Q & A
During my avian flu investigation, I conducted an interview with Angela Peck, MD. Angela is a senior fellow in pediatric infectious diseases, working at the UW, Children's Hospital, and Fred Hutchinson Cancer Research Center. Angela has worked at the CDC in the Respiratory and Enteric Viruses branch and was in Bangkok, Thailand when the bird flu first struck in 2004. This is our interview:
Q: In recent years, news about the bird flu has consistently appeared in the headlines, but hardly any news source has outlined what the bird flu is. Could you explain what exactly is the bird flu and its significance?
A: "Avian flu" refers to the respiratory illness caused by avian influenza virus. In humans, it causes primarily respiratory disease (cough, shortness of breath, pneumonia) with fever and may be accompanied by diarrhea. All influenza viruses have an envelope made of lipids with a single-stranded segmented genome (I'll talk a little more about this in your replication question). Two proteins project from the lipid envelope: the hemagglutinin (rod-like) and neuraminidase (mushroom-like) proteins. This is where the "H" and "N" come from in the name of each influenza virus. The hemagglutinin is important for the virus to attach to sialic acid receptors on cells, and the neuraminidase is important because this is the site of cleavage that allows new virus particles to be released from a cell and can then infect more cells. Humans and animals have distinct types of H and N - that is where the names such as H3N2 (a typical human influenza virus), H5N1 (highly pathogenic avian influenza), etc, come from. Birds act as a reservoir for a large variety of H and N proteins. A pandemic is a worldwide epidemic of influenza, and can occur when viruses with a new H or N emerge which causes severe disease in humans that is easily spread. Similarly, often birds carry certain types of avian flu and do not get sick. However, if a new type emerges and causes widespread activity in birds, there is concern that a human pandemic may occur. Since late 2003/early 2004, SE Asia has experienced the largest epizootic (in animals, large-scale outbreaks are generally called "epizootics" rather than "epidemics") ever seen.
Q: For years, scientists and public health experts have sounded the alarm on H5N1's lethality and the chances of it starting a pandemic. What would be necessary for H5N1 to start a pandemic and what are the chances of a pandemic occurring?
A: For a human pandemic to occur, the virus would have to evolve so that it can be efficiently transmitted from person to person. There are essentially 3 ways in which a pandemic could occur: 1) the virus may mutate so that there is direct and efficient introduction from birds to humans. Somehow, the hemagglutinin would have to be received equally well by receptors on both bird and human respiratory cells. There is suggestion that this is what happened in the 1918 H1N1 pandemic. 2) secondly, avian and human viruses may both infect an intermediate animal such as a pig. Because influenza has a segmented genome (more on #5), there may be reassortment and a new virus may enter humans that can be efficiently transmitted. 3) A third way for a pandemic to occur would be for the "mixing" of an avian virus and human virus to occur in a human infected with both, with reassortment leading to a new virus that could be easily passed from person-to-person.
So far, the humans that have been infected have had very close contact with poultry or a close family member - the virus has not yet undergone the proper changes that it needs to be easily passed from one human to another. But that is what we all worry about. I don't think anyone can predict the chances of it happening, but certainly we are in a more concerning time than ever before with the widespread infections of poultry despite efforts at containment.
Q: I have looked at everything, from Time to National Geographic to ABC's Primetime over the last month and a half. One thing that was inconsistent across the board was the estimated death toll, which ranged anywhere from 100 million to over 1 billion people dying of avian flu? What is the reasoning behind such a high death toll?
A: I alluded to this in the previous questions - if a new influenza virus emerges, the human population will have no immunologic protection (antibodies from past infections) to protect them from infection. Until 1997, H5 viruses had been seen in birds but not in humans. In Hong Kong in 1997 humans were first noted to be infected by H5N1: 18 persons were infected and 6 died. Most of those cases had contact with poultry, and the outbreak was controlled with the culling (mass killing) of all poultry. Over the intermittent years, the virus has changed and now is obviously causing a dramatic avian epizootic. Certainly, if the virus changed so that it could be efficiently passed from person to person, it is not difficult to imagine how quickly the virus could spread around the world. This is even more of a concern in our modern global society in which humans (and viruses!) easily travel around the world in less than a day's time.
