Date: November 17, 2005
Updated: July 6, 2007
by Chaya Venkat
Unless you have been living in a cave, you cannot have missed all the references to "bird flu", "avian flu", "H5N1 super flu" in the mainstream media. Politicians are talking about it, epidemiologists are talking about it, virologists are talking about it, Wall street pundits are talking about it. There are as many opinions about bird flu as there are chickens in China. I would like to add my two cents, but I will stay strictly focused on issues as they pertain to CLL patients. For starters, here are issues that I will not be discussing:
This article is about the special risks we face as CLL patients, as immune compromised individuals, and the game plan that we might want to consider in light of that. There are no easy solutions, for us or for anyone else on this planet for that matter, if / when this pandemic becomes a reality. I have no magic bullets to offer, just some commonsense observations in case you have not thought of them yourself. I also attach some up-to-date reference material that you might find handy, a bit more authoritative information than the typical newscast stuff.
I would like to point out one other thing. If you are not a CLL patient yourself but a family member of caregiver, remember your family forms an integral unit; most likely you will all share the same exposure risks. If one of you gets the virus, chances are the rest of your family will too if, as expected, the virus develops high degree of contagiousness. You and your family will have to address this new danger as a single unit, with an agreed upon game plan that protects the whole unit. The weakest link determines the strength of the chain.
If the pandemic flu does become reality, your best bet is probably going to be avoiding the H5N1 viral infection in the first place. In any serious confrontation you may have with this virus, no hard feelings mate but I think the smart money is likely to be on the side of the virus. Prudence is definitely the better part of valor in this situation. There are some rather obvious things to do, in your efforts to say no-thanks to this infection.
The consensus seems to be that Tamiflu (generic name "oseltamivir") is the only anti-viral that may have a chance of controlling the H5N1 virus. Relenza, another antiviral drug on the market, seems to be less popular, probably because it is not effective via oral route but needs to be inhaled. Cheaper and older drugs such as Amantadine are likely to be less effective since the virus may have developed resistance to these drugs due to excessive use in poultry farming in China and elsewhere. Tamiflu is not a vaccine. It is an anti-viral medication that interferes with the ability of the virus to multiply in your body. It is called a "neuraminidase inhibitor". Don’t get confused if you see that bit of jargon in some of the articles I list below.
Right now, no proven vaccine exists that protects people against H5N1 version of Avian Flu. Scientists and healthcare officials are hoping that once the virus has shown its true colors and broken out as a full-fledged pandemic, we will be able to come up quickly with the right vaccine to match it, manufacture it in record time and in sufficient quantities and get it out to the frontlines. I know, this is a very tall order, which is why a lot of folks who study pandemics are losing sleep over it. But eventually we will have a vaccine, it will work, and it will be manufactured, life will go on. Vaccination is the game plan, a way to protect the people who have managed to dodge the bullet that long and had not yet become infected. (In the case of those who became infected, there are only two outcomes: they died, or they survived and therefore developed immunity against the virus. In either case, they are no longer part of the population that needs to be protected by vaccination).
That raises an interesting question for us. As we discussed earlier, vaccinations do not work very well for CLL patients. Vaccinations depend upon the body mounting a sufficient response against the offending pathogen, and then remembering that response so that the next time it sees the pathogen it knows what to do. Part of the immune response depends on very specific immunoglobulins (Igs, for short). Igs are made by plasma cells, which in turn come from healthy B-cells as they mature. Well, there you have it, in a nutshell. CLL patients have plenty of B-cells, in fact way too many of them. But they are not healthy B-cells, they are stunted and deformed CLL B-cells. They do not mature to make good and helpful plasma cells which then become the factories for generating immunoglobulins directed against dangerous pathogens. That is why so many CLL patients suffer from low immunoglobulin levels, get frequent infections and need intravenous infusions of Igs to help them out (IVIg Benefits). Declining Ig levels are a common theme as the years go by after diagnosis if CLL, as the original plasma cells die off and are not replace by new ones.
In addition to not having sufficient levels of Igs and the inability to produce the right type of Igs when exposed to vaccinations, CLL patients also have poorly functioning T-cells, dendritic cells and other cell lines that all play an important role in directing the traffic, mounting an appropriate response to vaccinations. Loss of "memory" cells means our bodies become less able to remember pathogens we may have encountered in the past, or been vaccinated against, and therefore less able to mount a good defense the next time we see the same villain. Many of the chemotherapy drugs that are an unavoidable part of the CLL scene are also very effective at further depleting our immune system reserves.
