5 January 2006
Daniel R. Lucey, MD, MPH
Turkey Reports Two Deaths Due to H5N1 Virus:
The First Human Infections Outside China and SE Asia
Over the past 24 hours (January 4-5) Turkey has reported the laboratory-confirmed fatal infection of two teenage siblings with the H5N1 avian influenza virus. The 14 and 15 year old brother and sister ware thought to have been infected by close exposure to H5N1-infected poultry. NO evidence of a pandemic virus spreading in a sustained manner from persons-to-person-person-to person has been found. These two persons, however, are the first patients known to be infected with H5N1 outside of China and SE Asia (Vietnam, Thailand, Cambodia, and Indonesia).
The siblings lived in their agricultural town of Dogu Beyazit near the border with Armenia and Iran. They were hospitalized in the city of Van, also in eastern Turkey. Several other people from nearby areas are reported to be undergoing testing for H5N1 virus due to flu-like symptoms. Turkey’s second outbreak of H5N1 in birds/poultry was reported last week, this time from an area within 50 miles of Dogu Beyazit.
The WHO is sending a team of epidemiologists to help investigate the source of their infection, at the request of the Turkish government in Ankara. In addition, the European Union is reported to be sending a veterinary influenza expert to also provide assistance in evaluating the recent outbreak in poultry and its likely relationship with human cases. Such occurrences are likely wherever close contact exists between humans and H5N1-infected poultry, whether in Asia, Europe, Africa, the Americas, or anywhere else in the world.
18 January 2006
Daniel R. Lucey, MD, MPH
Turkey reports 21st patient with H5N1 this month and WHO is creating regional stockpiles of oseltamivir (anti-H5N1 drug) for developing nations. Is Africa next?
The accelerated pace of H5N1-related events continues. Today (18 January), Turkey reported the 21st patient with H5N1 since the outbreak began this month, with the great majority of patients being under 20 years of age, as was seen during the initial outbreak in 2004 in Vietnam and Thailand. Sequencing of one of the initial H5N1 viral isolates from a patient in eastern Turkey showed not only a change in the receptor-binding region of the virus (of uncertain significance) but also a susceptibility to the older anti-flu drug “amantadine”.
In addition, today the World Health Organization (WHO) Director-General Dr. LEE Jong-wook spoke in Beijing at the opening of the International Pledging Conference on Avian and Human Pandemic Influenza conference. He noted several positive steps that have occurred in Turkey this month. For example, “within one day, patient samples were collected, shipped, and received in the United Kingdom. The results were available within 24 hours. One hundred thousand treatment courses of oseltamivir were delivered within one day after the first cases were confirmed. A team of WHO experts traveled to Turkey within one day of the request by the Government”. He also noted that next week the WHO Executive Board will discuss immediate voluntary compliance with the revised International Health Regulations (IHR), prior to their currently planned June 2007 (17 months from now) “official entry into force”. These new regulations could then apply immediately if flu pandemic began before June 2007.
Yesterday, 17 January, the WHO announced that the company (Roche) that makes oseltamivir (“Tamiflu”) would donate 2 million additional treatment doses (10 tablets per course) to the WHO for a total pledge of 5 million treatment courses. The initial 3 million treatment courses, pledged last August, are to be stored centrally (near Geneva) for a “rapid response stockpile” to be used only at the onset of a pandemic. In contrast, the new 2 million treatment courses (20 million tablets) will be stored in different regions of the world and thus “will allow WHO to rapidly dispatch antiviral medicines to developing countries in greatest need, in the interests of affected nations and global public health” (according to the WHO on their website posting January 17th). In other words, these new regional stockpiles can be deployed now, and then reach patients ideally within hours after new human outbreaks are detected.
The new regional stockpiles of oseltamivir, the only oral drug to treat most patients with H5N1 influenza virus infection, is very welcome news indeed. How decentralized these stockpiles are remains to be seen, but hopefully they will provide rapid access to treatment for patients not only in Asia and parts of Europe, but also in the Middle East and Africa. In my opinion, H5N1 avian influenza will most likely reach Africa and the Middle East, as well as other nations in Asia, before the next pandemic of influenza occurs. Thus, strengthened preparedness for H5N1 avian influenza in Africa and the Middle East is needed now.
The WHO and US-initiated International Partnership on Avian and Pandemic Influenza should take action now to help better prepare nations in Africa where migratory birds that could carry the H5N1 virus are known to travel, including but not limited to nations along the Nile River such as Egypt, Sudan, and Ethiopia.
23 January 2006
Daniel R. Lucey, MD, MPH
WHO updates facts on H5N1 virus, including use of a 7-day incubation period for monitoring contacts, and consideration of 7-10 day therapy with oseltamivir (Tamiflu) for severe infection.
This weekend the WHO posted on their website a five-page document with important updates on their “Fact sheet” for avian influenza (“bird flu”).
The WHO update includes eight (8) topics: the disease in birds, the role of migratory birds, countries affected by outbreaks in birds, the disease in humans, history and epidemiology, assessment of possible cases, clinical features, and countries with human cases.
Eight (8) important clinical features warrant emphasis:
- “The incubation period for H5N1 avian influenza may be longer than that for normal seasonal influenza, which is around 2 or 3 days. Current data for H5N1 infection indicate an incubation period ranging from 2 to 8 days and possibly as long as 17 days…WHO currently recommends than an incubation period of 7 days be used for field investigations and the monitoring of patient contacts.”
- “Watery diarrhea without blood appears to be more common in H5N1 avian influenza than in normal seasonal influenza.”
- “On present evidence, difficulty in breathing develops around 5 days following the first symptoms…most recently, blood-tinged respiratory secretions have been observed in Turkey.”
- “Another common feature is multiorgan dysfunction, notably involving the kidney and heart.”
- “Common laboratory abnormalities include lymphopenia, leucopenia, elevated aminotransferases, and mild-to-moderate thrombocytopenia with some instances of disseminated intravascular coagulation”.
- “As the duration of viral replication may be prolonged in cases of H5N1 infection, clinicians should consider increasing the duration of treatment to 7 to 10 days in patients who are not showing a clinical response.”
- “In cases of severe infection with the H5N1 virus, clinicians may need to consider increasing the recommended daily dose or the duration of treatment, keeping in mind that doses above 300mg per day are associated with increased side effects.”
- “In severely ill H5N1 patients or in patients with severe gastrointestinal symptoms, drug absorption may be impaired. This possibility should be considered when managing these patients.”
With the additional of two more H5N1-infected young people from Indonesia today, the total number of WHO-lab confirmed patients has now reached 151 with 82 fatalities (54%). The update on clinical, epidemiologic, and avian-veterinary issues by the WHO is timely and very helpful.
A request to the WHO:
A detailed clinical, epidemiologic, and demographic summary of the all lab-confirmed patients, including recent ones from Turkey, Indonesia, and China would be very valuable and greatly appreciated by clinicians and hospital and public health planners worldwide.
For example, how often do clinically significant kidney and cardiac manifestations of H5N1 infection, mentioned in this WHO update, occur? How many patients have received oseltamivir (Tamiflu) within 48 hours of onset of illness, how many within 72, 96, or 120 hours of onset of illness, what data is available for adjunctive use of steroids for H5N1 lung disease (steroids were also used for SARS pneumonia as that epidemic unfolded), how many patients have been placed on ventilators, and of those how many have survived, what evidence is there regarding efficacy of N-95 respirators or surgical masks to prevent H5N1 infection, what data is there regarding patients with H5N1 infection who have received 7-10 days of oseltamivir therapy or 300 mg per day rather than the standard 150 mg (75 mg every 12 hours) for seasonal influenza, and other such key clinical issues that would benefit clinicians and planners everywhere?
28 January 2006
Daniel R. Lucey, MD, MPH
WHO Announces a 3rd Strategy to Address Pandemic Flu: Rapid Response and Containment Protocol and Training
On Friday, January 27 the World Health Organization (WHO) posted on their website (www.who.int) a 15-page document titled: “WHO pandemic influenza draft protocol for rapid response and containment” that constitutes a new, 3rd strategy for addressing the threat of the next flu pandemic.