Q: In most of the sources I've looked at, I've read that all avian influenza viruses originate among waterfowl. These viruses are said to be harmless to their hosts, but in recent months, avian influenza has been linked to the deaths of thousands of ducks and geese. Why is this phenomenon occurring?
A: I will again refer to the capacity for reassortment of the segmented genome which is unique to influenza and allows for selective pressure to cause changes in the virus, thus making it pathogenic for a variety of birds. Scientists have followed these viruses over time. I heard Dr. Malik Peiris, a virologist from Hong Kong, relate that they have done detailed surveillance on H5N1 since 1997. From 1998-2000, it was occasionally seen in imported geese, but then around 2001 appeared to move from geese back to chickens, triggering another cull of poultry in the markets. From 2002-2003, the virus continued to change so that it became highly pathogenic for ducks and a wide variety of wild birds. By 2003, re-emergence of human disease was seen, and a dominant genotype of virus had appeared.
Q: How does H5N1 go about infecting cells and how does it replicate?
A: It's helpful to think of replication in several steps, as these are also places for antiviral targets to work.
- Absorption - Viral attachment occurs via the hemagglutinin.
- Entry, Cleavage, Uncoating - The virus is then taken up into an endocytic vesicle with an acidic environment (becomes acidic via M2 ion channels), which allows the hemagglutinin protein to unfold. This opens up a fusion domain so the virus can fuse to the endocytotic vesicle and open up, releasing RNA into the cytoplasm.
- Transcription and Replication - The nucleocapsid and polymerase complex migrate into the cell nucleus. Both the virus' own polymerase and the host cell's polymerase are necessary for viral transcription.
- Protein Synthesis - Protein synthesis is in the cytoplasm, but there is migration of the nucleoprotein back to the nucleus to form nucleocapsids, followed by migration of the new viral particles to the cell surface.
- Virus Budding and Release - At the cell surface, the virus gains it's envelope and is released, involving cleavage of the sialic acid receptor by neuraminidase.
**Key to this process is that influenza always has 8 separate RNA segments packaged in its genome, and these segments can reassort with one another during replication. So you can see how segments from 2 separate influenza viruses could reassort with one another if a cell was infected with both simultaneously, which could result in dramatic changes to the surface "H" and "N" proteins. (By the way, these major changes are referred to as antigenic "shifts," whereas smaller minor changes due to point mutations in the genes coding for "H" and "N" result in antigenic "drift." Drift generally occurs yearly, which is why the influenza vaccine is made every year on the basis of the best prediction of which virus strains are going to predominate in that year.)
Q: Recent news has indicated that the world is not prepared to handle a mass pandemic. Do you agree or disagree with this statement and why?
A: I don't claim to be an expert on pandemic preparedness, but I would agree. Development of an appropriate vaccine takes time, and would need to be targeted as close as possible to the pandemic strain. At this point, treatment with oseltamivir appears to be effective, but supplies are limited. And consider that even if we, in developed countries such as the U.S., were able to limit and control spread of the virus - think of the even larger populations in Asia and Africa, where intensive surveillance will be crucial in early detection and control of a pandemic. Certainly, this is a time for increased surveillance and preparedness planning.
Q: Currently, the two known drugs that can treat an H5N1 infection are zanamivir (Relenza) and oseltamivir (Tamiflu). How do these drugs fight the avian flu?
A: Both are neuraminidase inhibitors, so they prevent cleavage of the receptor holding the new virus particle, thereby inhibiting release and further cell-to-cell spread of the virus.
Q: I recently read an article about how sauerkraut could possibly treat the bird flu. Do you think this is possible and why?