So, what are our options? Surely we cannot count on becoming Howard Hughes type recluses all our lives. The answer lies in something called "herd immunization". If you are a lone un-vaccinated CLL patient surrounded by a sea of "normal" people who have all been appropriately vaccinated, chances are slim that you will come in contact with the virus. Your protection rests on the immune capabilities of those around you. In other words, as soon as a vaccine becomes available, you should make every effort to get your family vaccinated. You can try your luck with the vaccination shot as well, if your doctor agrees, and you may wish to discuss with him the usefulness of combining the vaccine shot with adjuvants such as cimetidine or ranitidine, along the lines discussed in an earlier article (Flu Preparedness). Well down the road, when the H5N1 flu pandemic is no more than a nasty memory in the general population, and everyone (except you) have developed healthy doses of protection against this particular pathogen in their bodies, you can hope to get IVIG therapy whereby you can "borrow" the immunity developed by your fellow citizens.
If I have been a little too flip and if my particular brand of humor did not go over too well, I would not blame you. This is a serious subject; perhaps too serious and that is my excuse for trying to lighten it up with lame humor. Do I believe there is significant risk here? I am afraid I do. If not this year, then perhaps in the next few years it will be a real threat. But once again, the name of the game is to play the cards we are dealt to best advantage. Bitching and moaning does not get us anywhere. Getting panicked is even worse since it makes us do stupid things. Smart planning (and action) ahead of time may get us better odds. That is the whole point of this article, I wanted to try and spell out a few action items that you can consider, and implement if they make sense to you. A lot of very smart and well trained experts are looking at this threat. I have no crystal ball that can help me see the future more clearly.
Mid-Peninsula Citizen’s Preparedness Committee
This is a link to a comprehensive 68-page PDF document made available by a regional citizens' group in California. It has much useful information and practical preparation guidance for the individual citizen. This work was sponsored and supported by Jane and Peter Carpenter, who have also been strong supporters of CLL Topics since its inception (Peter is a former director of our corporation). This Citizen's Guide, dated July 1, 2007, is highly recommended reading. You might want to check if a more current version has been posted on the Flu Wiki website.
CIDRAP (Center for Infectious Disease Research and Policy)
This is a link to the CIDRAP website, you may wish to read their well written article on "cytokine storm", as well as browse the website for additional information. This site is a good way to get a good (and current) officially sanctioned overview.
NEJM Article - H5N1 in Humans
If you are going to read just one paper on H5N1 flu in humans, this is probably a good choice. As they say, know the face of your enemy before you go into a fight. This article does just that.
Avian Influenza A (H5N1) Infection in Humans (Full-text PDF Article)
N Engl J Med. 2005 Sep 29;353(13):1374-85.
Avian influenza A (H5N1) infection in humans.
Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY; Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
NEJM Article 2 - Tamiflu
This is a slightly older article, 1999 vintage, but it has a lot of interesting details and you can get the full text by clicking on the link below.
NEJM Tamiflu Article (Full-text Article)
N Engl J Med. 1999 Oct 28;341(18):1336-43.
Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza.
Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, Huson L, Ward P, Mills RG.
Department of Medicine, University of Virginia, Charlottesville, VA
BACKGROUND: Safe and effective antiviral agents are needed to
prevent infection with influenza A and B virus. Oseltamivir (Tamiflu) (GS4104),
which can be administered orally, is the prodrug of GS4071, a potent and
selective inhibitor of influenzavirus neuraminidases. We studied the use of
oseltamivir for long-term prophylaxis against influenza in two
placebo-controlled, double-blind trials at different U.S. sites during the
winter of 1997-1998.
METHODS: We randomly assigned 1559 healthy, nonimmunized adults 18 to 65 years old to receive either oral oseltamivir (75 mg given once or twice daily, for a total daily dose of 75 or 150 mg) or placebo for six weeks during a peak period of local influenzavirus activity. The primary end point with respect to efficacy was laboratory-confirmed influenza-like illness (defined as a temperature of at least 37.2 degrees C accompanied by at least one respiratory and at least one systemic symptom).