Until now the first primary strategy included containing outbreaks of avian flu in poultry, strengthening the early warning systems, and decreasing the potential for human infections from poultry. The second primary strategy has been to increase national preparedness plans, access to antiviral drugs, development of vaccines against a future pandemic flu virus, and improve public health and communication preparedness efforts.
This 3rd strategy is complementary to the first two, namely: “…national and international planning and resources are coordinated and focused for the purpose of rapidly detecting, and potentially stopping—or containing—an emerging pandemic virus near the start of a pandemic. The purpose of this protocol is to facilitate rapid detection and assessment of potential “signals” that the virus is improving its transmissibility, and to guide implementation of effective response interventions before an emerging pandemic virus has spread beyond an initial outbreak zone”.
WHO admits that containment of a pandemic of influenza has never been attempted before because “the world has never before received an advance warning that a pandemic may be imminent”.
The WHO will serve as the coordinating body for all international efforts to contain the initial outbreak of a pandemic virus. This initial rough draft protocol contains information on training personnel, global and regional antiviral (oseltamivir) stockpiles, non-pharmaceutical stockpiles to include N-95 respirators and surgical masks, and timelines for the next three months.
WHO will devote 3-5 staff and ask partner organizations to lend (“second”) staff to work full-time to implement the protocol. A pool of highly trained persons to mobilize on short notice and be deployed to the area of the world where the pandemic starts is another short-tem high priority.
In terms of stockpiles, the WHO has been promised a total of 5 million “treatment courses” (assuming the current treatment course estimate of 10 tablets/course is sufficient to treat one patient). Three million treatment courses will be kept “for containment purposes”; the additional two million courses (20 million tablets) “is flexible and under discussion”. “For reasons of security and logistics flexibility, one half of the supply is stored in Switzerland and one half in the USA”.
Non-drug supplies in the inventory include: Personal protective equipment kits with N-95 respirators and surgical masks, gloves, goggles, boot covers, disinfectant wipes, biohazard bags, and pictograph directions. In addition, hand washing soaps or alcohol-based hand rubs, and instructions in multiple languages are included.
From March 6-10, 2006 a global meeting will be held in Geneva to reach agreement on the key concepts and procedures for this new strategy. By May 1, 2006 a training faculty will be recruited and teaching materials developed.
While some may view this unprecedented 3rd strategy of the WHO as quixotic, the international cooperation that the details of this protocol mandate signifies valuable progress in and of itself. Global lessons learned from this protocol could be generalized to other future outbreaks in addition to pandemic flu, e.g., the next SARS-like novel respiratory virus.
In addition, it would be an important expression of this global cooperation to deploy some of the 50 million tablets of oseltamivir to regions of the world with human H5N1 infections, for example to stockpiles in two or more locations in Asia, rather than having all of the stockpiles in Switzerland and the USA.
8 February 2006
Daniel R. Lucey, MD, MPH
Japan-WHO Joint Meeting on Early Response to a Potential Influenza Pandemic
A joint meeting on the potential influenza pandemic was convened by the Government of Japan and the World Health Organization (WHO) on January 12-13, 20006, in Tokyo, Japan. One hundred and thirty participants attended the meeting in Tokyo, including representatives from 14 Asian countries, donor countries, regional and international organizations. The participants expressed the need to develop mechanisms to facilitate rapid response and containment of Avian Influenza. The participants identified that avian influenza is already entrenched in many countries in Asia and that it has the potential to cause a serious global pandemic. Participants also realized that a crisis of this proportion could create serious social, economic, and health devastation in Asia and across the globe. The meeting in Japan identified specific “action areas” for decreasing the threat of an influenza pandemic, and made recommendations to both the participating countries and also to the WHO.
The meeting recommendations for countries included strengthening of national and local capacities for early detection and rapid response to a potential outbreak by using surveillance methods, increasing community awareness, and providing health officials with appropriate knowledge about early detection and reporting. Countries were urged to comply with the provisions of the International Health Regulations (2005), which facilitate early reporting and recognition of warning signals that are of international interest. Countries are additionally urged to report any early signs of a pandemic to the WHO, and promptly send laboratory samples for testing. Countries should review preparation and procedures prior to a potential pandemic, so any modifications can be made in a timely manner, especially any necessary modifications to a rapid-containment procedure. Country plans are also suggested to correspond appropriately with national, regional and international partners.
In addition to country recommendations, experts also developed urgent recommendations for both the WHO and other partners regarding early detection, rapid response, and containment. Recommendations for the WHO include developing and strengthening national capacities for early detection and helping countries strengthen their laboratory facilities, in addition to strengthening their own global laboratory networks. It has been recommended that WHO immediately develop or further development of the following: rapid response and containment strategies; an action plan composed of protocols, timeframe, coordination, and partner participation; training modules and education program regarding detection, response and containment; and a risk communication strategy for such an outbreak. Also, WHO should establish a response and containment decision-making process and an external advisory Influenza Pandemic Task Force to provide assessments on critical events related to an avian influenza pandemic. Lastly, WHO should use its Global Outbreak Alert and Response Network (GOARN) and other resources to mobilize staff and experts for rapid response and containment
Recommendations for other partners in collaboration with the WHO include development and strengthening of regional, national, and international capacities, development of communication strategies, and development of operational plan on stockpiles. All partners should coordinate the supply contents and use of their stockpiles with one another for rapid response
Given the potential threat of a human influenza pandemic as declared by the WHO, it is critical that governments, public health and medical communities, and international experts are prepared for early detection, response, and containment of what could potentially be a catastrophic event.
Danielle Meyer, Sarah Nordstrom, Cari Beesley, Javita Everhart, Joel Guerrero, Yang Li, Kristina Meko.
Georgetown University School of Medicine Master of Science course “Emerging Diseases: The Past as Prologue”.
10 February 2006
Daniel R. Lucey, MD, MPH
Dulling Occam’s Razor: The Challenge of Emerging Infectious Diseases When Applying the Single Explanation Principle in Public Health Policy
In February 2003 dozens of people began to suffer from high fevers accompanied by mild respiratory symptoms in several locations in Asia. Within days, similar symptoms involving individuals halfway around the world, in the Netherlands, were reported to the World Health Organization. Was this the beginning of the feared next influenza pandemic?
“All things being equal, the simplest explanation is the best one,” according to a principle attributed to the thirteenth-century philosopher William of Ockham. Following this logic, the anticipated pandemic was almost certainly in progress in 2003—a single viral strain was the simplest explanation for the similar symptoms. But scientists and policymakers employing Occam’s Razor, so often reliable, would have slipped badly in this case. What was actually occurring was a coincidence of three viral outbreaks: the primary emergence of what came to be called Severe Acute Respiratory Syndrome (SARS), which did eventually spread to multiple countries on several continents, an episode of H5N1 avian influenza, and another episode of H7N7 avian influenza.
These three diseases striking in the winter of 2003, observed in the context of the recent reappearance of the H5N1 strain, also show that Occam’s Razor still cuts too sharply when it comes to presumptively advocating a single contagion-control method to stem potential pandemic threats. In 2003, the two avian strains had a direct connection to animals (zoonosis)—being spread to humans by their direct association with avian species, but not observed spreading readily from human to human—whereas SARS was found to be readily contagious over short distances between people (little was observed about its ability to spread to or through animal populations). Since then, SARS has not reappeared, but the H5N1 flu has, and scientists are carefully monitoring for a mutation which would make interhuman contagion possible. Such mutations, often beyond the awareness of the public, mean that even if only one viral agent is evident, it is possible that it may be transmitted through multiple pathways: by droplets, through the air (aerosol), by interchange of bodily fluids, or through contamination of environmental surfaces (“fomites”).