A: I can't think of any basis of why this would be possible, although I certainly don't know all there is to know (or much at all!) about kimchi, which was the traditional food of South Korea to which the articles refer. Apparently, from my quick perusal, 13 chickens were fed kimchi and 11 started to recover a week later. Apparently the spokesperson for NIH's National Institute of Allergy and Infectious Diseases said, "Although it certainly sounds interesting, NIAID, unfortunately, can't comment on the dish's effectiveness as we have not studied it." As an aside - I can't seem to find the actual report, but I do have concerns that it wasn't a very-well designed study. To really compare the effects of a "treatment," even in this situation, it would be necessary to give other infected animals a placebo treatment to see if they did equally as well. It could be many other things about that population of chickens that made them more likely to recover.
Q: While we are still on the topic of possible cures, what are scientists currently researching in regards to the bird flu?
A: To my knowledge (and after recent literature review), there are 3 compounds with antiviral activity against influenza. The first is ribavirin, an antiviral shown active in vitro but not widely studied in vivo. Practically, this would not work well in a pandemic situation, as it is best given in an aerosolized formulation and has potential toxicities. It is currently only used for high risk infants and severely compromised patients with respiratory syncytial virus infection (similar to, but still quite different from influenza). Amantadine and rimantadine are M2 hydrogen ion channel blockers, but lead to rapidly resistant influenza virus and have not been shown to be effective against avian influenza strains. So, that leaves the neuraminidase inhibitors zanamivir and oseltamivir. H5N1 isolates are generally sensitive to oseltamivir, but resistance has been shown to occur.
Q: Could you describe your experience in Bangkok at the time when avian flu first broke out?
A: It was fascinating to be in Bangkok - every day I opened the Bangkok Post (one of the 2 English language papers in BKK) to see what the new avian flu numbers were, number of people infected and dead). It was actually a very disturbing time in Thailand as there was much violence in southern Thailand (there was a bomb threat in a hospital we were visiting!) and the avian flu saga - a bit overwhelming for the prime minister, I'm afraid. For me, work went on as usual although I thought I may be asked to be involved at any time, or to extend my stay in Thailand, but that didn't happen. It was great for me to be able to attend a SE Asia regional avian flu meeting while I was there. Personally, I stopped eating the rather uncooked eggs that were served every day for breakfast, and to be honest, I was leary about ordering chicken dishes because I just didn't trust that it had been cooked thoroughly. I worked in the city, so my only contact with chickens was in food or briefly in the markets, so I didn't ever feel threatened. The government tried to have a big day to celebrate eating chicken in order to reassure the people but I don't think that went over very well! Being there, it's very obvious what a threat it is to the livelihood of so many people. Culling all chickens in affected provinces meant that the govenment had to try to offer some compensation to the chicken farmers. Cock fighting is a big deal over there, and the birds are worth much more than what the govt. was willing to compensate and so owners of fighting cocks tried to hide their birds, or smuggle them across borders so that they wouldn't be killed. Fascinating.
Q: What should the public know about avian influenza in general?
A: Although an immediate pandemic may not occur, it certainly seems that we are as close to another worldwide pandemic as we have ever been. Human influenza, including avian influenza that may become efficiently spread by humans, is likely to be spread primarily by large respiratory droplets. Therefore, practical issues of controlling respiratory secretions (with coughing, sneezing, etc) and basic hand hygiene are very important. Should a pandemic arise, non-pharmaceutical interventions may become necessary, such as the closing of schools and minimizing large public gatherings.
It is realistic to expect that a pandemic may occur in time. In the meantime, I would also not recommend hysteria - eating thoroughly cooked poultry and cooked poultry products should be safe, and even travel to areas with endemic avian flu is considered safe at this time, since human cases have involved intense contact with birds (or, in rare cases, with close family members). Any human infection with avian influenza represents an important opportunity for avian influenza to further adapt and gain the ability to transmit more easily among people. I have pointed out that a person with both infections (human and avian origin) simultaneously could act as a "mixing vessel" for new strains to be formed. As protection against human strains already circulating and to decrease human influenza infections, in general, I would strongly recommend vaccination against human influenza, certainly for international travelers but also for the general public.