RESULTS: In the two studies combined, the risk of influenza among subjects assigned to either once-daily or twice-daily oseltamivir (1.2 percent and 1.3 percent, respectively) was lower than that among subjects assigned to placebo (4.8 percent; P<0.001 and P=0.001 for the comparison with once-daily and twice-daily oseltamivir, respectively). The protective efficacy of oseltamivir in the two active-treatment groups combined was 74 percent (95 percent confidence interval, 53 to 88 percent) at all the sites combined and 82 percent (95 percent confidence interval, 60 to 93 percent) at sites in Virginia, where the rate of influenza infection was higher than the overall rate. For culture-proved influenza, the rate of protective efficacy in the two oseltamivir groups combined was 87 percent (95 percent confidence interval, 65 to 96 percent). The rate of laboratory-confirmed influenza infection was lower with oseltamivir than with placebo (5.3 percent vs. 10.6 percent, P<0.001). Oseltamivir was well tolerated but was associated with a greater frequency of nausea (12.1 percent and 14.6 percent in the once-daily and twice-daily groups, respectively) and vomiting (2.5 percent and 2.7 percent, respectively) than was placebo (nausea, 7.1 percent; vomiting, 0.8 percent). However, the frequency of premature discontinuation of drug or placebo was similar among the three groups (3.1 to 4.0 percent).
CONCLUSIONS: Oseltamivir administered daily for six weeks by the oral route is safe and effective for the prevention of influenza.
NEJM Article on Tamiflu and other neuraminidase inhibitors
This is a brand new article in the New England Journal of Medicine, full text available free of charge. It discusses Tamiflu and other neuraminidase inhibitors in great detail, in the context of a flu pandemic.
New NEJM Tamiflu Article (Full-text Article)
N Engl J Med. 2005 Sep 29;353(13):1363-73.
Neuraminidase inhibitors for influenza.
Department of Pediatrics, Weill Medical College of Cornell University, New York, NY
The impact of influenza infection is felt globally each year when the disease develops in approximately 20 percent of the world's population. In the United States, influenza infections occur in epidemics each winter, generally between late December and early March. Recent events, including human cases of avian influenza, have heightened awareness of the threat of a pandemic and have spurred efforts to develop plans for its control.
Although vaccination is the primary strategy for the prevention of influenza, there are a number of likely scenarios for which vaccination is inadequate and effective antiviral agents would be of the utmost importance. During any influenza season, antigenic drift in the virus may occur after formulation of the year's vaccine has taken place, rendering the vaccine less protective, and outbreaks can more easily occur among high-risk populations. In the course of a pandemic, vaccine supplies would be inadequate. Vaccine production by current methods cannot be carried out with the speed required to halt the progress of a new strain of influenza virus; therefore, it is likely that vaccine would not be available for the first wave of spread of virus.1 Antiviral agents thus form an important part of a rational approach to epidemic influenza and are critical to planning for a pandemic.
Hong Kong Paper on Human Infection by H5N1
A very authoritative and no-nonsense paper from Hong Kong. Let us know if you wish to locate a full text version of this paper. Well written, lots of valuable information that is not out of the reach of the interested layperson reader.
Hong Kong Med J. 2005 Jun;11(3):189-99.
Human infection by avian influenza A H5N1.
Yuen KY, Wong SS.
Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong.
The Southeast Asian outbreak of the highly lethal avian influenza A H5N1 infection in humans is unlikely to abate because of the enormous number of backyard farms providing poultry as the main source of food protein in developing countries. This increases the risk of the emergence of a reassortant pandemic influenza virus with improved human-to-human transmissibility. Currently triage of suspected cases by epidemiological risk factors remains the only practical way of case identification for laboratory investigation and infection control. The clinical usefulness of rapid diagnostic laboratory tests requires more vigorous evaluation. The lethality of this disease may reflect systemic viral dissemination, cytokine storm, or alveolar flooding due to inhibition of cellular sodium channels. The present circulating genotype Z is intrinsically resistant to amantadine and rimantadine. Prognosis may be improved by early treatment with a neuraminidase inhibitor with good systemic drug levels, and post-exposure prophylaxis for health care workers is recommended. The role of immunomodulators and other modalities of therapy requires evaluation in randomised controlled trials, with prospective monitoring of the viral load and cytokine profiles in various clinical specimens. In view of the high fatality of the disease, a combination of contact, droplet, and airborne precautions are recommended as long as resources allow despite the fact that the relative importance of these three modes in nosocomial transmission of avian influenza is still unknown.
Choices in Handling a Pandemic
This article discusses the issues from the perspective of society having to make choices on how to handle a flu pandemic scenario. Once again, you can get the full article free of charge, just click on the link below.
Neth J Med. 2005 Oct;63(9):339-43.
Use of antiviral agents and other measures in an influenza pandemic.