The underlying complexity of the viral illnesses observed in February 2003 has lessons for those combating natural outbreaks of diseases in the future and for those anticipating intentionally-generated bioevents (infectious biological agents used as terrorist devices); it highlights the potential disconnect between the tendency common among scientists and politicians to look for a single workable philosophical solution and the fact that there can be more than one explanation for a given set of symptoms, and thus there might be more than one response to them.
In order to work effectively against the threat to public health from emerging infectious diseases, scientists and policymakers should be aware of the general inclination to try to find a single (causal) explanation for similar illnesses that are temporally related, but that eventually may turn out to be caused by more than one emerging infectious disease.
Christina Petrides
Georgetown University School of Medicine
Master of Science course in “Emerging Diseases: Past as Prologue”.
14 February 2006
Daniel R. Lucey, MD, MPH
Feb 7th-14: Avian Flu outbreaks reported in Nigeria, Azerbeijan, Greece, Italy, Bulgaria, Slovenia, Austria, Germany and Iran. Is this how quickly human flu will spread when the next pandemic hits?
Over the course of one week from Feb 7-14 laboratory-proven H5N1 infection of animals was reported for the first time from five nations (Nigeria, Azerbaijan, Greece, Italy, and Bulgaria). Initial results for H5N1, pending official confirmation in a second reference laboratory, were also reported from Slovenia, Austria, Germany, and Iran. Fortunately, so far no human infections with H5N1 have been confirmed in any of these countries, although some persons are being tested for this H5N1 avian flu virus.
Nigeria is the first nation in Africa to have reported H5N1 outbreaks. Chickens were reported to be infected with this virus and a die-off of chickens in northern Nigeria began in mid-January, approximately one month previously. In a WHO update 13 February, posted on their website, it was stated that “Occurrence of the bird flu has so far been confirmed in poultry in the three northern states of Kaduna, Kano and Plateau. Unconfirmed cases, also in poultry, have however been reported in Yobe, Nassarawa and Jigwa states as well as in the Federal Capital Territory—all in the north of the country”. The WHO has sent a team of experts to Nigeria to work as partners with the Nigerian team already in place.
Most of the other H5N1 outbreaks reported in the past week do not involve poultry at this time. Instead, birds and particularly swans have been found to be infected with the H5N1 avian flu virus. Predictably, there will likely be more nations, from Europe to the Middle East, Asia to Africa that will report additional H5N1 avian outbreaks in the weeks ahead.
Key lessons learned from the past 25 months of outbreaks of H5N1 must routinely be applied to these and future outbreaks. Such lessons include educating young persons and adults to avoid close contact with ill or dead poultry, and testing and rapidly treating patients with such exposure to poultry for H5N1 virus infection.
One can reasonably anticipate that when the next human pandemic of influenza occurs, whether directly related to the H5N1 virus or not, that the nation-by-nation spread of the pandemic human flu virus will at some point be as rapid as the avian outbreaks of H5N1 have been in the past week. If we are not much better prepared for the next human pandemic of influenza than we are today, then eventually the survivors will have investigations and commissions that will try to examine why we did not use the time we have now to prepare better for the pandemic.
17 February 2006
Daniel R. Lucey, MD, MPH
Recent Advances In Vaccine Development for the Treatment of Dengue
Dengue virus belongs to the Flavivirus family characterized by single stranded, positive sense RNA genome. Mutation rates in RNA viruses are exponentially greater than agents with DNA genomes due to the lack of proof reading mechanisms in the RNA dependant RNA polymerases of the former. This leads to the development of antigenic diversity because of varying levels of inter-virus genetic recombination. Although no licensed vaccine is currently available to combat dengue, a substantial amount of research has been undertaken over many years and in several countries. As a result, a number of conventional and novel vaccines are being developed and several are undergoing clinical trials.
In theory, an effective vaccine against dengue is possible because it causes an acute infection and the viral levels are effectively controlled in a span of 3 to 7 days. Further, an individual exposed to a particular type of dengue is immune against re-infection with that subtype, thus leading to experiments in animal models, which have shown that passive transfer of virus specific antibodies are protective against subsequent challenge with that specific viral subtype. The major obstacles relating to the development of an effective dengue vaccine include a lack of complete understanding regarding the pathogenesis of dengue hemorrhagic fever and the absence of a representative animal model. Pre-existing heterotypic dengue antibody is a risk factor for DHF; therefore, an effective vaccine will have to be tetravalent and needs to prevent infection with all four DV serotypes.
Recent advances in molecular biology and recombinant DNA technology have made it possible to create new strains that have the non-structural proteins of a certain subtype flanked by envelope antigens from a combination of different strains. This has lead to the emergence of the chimeric dengue vaccine. Recent studies have shown that by means of DNA shuffling and screening techniques, an envelope antigen capable of inducing neutralizing antibodies against all 4 types of dengue virus has been developed. Another approach has been the introduction of antibody inducing plasmid into DNA vaccines. This has also shown to produce significant antibody response in animal trials. Some other areas of interest include recombinant envelope vaccine, whole cell inactivated dengue vaccine and the development of a tetravalent live attenuated vaccine. Studies have shown that non-structural proteins in comparison to envelope antigens do not elicit efficient immune response on exposure. Novel approaches to find attenuated strains that selectively identify infected dendritic cells are underway. This increases the effectiveness and the safety of the vaccine.
The importance of understanding the correlation between protection and mechanisms of pathogenesis cannot be neglected. However, there is an escalating need to provide a solution to the global threat of dengue infection and the complications associated with the same. Better disease management, vector control and improved public health measures will help reduce the current disease burden, but a safe and effective vaccine is probably the only long-term solution to this problem.
Deepu Alex, Carlene Gong, Chelsea Johnson, Cheryl King, Anthony Ho, Katarro Rountree, and Lisa Sani
Graduate Students, Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases. Georgetown University School of Medicine Department of Microbiology and Immunology. Washington, DC
References
1. Tetravalent neutralizing antibody response against four dengue serotypes by a single chimeric dengue envelope antigen
Apt D, Raviprakash K, Brinkman A, Semyonov A, Yang S, Skinner C, Diehl L, Lyons R, Porter K, Punnonen J.
Vaccine. 2006 Jan 16; 24(3): 335-44. Epub 2005 Aug 10.
2. Non-structural proteins of dengue 2 virus offer limited protection to interferon-deficient mice after dengue 2 virus challenge
Calvert AE, Huang CY, Kinney RM, Roehrig JT.
J Gen Virol. 2006 Feb; 87(Pt 2): 339-46.
3. Comparison by flow cytometry of immune changes induced in human monocyte-derived dendritic cells upon infection with dengue 2 live-attenuated vaccine or 16681 parental strain
Sanchez V, Hessler C, Demonfort A, Lang J, Guy B.
FEMS Immunol Med Microbiol. 2006 Feb 1; 46(1):113-23.
4. Understanding dengue pathogenesis: implications for vaccine design
Stephenson
Bull World Health Organ.2005 Apr; 83(4): 308-14. Epub 2005 Apr 25
5. Dengue vaccines: problems and prospects
Chaturvedi U C, Shrivastava R, Nagar R
Indian J Med Res. 2005 May;121(5): 639-52. Review.
22 February 2006
Daniel R. Lucey, MD, MPH
Dengue Fever 2006: New Year, New Outbreaks
Dengue fever can produce widespread epidemics characterized by high morbidity rates, but the vector-borne flavivirus generally causes much lower mortality rates unless shock and hemorrhage occur. Four different dengue virus serotypes exist. All four cause febrile illness in humans, which can lead to dengue hemorrhagic fever in more severe cases. The CDC stated recently: “In 2005, dengue is the most important mosquito-borne viral disease affecting humans; its global distribution is comparable to that of malaria and an estimated 2.5 billion people live in areas at risk for epidemic transmission” [1].
