmission of the Spanish flu.

“We felt we had to recreate the virus and run these experiments to understand the biological properties that made the 1918 virus so exceptionally deadly,” said lead investigator Terrence Tumpey, PhD, senior microbiologist at the Influenza Branch of the Centers for Disease Control and Prevention (CDC), who helped reconstruct a living copy of the 1918 virus (Science. 2005;310:28-29). “We wanted to identify the specific genes responsible for its virulence, with the hope of designing antivirals or other interventions that would work against virulent pandemic or epidemic influenza viruses.”

Dr Tumpey and colleagues used the full genome sequence constructed by Jeffery Taubenberger, of the Armed Forces Institute of Pathology, Rockville, Md (Nature. 2005;437:889-893) and used an approach called “reverse genetics,” which involves transferring gene sequences of viral RNA into bacteria and then inserting combinations of the genes—often after manipulating them—into cell lines, where they combine to form a virus.

The researchers also produced variations of the virus for comparison, with certain Spanish flu genes replaced with corresponding genes from other flu viruses. The effects of the viruses in mice, chick embryos, and human lung cells helped identify the constellation of genes responsible for the extreme virulence of the 1918 influenza.

One high-virulence gene was HA, which encodes the hemagglutinin surface protein that helps the virus attach to cells and replicate properly and seemed to be responsible for much of the severe lung damage in patients infected with the Spanish flu. The 3 genes encoding the viral polymerase enzymes, which form the virus’ basic replication mechanism, were also found to be important for high virulence.

“Given that HA is responsible for so much pathology in the lung, if we could identify the mechanism for how that happens and then block it, perhaps it would be useful for antiviral development. With the identification of the polymerase genes contributing to disease, that represents another set of genes that might also be a good target for prophylactic and therapeutic interventions,” said Dr Tumpey.

“One thing that happened in the so-called Spanish flu was a high mortality rate among the healthiest individuals,” Dr Torres pointed out. “The healthier they were, the more susceptible they were.”

These findings reveal “essential information to help us speed our preparation for—and potentially thwart—the next influenza pandemic,” said Anthony S. Fauci, MD, director, National Institue of Allergy and Infectious Disease, National Institutes of Health, and Julie L. Gerberding, MD, MPH, director of the CDC.

Clinical Features

The incubation period of H5NI generally ranges from 2 to 4 days but can be up to 8 days, according to data published in the New England Journal of Medicine (2005;353:13741385). Initial symptoms usually include high fever and a flulike illness, usually with lower respiratory tract symptoms but sometimes with upper respiratory tract symptoms. Symptoms may also include diarrhea, vomiting, abdominal pain, pleuritic pain, bleeding from the nose and gums, respiratory distress, tachypnea, and inspiratory crackles. Nearly all patients present with clinically apparent pneumonia. Multiorgan failure, with renal dysfunction and occasionally cardiac compromise, including cardiac dilation and supraventricular tachyarrhythmias, have been widely reported.

Patients suspected of having the H5N1 virus should immediately be given a neuraminidase inhibitor—oseltamivir (Tamiflu) or zanamivir (Relenza)—pending the results of diagnostic testing. Recent human H5N1 viruses have been shown to be extremely resistant to the M2 inhibitors amantadine (Symmetrel) and rimantadine (Flumadine). A resistant variant of H5N1 was identified in a number of patients treated with oseltamivir, resulting from the replacement of a single amino acid in N1 neuraminidase (His274Tyr), according to the WHO.

“Resistance is ever present with the use of any antimicrobial, and we have to be aware that the emergence of resistance is generally due to the selective pressure of the use of antimicrobials,” said Dr Ryan. “We are not aware of any significant resistance to oseltamivir in human treated cases, both for normal influenza and for this particular strain of influenza.”

Although there is no vaccine currently available against the H5N1 virus, Sanofi Pasteur is developing a promising investigational vaccine against the avian flu virus, and around the world countries are stockpiling antivirals. However, the fear is that a pandemic will occur long before enough vaccine becomes available.

“Clearly we don’t have enough antivirals in the world to deal with all the potential cases that may occur in a pandemic, and WHO does believe that there is a public health need to look into this issue,” Dr Ryan pointed out. “However, we do have an effective drug license, and we are looking at all kinds of ways production can be scaled up and licencing arrangements and other things.”

In an effort to make more antivirals available in the United States, the FDA granted Roche approval of an additional capsule manufacturing site in the United States for the supply of oseltamivir, and the company has announced plans to significantly increase worldwide production capacity of the agent.

Look for Warning Signs

Health officials should be on the lookout for clusters of patients who have clinical symptoms of influenza and are closely related in time and place, as this suggests human-to-human transmission, according to the WHO. Cases in health care workers caring for patients with H5N1 infection should also trigger suspicions of human-to-human transmission.

“There was no advance warning for the 3 pandemics in the previous century,” said Dr Lee. “We have to keep a lookout in the pattern of human flu cases. We must detect human-to-human transmission at the earliest stage possible. We must pounce on human flu outbreaks with medicines and quarantine measures. We want to contain the pandemic, or at least slow its spread, at the earliest possible moment.”

Table. Number of human cases of H5N1 flu, 2003 to date

Country Cases Deaths

Cambodia 4 4

Indonesia 7 4

Thailand 19 13

Vietnam 91 41

Source: WHO.

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