Groeneveld K, van der Noordaa J.
Health Council of the Netherlands, PO Box 16052, 2500 BB The Hague, the Netherlands.
The Dutch Ministry of Health asked the Health Council for advice on how to prepare for a possible influenza pandemic. In two advisory reports the Committee responsible indicated the measures that it believes would need to be taken if such a pandemic were to reach the Netherlands. During a pandemic, the Committee recommends that every resident of the Netherlands with influenza-like illness should be treated with neuraminidase inhibitors such as antiviral agents. This approach serves to mitigate the course of the disease, to reduce infectivity and to allow patients to build up immunity to the virus. Since up to 30% of the population could become ill, the Committee anticipates that a stock of five million courses of the neuraminidase inhibitor oseltamivir is sufficient. If a pandemic were to occur at a time that the stock does not exceed the present 225,000 courses, the committee advises restricting treatment to three specified groups of patients. If the first few patients are traced shortly after they fall ill, the Committee recommends treatment of the patient and postexposure prophylaxis for his/her close contacts. The Committee does not advocate prophylaxis in general, but it can envisage prophylaxis for particular groups of patients or under particular circumstances. The Committee believes that in order to reduce rapid spread of the virus, schools should be closed and events where large numbers of people gather in a confined space should be cancelled. Because this recommendation would have major social and economic consequences, the Committee understands that its implication will depend on the anticipated severity and extent of the pandemic. The Committee regards vaccination against influenza as the best means of protecting the population. The development of a vaccine should be the absolute priority.
As the title implies, this article has the scoop on "cytokine storm" that accompanies H5N1 infection. You can get the full text article by clicking on the link, but I must warn you the jargon is a little intimidating in this one.
Respiratory Research 2005 Nov 11;6(1):135 [Epub ahead of print]
Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells.
Chan MC, Cheung CY, Chui WH, Tsao GS, Nicholls JM, Chan YO, Chan RW, Long HT, Poon LL, Guan Y, Peiris JS.
BACKGROUND: Fatal human respiratory disease associated with
influenza A subtype H5N1 has been documented in Hong Kong, and more recently in
Vietnam, Thailand and Cambodia. We previously demonstrated that patients with
H5N1 disease had unusually high serum levels of IP-10
(interferon-gamma-inducible protein-10). Furthermore, when compared with human
influenza virus subtype H1N1, the H5N1 viruses in 1997 (A/Hong Kong/483/97)
(H5N1/97) were more potent inducers of pro-inflammatory cytokines (e.g. tumor
necrosis factor-alpha) and chemokines (e.g. IP-10) from primary human
macrophages in vitro, which suggests that cytokines dysregulation may play a
role in pathogenesis of H5N1 disease. Since respiratory epithelial cells are the
primary target cell for replication of influenza viruses, it is pertinent to
investigate the cytokine induction profile of H5N1 viruses in these cells.
METHODS: We used quantitative RT-PCR and ELISA to compare the profile of cytokine and chemokine gene expression induced by H5N1 viruses A/HK/483/97 (H5N1/97), A/Vietnam/1194/04 and A/Vietnam/3046/04 (both H5N1/04) with that of human H1N1 virus in human primary alveolar and bronchial epithelial cells in vitro.
RESULTS: We demonstrated that in comparison to human H1N1 viruses, H5N1/97 and H5N1/04 viruses were more potent inducers of IP-10, interferon beta, RANTES (regulated on activation, normal T cell expressed and secreted) and interleukin 6 (IL-6) in primary human alveolar and bronchial epithelial cells in vitro. Recent H5N1 viruses from Vietnam (H5N1/04) appeared to be even more potent at inducing IP-10 than H5N1/97 virus.
CONCLUSION: The H5N1/97 and H5N1/04 subtype influenza A viruses are more potent inducers of proinflammatory cytokines and chemokines in primary human respiratory epithelial cells than subtype H1N1 virus. We suggest that this hyper-induction of cytokines may be relevant to the pathogenesis of human H5N1 disease.
Slide Presentations from SUNY Albany
Here are some well-designed and authoritative presentations from the State University of New York at Albany. The first one (you need to scroll down the page), Avian Influenza: the State and Worldwide View is particularly recommended. If you are visually inclined, these slides will help you get the picture.
Center for Public Health Preparedness, SUNY Albany.
Proceedings of Avian Influenza: Preparation and Response Regional Workshop.
University at Albany School of Public Health, Rensselaer, NY, June 22, 2005.
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