Reported outbreaks of dengue fever, precautionary measures against the virus, and other dengue news occurred in the following countries last month:
BRAZIL: A dengue fever outbreak continues to spread throughout two districts of Rio de Janeiro: Barra da Tijuca and Jacarepagua. According to Reuters, a 45 year-old-woman recently succumbed to the virus and doctors suspect two more dengue-related deaths [2]. When the outbreak initially began in December, a 52-year-old man passed away from the disease, which marked the first death of the outbreak. Rio health authorities confirmed 432 new cases of dengue fever last month – a tremendous increase from the 58 cases reported in January 2005 [3].
SRI LANKA: To prevent and control the spread of dengue fever, the Health Ministry plans to seek Cabinet approval for “The Prevention of Mosquito Breeding Act,” which would ban the manufacture and use of polythene and plastic containers [4, 5]. Disposable items like plastic cups serve as ideal breeding grounds for mosquitoes and have contributed to the spread of dengue throughout the country. According to South Asian Media Net, a ministry official told the Daily Mirror that although the number of dengue cases declined from 15,463 in 2004 to 5,211 in 2005, reports from last month alone indicate 698 new cases along with one death [5].
MALAYSIA: Health Ministry Director Ismail Merican announced an outbreak of dengue fever in the Tanah Merah district of Kelantan [6]. Officials recently learned that the two 13-year-old girls who died in the district last month tested positive for dengue, not Japanese encephalitis. In addition, 11 other dengue cases were reported in Tanah Merah last month. According to AsiaNews.it, Ismail stated, “We have beefed up our control measures. Whether it is dengue or JE, the root cause is mosquitoes, so we have taken measures to ensure cleanliness” [6].
ECUADOR: According to El Comercio, Health Minister Ivan Zambrano acknowledged a second death in Ecuador from the current outbreak of dengue fever [7]. Like the first fatality that occurred on January 13th, the 65-year-old woman who recently past away suffered from dengue hemorrhagic fever. Zambrano reports efforts between the Crisis Committee, province directors, the Malaria Program, and local epidemiologists to control and prevent future cases. Approximately 4,000 cases of classic dengue fever occurred in 2005 along with 75 cases of hemorrhagic dengue, as reported by El Diario [8].
PARAGUAY: To prevent a potential outbreak of dengue fever, Public Health Ministry officials have recommended that community members in Asuncion eliminate mosquito-breeding sites that form after rainfall [9]. Because areas within Asuncion average a 4.1 percent larval infestation index, the ministry aims to reduce the index to less than one percent, which decreases the odds of virus transmission. ABC Digital reports that prevention success also depends on increased vector surveillance and participation by the entire community to implement corrective measures [9].
Comments: The proposed “Prevention of Mosquito Breeding Act” in Sri Lanka may prove beneficial, while recognizing that containers made from other materials like glass and aluminum can also serve as breeding grounds for mosquitoes. As noted in reports from Paraguay, prevention success greatly depends on cooperation among all members of the entire community. Everyone in dengue-afflicted areas must therefore work together to eliminate mosquito breeding sites by properly disposing of trash, covering buckets of water, and removing other outdoor items that collect rain. Surveillance also plays a pivotal role in the battle against infectious disease. Transparency remains essential to control disease outbreaks and prevent future cases; early notification enables health officials and the public to adopt precautionary measures in a timely fashion.
References
1. CDC. Division of Vector-Borne Infectious Diseases. Dengue Fever, Current Trends. Available at: http://www.cdc.gov/ncidod/dvbid/dengue/. Accessed on 8 February 2006.
2. Reuters. At least two dead in Rio dengue fever outbreak. Available at: http://www.alertnet.org/thenews/newsdesk/N26376317.htm. Accessed on 12 February 2006.
3. Agencia Brasil. Rio Physicians’ Syndicate issues international dengue alert. Available at: http://internacional.radiobras.gov.br/ingles/materia_i_2004.php?materia=254853&q=1&editoria=. Accessed on 12 February 2006.
4. South Asian Media Net. Plastic containers and bags to be banned. Available at: http://www.southasianmedia.net/Archive_full.cfm?nid=268239. Accessed on 6 February 2006.
5. Daily News. New act on “Prevention of mosquito breeding” soon. Available at: http://www.dailynews.lk/2006/02/06/. Accessed on 6 February 2006.
6. AsiaNews.it. Malaysia scrambles to contain dengue outbreak. Available at: http://www.asianews.it/view.php?l=en&art=5287. Accessed on 6 February 2006.
7. El Comercio. Otra persona falleció por el dengue hemorrágico. Available at: http://www.elcomercio.com/noticia.asp?seccion=2&id=23571. Accessed on 6 February 2006.
8. El Diario. Manabí ya supera los 20 casos de dengue. Available at: http://www.eldiario.com.ec/?module=displaystory&story_id=59446&format=html. Accessed on 6 February 2006.
9. ABC Digital. Story available at: http://www.abc.com.py/articulos.php?fec=2006-01-30&pid=231372&sec=3.
Deepu Alex, Carlene Gong, Chelsea Johnson, Cheryl King, Anthony Ho, Katarro Rountree, and Lisa Sani
Graduate Students, Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases, MICB-524 “Emerging Diseases: Past as Prologue”
Department of Microbiology and Immunology
Georgetown University School of Medicine
27 February 2006
Daniel R. Lucey, MD, MPH
H5N1 spreads to Niger, to more areas in Egypt and Nigeria, to turkeys in France. China warns of “massive outbreak,” and WHO expands website with maps, key documents in Arabic, and updated Hospital Infection Control Guidelines.
The rapid pace of new information on the avian spread of H5N1 continued over the past week with reports this morning that domestic ducks in southern Niger, near the town of Magaria, close to the border with Nigeria, have tested positive for H5N1. Reuters, AP News, and CNN cite OIE today as confirming this initial H5N1 outbreak in Niger. In Nigeria, at least seven of the 36 states, along with the central Federal Capital Territory, are reported to have H5N1 outbreaks, with two more states undergoing tests. Multiple governates (provinces) in Egypt have also reported H5N1 this month.
Updates on H5N1 in Egypt, with at least eight (8) key documents in Arabic, can be found on the Eastern Mediterranean Regional Office (EMRO) website: www.emro.who.int . This information can be found in a newly optimized WHO website section on avian and pandemic influenza begun last Friday, February 24th. This new website also contains excellent color maps illustrating outbreaks in humans, wild birds, and poultry. These maps can be found at: http://gamapserver.who.int/mapLibrary/app/searchResults.aspx
The Western Pacific office of the WHO, also listed on this newly consolidated WHO website, includes an important updated article (as of February 9th) on Infection Control for hospitals, including use of fit-tested N-95 respirators for health care personnel. The 58 page document, at the following URL is titled: “Avian Influenza, including Influenza A(H5N1), in Humans: WHO interim Infection Control Guideline for Health Care Facilities.” www.wpro.who.int/health_topics/avian_influenza/publications.htm
Over the past week France has reported an outbreak of H5N1 in turkeys, and decided to begin vaccination against H5N1. Japan announced it will ban poultry imports from France.
In the past 48 hours the State Agriculture Minister of China, Mr. Du Qinglin, reported another poultry outbreak and two more human cases (one in a pregnant woman). He is also quoted as saying “In light of the current situation, the possibility of a massive bird flu outbreak cannot be ruled out,” according to today’s South China Morning Post (Feb 27 by Bill Savadove in Shanghai). This comment was also carried in the China Daily, and China View (www.chinaview.cn).
In Indonesia today, the WHO confirmed the 20th fatality of the 27 laboratory-confirmed patients with H5N1 infection. This brings the WHO total global number of deaths due to H5N1 virus to 93, from a total of 171 WHO lab-confirmed patients (54%) in seven nations.
This highly accelerated pace of H5N1 spread from Asia to multiple nations in Europe and Africa is likely to continue as migratory birds transport the H5N1 virus to further regions over the next three months.
In addition, the potential role for human transportation of H5N1-infected poultry and exotic birds is emphasized by the two reports 21 February in ProMED Mail (Archive Number 20060221.0565) item #4: ”Spain, smuggled Chinese poultry meat.” 21 tons of poultry was confiscated by police in the coastal town of Benidorm in the province of Alicante, Spain. The meat included chicken and duck, “thought to have been imported from China illegally.” It is thought that the meat was to have been brought to Spain by lorry, and that its final destination was to have been Chinese restaurants across the Province of Alicante.”
Immediately following this report, the moderator noted that “2 days ago, 20kg of chicken tongues from China were intercepted at Rio de Janeiro’s international airport, presumably destined for Chinese restaurants in Brazil.”
Sooner or later, one way or another, the H5N1 highly pathogenic avian influenza virus (HPAI) will arrive in the Americas. If the USA fails to prepare comprehensively for avian and pandemic influenza, then it will not be a ‘failure of imagination” (to use the term applied by some to the 9/11 attacks) or a “failure of initiation” (to use the term applied by some to the Hurricane Katrina disaster), but a “failure of implementation” because the warning has been years in coming and a national and international response initiated.
The catalyst to implement comprehensively the international global partnership on avian and pandemic influenza, admirably begun in the autumn of 2005, should not have to be the arrival of the H5N1 virus in the USA.
3 March 2006
Daniel R. Lucey, MD, MPH
WHO: New H5N1 prototype strain, A/Indonesia/5/2005, is available for pandemic vaccine development
The World Health Organization (WHO) announced today that the WHO Collaboration Centres (WHOCCs) and Reference Laboratories have begin development of several new recombinant H5N1 prototype vaccine strains that represent genetic sub-groups of viruses. One specific H5N1 vaccine strain, made from A/Indonesia/5/2005 by the WHOCC at the Centers for Diseases Control and Prevention, Atlanta is now “available for distribution, under a Material Transfer Agreement (MTA)”.
Interested companies and organizations can contact the Global Influenza Programme or the WHOCC at the CDC in Atlanta, Georgia.
WHO also noted that work on H5N1 prototype vaccine strains based on viruses circulating recently in Africa and Europe is underway in other WHO Collaborating Centres and Reference Laboratories.
Meanwhile, plans from 2005 to stockpile an earlier prototype H5N1 vaccine in the USA were updated by the vaccine manufacturer, Chiron Corporation, last Friday (Feb 24). They announced that the US Department of Health and Human Services “agreed to extend delivery terms for a stockpile of H5N1 bulk influenza vaccine”.
Specifically, Chiron reported production of this H5N1 vaccine has been ongoing at its Liverpool, England facility, and that they will “complete approximately 70 per cent of the order before turning operations to annual production of FLUVIRIN® influenza virus vaccine in March” (this month). Chiron anticipates resuming work on this H5N1 vaccine contract after completion of the FLUVIRIN (annual human influenza vaccine) effort in the autumn of 2006.
The real-time WHO Collaborating Centres and international Reference Laboratories are providing a much-needed service in constantly updating antigenic and immunological studies as the H5N1 virus continue to evolve. Whether more than one H5N1 vaccine will become necessary to afford protection against strains that evolve as the virus spreads from three continents (Asia, Europe, and now Africa) is a critical question that only such global collaborative work can best answer.
March 9. 2006
Daniel R. Lucey, MD, MPH
US Pandemic Plan Preparedness & Response Update
Federal Updates
On February 6, the Department of Human and Health Services (HHS) proposed a $698 billion budget for FY 2007, an increase of $58 billion from last year. Included in the proposed budget are further allocations of funds for pandemic preparedness and response:
- $23 billion allowance for the expansion of domestic vaccine and surge capacities, antiviral stockpiles, research and development of vaccines and antivirals, and supplies for the Strategic National Stockpile (SNS)
- $352 million for the expansion of capabilities in surveillance, detection, risk communication, response, and containment
- $1.3 billion HHS investment in the improvement of state and local public health preparedness
- Increased funding of $110 million for the development of new medical countermeasures for the SNS
- A $20 million increase in funding for improving safeguards to the national food supply during a public health emergency or terrorist attack.
For more on the breakdown of the proposed 2007 HHS budget, visit http://www.hhs.gov/budget/07budget/overview.html.
Environmental Protection Agency (EPA) releases list of disinfectants that can be used in poultry facilities against avian influenza
The U.S. Environmental Protection Agency (EPA) recently released a list of 90 registered disinfectants that can be used and are currently in use in poultry facilities to protect against influenza A viruses. Though these disinfectants are not specific for H5N1, the EPA believes that these products will be effective against the H5N1 avian influenza strain. For a list of these registered disinfectants and guidelines on their use, visit the EPA site at http://www.epa.gov/pesticides/factsheets/avian_flu_products.htm.
Business Planning:
In order to assist businesses in planning for pandemic influenza, HHS and the CDC have developed guidelines and checklists for planning for the impact on businesses, employees and consumers. It has guidelines on establishing policies during pandemic, information on allocating resources, and strategies for educating and communicating with employees[1].
A national conference on business planning for pandemic influenza was held on Feb 14 and 15 in Minneapolis, sponsored by the University of Minnesota Center for Infectious Disease Research and Policy (CIDRAP), along with the US and Minnesota Chambers of Commerce. A poll taken during the conference on business preparedness indicated only 18% out of 300 businesses who participated declared that they had plans in place for pandemic influenza, 59% started to plan, 21% had not started yet and 2% rely on their existing crisis management plans. Key areas of importance for business planning included focusing on workers, the involvement of business leaders in planning strategies, reconsidering methods for obtaining supplies and materials, and government restrictions[2].
Family Planning:
In order for households to prepare for a pandemic, the government has provided information that gives planning suggestions to individuals and families and can be accessed at www.pandemicflu.gov. These suggestions include a checklist, health information sheets, emergency contact forms and general information on what people can expect in the event of a pandemic. The checklist includes activities such as stockpiling supplies of non-perishable foods and water, becoming familiar with your local community flu plan, and practicing good hygiene to avoid infection. The health information sheets and emergency contact forms will be helpful if medical attention is needed. They provide contact information, blood type, allergies and medical conditions for each person in the household. In order for people to be prepared and informed in the event of a pandemic they should be ready for disruptions in usual services, schools, travel and other aspects of daily life, and they should inquire about the possibility of working from home. By using these resources people can begin to take steps in their own homes to prepare for pandemic flu.
Trisha Asuncion; Dr. Thomas Calhoun, MD, FACS; Susan Francisco, Aisha Salazar, and Dr. Camelia Savulescu, MD, MPH
Graduate Students, Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases
Georgetown University School of Medicine, Department of Microbiology and Immunology
Washington, DC
12 March 2006
Daniel R. Lucey, MD, MPH
Cameroon reports H5N1 near Nigerian border as WHO Director- General outlines steps to limit H5N1 spread in Africa
On Sunday, March 12, the Associated Press reported that the government of Cameroon reported on state radio that the H5N1 avian influenza virus has been found in a duck on a farm in the northern part of the country near the border with Nigeria. If confirmed, Cameroon would become the 4th African nation with the H5N1 virus, following Nigeria, Niger, and Egypt over the past month. Human infections will be diagnosed in the future in Africa, as have over 175 patients previously identified by lab-testing from East and SE Asia, Iraq and Turkey.
The Cameroon government reported that the virological identification of the virus as H5N1 had occurred at a reference laboratory in Paris, France. A second media report, by Reuters (South Africa), quoted France’s RFI radio as reporting that the Pasteur Institute in Paris identified the virus as H5N1 and also reported that it was isolated from a duck. Reuters cited the Cameroon English-language state radio as reporting that young chicks in the northern town of Maria may have been infected with H5N1 virus as well. Reuters also reported that 1,000 dead one-day old chicks had been found dumped near administrative offices in Morgue.
On Thursday, March 9th, the WHO Director-General, Dr. LEE Jong-Wook, announced during a trip to Madagascar, Mauritius, and Kenya that African nations must take action to limit the spread of H5N1 in animals and the risk of infecting humans. Among these actions he included:
One: Identify, confirm and rapidly report H5N1 in bird; then act to stop the outbreaks, including by “on-the-spot” cash compensation to backyard poultry owners.
Two: Identify, confirm, and treat people infected with H5N1 virus.
Three: Collect, examine, and share H5N1 specimens to determine mutations in the virus that might allow the onset of a human pandemic, and to develop better vaccines. All nations must have both an avian influenza and a human pandemic influenza preparedness plan.
The WHO Director-General went on to congratulate Kenya for its very proactive role in influenza preparedness, including participating in both the November 2005 meeting in Geneva and the January 2006 influenza meeting in Beijing. He also emphasized the vulnerability of Africa given its “already overburdened health care systems”. In addition, he cited the fact that “We do not know, for example, what kind of an impact a pandemic influenza virus would have on people who are already immunosuppressed as a result of HIV”.
The USA and other willing partners in the international community should immediately take action to support the preparedness and response needs of nations in Africa to prevent and control the further spread of H5N1 avian influenza across the continent. A failure to seize this initiative now means that the H5N1 virus will become widely endemic in Africa and thus more deadly, more economically ominous, and much more difficult, if not impossible, to prevent and control.
Lessons from the past quarter century of global experience with another virus, HIV, and its AIDS/SIDA pandemic, as well as the spread of H5N1 influenza across Asia into Europe and Africa over the past three years, should make perfectly transparent the need for such immediate action by the USA and international partners.
March 18, 2006
Daniel R. Lucey, MD, MPH
Dengue virus update
Saudi Arabia: As the result of four cases of dengue fever in the town of Jeddah, several entrepreneurs were reported to be selling adulterated insecticides as a “magic fix” to kill mosquitoes. Health officials worry that these chemicals might cause adverse health effects. In recent weeks, the city of Jeddah has started to fill swamps and still water sites to control the mosquito population. (1)
Vietnam: In the last week of February, 375 new cases of Dengue fever were reported nationwide, raising the total to 4,800 so far this year. Most of the cases center around Ho Chi Minh City. Health officials are worried that the Dengue outbreak might become an epidemic since the rainy season has not started yet (it peaks around May) (2).
Brazil: In comparison to last year, the case rate so far this year is much lower (33,000 in 2005 versus 25,000 in 2006). The outbreak is centered around two cities, Rio de Janeiro and Goiania. The Secretariat of Health Vigilance, Jarbas Barbosa, says that the dengue problem is a matter of effective prevention, stating that where adequate prevention measures were implemented there have been no problems. (3)
Ecuador (Easter Island) Dengue fever threatens to become endemic in the Easter Islands. The virus is believed to have been brought to the island by tourists. (4)
India: In February, there were 91 cases of Dengue fever in Thiruvananthapuram. (5)
Hong Kong: So far, all of the reported cases of dengue fever in Hong Kong have been imported. Health officials are initiating an education campaign about dengue fever and how to avoid exposure. (6)
US Virgin Islands: There have been no reported outbreaks this year. Based on last year’s outbreaks, which affected tourist areas, the health department has created posters about dengue fever and posted them around various neighborhoods. They have also distributed free mosquito nets to families with infants and young toddlers and plan long-term information campaigns in the public schools about dengue and mosquitoes. (7)
References:
1. Gulf News: Traders exploit dengue to sell adulterated insecticides
Gulf News (Dubai, United Arab Emirates)
March 7, 2006
2. South Vietnam faces dengue epidemic
http://english.vietnamnet.vn/social/2006/02/545951/
Vietnam News Briefs:
Health & Environment: 75.5% of Dengue Fever Patients Identified in Mekong Delta
Vietnam News Briefs (Vietnam)
February 15, 2006
3. Aumento de casos de dengue no Rio não representa epidemia, diz ministro interino
Alana Gandra
Repórter da Agência Brasil
http://internacional.radiobras.gov.br/ingles/
4. Radio New Zealand Broadcast
5 Alert against dengue outbreak sounded.
The Hindu
http://www.hindu.com/2006/03/04/stories/2006030421860300.htm
6. The People’s Daily Online
HK confirms one imported dengue fever case
http://english.people.com.cn/200602/28/eng20060228_246761.html
7. Health begins campaign to prevent dengue fever
By JOY BLACKBURN
Saturday, February 18th 2006
The Virgin islands Daily News
http://www.virginislandsdailynews.com/index.pl/article_home%20?id=13408667
Deepu Alex, Carlene Gong, Chelsea Johnson, Cheryl King, Anthony Ho, Katarro Rountree, and Lisa Sani
Graduate Students, Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases, MICB-524 “Emerging Infectious Diseases
30 March 2006
Daniel R. Lucey, MD, MPH
US To buy 50 million N-95 Respirators as part of Updated Pandemic Flu Planning
The Secretary of the Department of Health and Human Services, Michael Leavitt, posted online (www.pandemicflu.gov) this month (March 13th) a 12-page update on the US Pandemic Influenza Plan that includes purchase this year of 50 million N-95 respirators. Other non-pharmaceutical countermeasures for a future flu pandemic to be stockpiled this year by the US include 6,000 ventilators, 50 million surgical masks and an unstated number of face shields, gloves, and gowns.
Such countermeasures are a welcome addition to the US preparedness stockpile for the future flu pandemic, as well as for other respiratory-transmitted biological threats, both natural and man-made. In particular, the addition of the 50 million N-95 respirators will prove extremely helpful for optimal protection of health care and other first responders in situations when the future pandemic flu virus is transmitted not only by droplets, but by smaller droplet nuclei (“airborne precautions”), for which fit-tested N-95 respirators are required.
This updated plan by Health and Human Services (HHS) also reported that this month over 14 million courses (not doses) of the anti-flu drugs “Tamiflu” (oral capsules) and “Relenza” (an inhaled drug) had been purchased. Thus, the total national stockpile has been increased to almost 20 million courses. The overall US goal is 81 million courses of anti-flu drugs by the end of 2008 (33 months from now). HHS plans to purchase 50 million of these courses and subsidize by 25% the remaining 31 million courses that the individual states must purchase.
Much information is contained in this document on pre-pandemic vaccines (e.g., against the two current clades of H5N1 virus) and future pandemic flu vaccine(s) (that can only be made after a pandemic flu virus appears in the world). Most immediately notable, HHS Secretary Leavitt noted that the US is beginning development of a 2nd H5N1 vaccine based on an antigenically distinct clade of the virus that has evolved and spread in several areas. This new clade of H5N1 is based on an H5N1 virus isolated from a person in Indonesiain 2005. Thus, is referred to as an “Indonesia 2005” strain of H5N1, in contrast to the initial H5N1 vaccine currently being studied and stockpiled in the USA that is referred to as “Vietnam 2004”.
Additional pre-pandemic and pandemic vaccine issues addressed in this update include development and funding for research of cell-culture based influenza vaccines, liability protection for the vaccine industry, new FDA written guidance (posted on the FDA website www.fda.gov) on criteria for clinical development and licensure of avian and pandemic flu vaccines, and recognition of the importance of “antigen-sparing” vaccines that use vaccine adjuvants or are given intradermally (ID) rather than intramuscularly (IM).
Overall, this 12-page document is a very practical and useful update on multiple fronts in the preparedness effort against the future pandemic influenza. In particular, the purchase of 50 million N-95 respirators is critically important.
Stockpiling of N-95s and fit-testing of emergency response personnel has been repeatedly advocated by this author over the past 24 months, since coordinating the purchase of approximately 500,000 N-95 respirators (and 2.5 million surgical masks) by the Washington, DC Department of Health in anticipation of both natural threats (e.g., pandemic flu, another SARS-like virus, others) and bioterrorism threats (smallpox, genetically-engineered threats, reaerosolized anthrax over large urban areas, and others).
April 5, 2006
Daniel R. Lucey, MD, MPH
Avian Flu Vaccine and Drug Preparedness 2006 Update
March 29, 2006
The Food and Drug Administration approved Relenza (zanamivir) for prevention of influenza A and B in adults and in children above the age of five. In several trials Relenza was shown to significantly reduce the development of symptoms in households where flu was present. The side effects noted during the study were fairly mild in both children and adults; however some severe side effects were noted. Of note, Relenza is not recommended for use by individuals with respiratory problems, including asthma. This drug is being added to the Strategic National stockpile to prepare for a flu pandemic.
The National Institutes of Health and the National Institute of Allergy and Infectious Diseases released the results of the first H5N1 vaccine trials in healthy adults. About half (54%) of the individuals made virus-neutralizing antibodies to the H5N1 virus after two shots of the highest dose (90ug) of the vaccine. This trial had two parts. The initial part consisted of four trial groups and one control group, each of which received a different amount of vaccine (7.5, 15, 45, and 90ug). One month after vaccination the individuals were tested for antibody levels. The groups then received a second vaccination, followed by antibody testing one month later. After this initial trial proceeded without any complications a larger trial was preformed using the same protocols. In general, the complications noted from vaccination were mild and the vaccine was well tolerated. This vaccine was produced by Sanofi Pasteur, in Pennsylvania, and was prepared from an H5N1 strain isolated in Southeast Asia during 2004. The March 30, 2006 issues of the New England Journal of Medicine contained the complete publication of the study.
March 26, 2006
Sequence information on the second clade of H5N1 was released. The sample was isolated from a patient in Indonesia. Antigenic differences between clade 1 and clade 2 are significant enough to require the production of separate vaccines for the two clades. The same March 30th issue of the New England Journal of Medicine also included a case report of a woman I Anhui province in China who during her pregnancy was infected with this clade 2 of H5N1, and died. An accompanying editorial noted that even with vaccination against clade 1 of H5N1 this patient would likely not have been protected against her clade 2 H5N1 infection.
March 22, 2006
The Department of Health and Human Services has ordered 2.2 million more treatment courses of the antiviral drug Relenza from GlaxoSmithKline and 3.8 million more treatment courses of Tamiflu from Roche. These treatments will be added to the Strategic National Stockpile. This brings the total number treatment courses to 26 million. The goal of the Strategic National Stockpile is to purchase enough antiviral drugs for 25% of the United States population. This would total 75 million courses with an additional 6 million courses for initial immediate containment effort sin the USA, thus totaling 81 million courses by 2008.
March 2, 2006
The Food and Drug Administration has started an initiative to expedite the development of seasonal and pandemic flu vaccine. To do this the FDA provided guidelines for the submission of clinical data that shows efficacy and safety. This fast track approval process was used to approve last year’s flu vaccine, Fluarix. By doing this, the FDA is trying to provide vaccine developers with ways to quickly create safe and effective vaccines for both seasonal and pandemic flu in an effort to better protect the U.S. This work is in parallel with new guidance from the FDA for the development of cell culture technology will be essential for the production of large amounts of influenza vaccine.
March 2006
The World Health Organization released a new vaccine strain made available for vaccine development. In October 2005 the WHO Global Influenza Programme reported that a significant enough number of changes had occurred in the haemagglutinin genes to warrant the changing of the vaccine strain. The new circulating strains were found to be genetically distinguishable from the previous vaccine strain chosen in 2004. This new strain is available from both the Centers for Disease Control and Prevention and the WHO and is know as the A/Indonesia/5/2005 strain of H5N1 influenza. The sequence of the haemagglutinin and neuraminidase genes is available from Los Alamos National Laboratory database. This information can be distributed to companies for vaccine development.
February 3, 2006
The Food and Drug Administration approved a new laboratory test to detect human infections with avian influenza A/H5 viruses. This test was developed by the CDC to diagnose H5 strains of influenza in patients. The product is known as the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set. This new test can provide preliminary confirmation of H5 viruses in about four hours, while the previous tests required two to three days for results. This test has been distributed to about 140 labs that are part of the Laboratory Response Network, and are currently in all fifty states. The CDC has been working with the WHO to share this technology with centers around the world that are performing H5 influenza testing.
Jennifer Harris and James Sidas
Graduate Students, Georgetown Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases. MICB-524 course: “Emerging Infectious Diseases: The Past as Prologue”.
11 April 2006
Daniel R. Lucey, MD, MPH
WHO Calculates Large Numbers of Masks Needed for Patients and Health Providers During a Flu Pandemic
The World Health Organization (WHO) posted on their website April 7th a pragmatic 53-page document that provides guidelines for humanitarian agencies titled, “Pandemic influenza preparedness and mitigation in refugee and displaced populations”.
New, explicit guidance is provided on collection of diagnostic patient specimens (page 14). For example, the emerging evidence from WHO that throat swabs are proving more useful that with seasonal flu in making the laboratory diagnosis of H5N1 is reflected in the WHO advice that: “Nasopharyngeal and throat sampling of tonsils and posterior pharynx with a Dacron swab is recommended.
The annex section of this document gives clinically useful information on infection control issues, disinfectants, the dosing of oseltamivir (Tamiflu), and how to calculate the number of surgical masks needed during a pandemic. In annex 6 (page 45) WHO estimates that in a sample population of 10,000 persons it should be anticipated that 3,000-5,000 will seek health care over the course of the pandemic and that 500 inpatient admissions should be expected.
Surgical Masks Calculations for patients with Influenza-Like Illness (ILI):
This calculation is based on two estimates: (1) Persons being initially evaluated and (2) inpatients. WHO recommends one surgical mask for each patient with influenza-like illness who seeks evaluation. Therefore, 3,000-5,000 surgical masks will be needed for this first part of the calculation. WHO estimates that for the 400-500 inpatients one mask per day for ~ 7 days will be needed. Thus, a total of 2,800-3,500 surgical masks are needed for inpatients to decrease the spread of influenza virus particularly during coughing or sneezing.
Thus, the total number of surgical masks for symptomatic patients in this 10,000 person sample population is between (3,000-5,000) + (2,800-3,500) = 5,800-8,500 masks.
Surgical Mask Calculations for Health Care Workers (HCWs) and other Staff:
This calculation is also based on two estimates: (1) HCWs, and (2) other potentially exposed staff. The HCW calculation is based on a WHO estimate of 4 mask changes per day, times the number of health staff, times the duration in days of the pandemic (90-180 days), PLUS a 50% buffer stock of surgical masks. Thus, 4 x 90= 360 + 50% buffer stock (i.e., 180 more masks) = a minimum estimate of 540 masks PER HCW assuming a 90 day pandemic duration. If the pandemic duration of 180 days is used instead of 90 days, then twice as many surgical masks will be needed, i.e., 1080 masks PER HCW.
For other potentially exposed staff such as food and water handlers, cleaners, and security guards, the WHO estimates that only two mask changes per day will be needed rather than the four mask changes per day for HCWs. Thus, for a 90 day pandemic 270 surgical masks PER PERSON would be needed. For a 180 day pandemic, 540 masks would be needed PER PERSON.
For HCWs WHO recommends that surgical masks “should be thrown away when leaving isolation wards, OR every 4 hours or when wet or visibly soiled” (page 24).
For other essential staff without direct patient care responsibilities surgical (or procedural) masks should be changed “every 4 hours, or when wet or visibly soiled” (page 24).
This is the first guidance and rationale on how to estimate the number of surgical masks both for patients and for persons involved directly and indirectly in their care during an influenza pandemic. The resulting total number of masks needed in nations with tens or hundreds of millions of people is very large.
Estimates of the number of (fit-tested) N-95 particulate respirators, considerably more expensive than surgical masks, is not provided, although WHO recommends such particulate respirators for any type of aerosol-generating procedure.
These calculations of surgical masks numbers for the next flu pandemic should be evaluated within national, regional, and local contexts, including the announcement March 13thby HHS Secretary Leavitt that the US plans this year to purchase 50 million surgical masks (and 50 million N-95 particulate respirators).
April 20, 2006
Daniel R. Lucey, MD, MPH
Dengue Emerging Infectious Disease Update
Dengue continues to hold its position as an infectious disease with wide reaching effects in tropical and subtropical areas across the globe. The month of March, 2006 saw cases of dengue in Mexico, Paraguay, Ecuador, the Philippines, Malaysia, Saudi Arabia, Madagascar, Maldives, Bolivia, the French Islands, Indonesia, Argentina, Brazil and Venezuela.
MEXICO: A case of fatal dengue hemorrhagic fever was confirmed on March 23 in Nuevo Leon [1]. The victim, a 15 year old girl from the Linares community is the first victim of this disease since 1999. The Nuevo Leon sub-secretary for disease prevention and control, Ricardo Huerta-Gallaga, blames this year’s increased rate of dengue fever on low winter 2005 populations of mosquitoes. Vector extermination was not used as it had been previously. During this year, it is estimated that 3,000 people will be infected with the disease.
PARAGUAY: On March 26, two cases of dengue were confirmed in a 26-year-old woman in Asuncion and an 11-year-old boy in Itaugu [1]. Factors such as warm weather, rainfall, virus circulation in neighboring Brazil and ubiquitous water collecting sites in metropolitan areas create the risk for a dengue outbreak. While community preventative measures involving the elimination of water collecting sites are needed to prevent an outbreak, they are usually not used.
10 cases have been confirmed in Loma Pyta and 7 cases in La Encarnacion. [6].
ECUADOR: The Guayaquil, Guayas province saw 5 confirmed cases of dengue hemorrhagic fever [1]. There have been 57 cases of dengue hemorrhagic fever with four deaths this year alone. Many Ecuadorians are at risk of developing dengue hemorrhagic fever because of previous exposure to classic dengue fever [5].
PHILIPPINES: In the city of Zamboanga there were 9 cases of dengue. A 3-year old from Sitio Luyahan, Barangay Pasonanca died from the disease [1]. A citywide clean up by residents, involving the destruction of mosquito breeding grounds, is expected to take place in Zamboanga in April.
MALAYSIA: From the beginning of the year until March 12, 304 cases of dengue have been reported [2]. The victims, ages 7-52 years old, are from 13 housing estates and villages from 5 districts in Kedah. The State Health Committee chairman, Datuk Saravanan, needs neighborhood organizations to cooperate in eliminating mosquito breeding grounds.
In Malacca, there were 10 cases of dengue in the last month [2]. The Malacca city council and Health Department have started a mobile dengue awareness campaign, however it has not been well received.
From February 26 to March 5, there were 58 cases of dengue in Penang [4]. That is a 93% increase in cases from the week before when there were only 30 reported cases in the state. The Health Ministry Parliamentary Secretary, Datuk Lee Kah Choon, says the situation is no need for alarm, as these numbers are apparently normal for the area. According to health Committee chairman, Datuk V. Saravanan, mosquito fogging has been conducted in 2 dengue hotspots in Alor Star, where dengue hemorrhagic fever cases have been on the rise since February.
SAUDI ARABIA: Jeddah is battling an outbreak of dengue, where 400 cases have been reported [2]. The Council of Ministers has approved 378 million (USD) on projects to tackle mosquito-borne disease. Culture and Information Minister Iyad Madani said programs to combat dengue include filling in areas with stagnant water, health awareness campaigns, aerial spraying, and refurbish rainwater canals. A three-year insect surveillance program will begin soon.
MADAGASCAR (SAINTE-MARIE): The eastern island of Sainte-Marie is battling an outbreak of dengue fever [2]. A medic on the island said medical services could not cope with the number of victims, with 30-50 people being sent the island’s only hospital every day. The island does not have the resources to fight the outbreak.
MALDIVES: From January to March 5, 2006, there were 602 cases of dengue fever, with 64 cases of dengue hemorrhagic fever and 9 cases of dengue shock syndrome [2]. Aedes aegypti is the presumed vector in the Maldives, biting during the day and resting and feeding mainly indoors. The Communication for Behavioral Impact (COMBI) Approach is seen as a strategy to promote mosquito control through the mobilization of communities. The COMBI approach works by encouraging populations to practice dengue control and prevention actions through communication, behavioral-change theories and health education [3].
BOLIVIA: During the week of March 2, 12 cases of classic dengue fever were reported in Santa Cruz and 2 cases were reported in La Paz [4]. From January to March, there have been 86 cases of dengue [6].
FRANCE (ST. MARTIN): The French side of St. Martin is facing an outbreak of classic dengue fever [5]. Stanley Hanson, the head of the Health Department, says the outbreak is manageable, with 2-3 cases reported a week. Currently, DSDS is managing the situation by spraying aircraft coming into St. Martin, as well as recommending the elimination of mosquito breeding sites.
FRANCE (REUNION ISLAND): Dengue was detected, along with Chikungunya virus, in 15 patients on Reunion Island [5]. Both viruses are transmitted by the mosquito species Aedes albopictus. The last epidemic on the island, involving several hundred people, occurred in 2004.
INDONESIA: Dengue is on the rise in the Bekasi region of Indonesia [6]. From January to March, there were 924 cases of dengue in Bekasi, with 8 deaths. Due to the alarming level of infections, the Bekasi Municipal Administration has allocated funds to dengue prevention (30,000 USD).
In Jakarta, the cases of dengue are also increasing [6]. In the greater Jakarta area there were 2470 cases of dengue in January, 2433 cases in February and 2718 cases in March.
ARGENTINA: In Puerto Iguazu, there were 3 reported confirmed cases [6]. The Public Health Ministry is performing environmental control actions.
BRAZIL: 2 cases of dengue were confirmed in Penapolis, with a total number of 3 since January [6].
VENEZUELA: During the epidemiological week of Mar 5-Mar 11, there were 665 cases of dengue fever [6]. 38 of those cases were dengue hemorrhagic fever. There have been 8277 total cases since the beginning of the year.
VIETNAM: In the southern localities of the Mekong delta region, including Ho Chi Minh City, there was a 20% increase in a year-on-year comparison. This substantial increase before the peak rainy season is due to environmental sanitary conditions. The total number of confirmed cases during the 1st quarter of the year stands at over 8,000 with 4 confirmed fatalities.
TAIWAN: The Taiwanese Centers for Disease Control has reported that the incidence of imported dengue fever has risen 60% in a year-on-year comparison. So far there have been 16 imported cases of dengue fever from South and Southeast Asian countries.
VACCINE UPDATE:
In a journal published 24 March 2006, by Zhou H. and Deem M.W., a novel vaccine procedure known as a polytopic injection can be used to elicit a host immune response to dengue fever and reduce immunodominance. Using the polytopic injection, different vaccine serotypes are injected into different regions of the body. These injections contain epitopes of different dengue serotypes (1-4) that are subdominant; therefore eliciting T cell responses in separate regional lymph nodes. This will then prime the immune system to seek out the subdominant determinants instead of the cross-reactive dominant epitopes for each of the 4 dengue serotypes. This will allow for the avoidance of an immunodominance reaction and provide the host immunity against each serotype of dengue virus.
References:
1. Dengue/DHF update 2006 (12). ProMed-mail. 2006. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:117264820838218646::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32488. Accessed April 1, 2006.
2. Dengue/DHF update 2006 (11). ProMed-mail. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:1730551883410139200::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32375. Accessed April 13, 2006.
3. PAHO regional program on dengue. Pan American Health Organization. Available at: http://www.paho.org/English/AD/DPC/CD/dengue-program-page.htm. Accessed April 13, 2006.
4. Dengue/DHF update 2006 (10). ProMed-mail. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:1730551883410139200::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32316. Accessed April 13, 2006.
5. Dengue/DHF update 2006 (9). ProMed-mail. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:5629139836179426979::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32236. Accessed April 18, 2006.
6. Dengue/DHF update 2006 (13). ProMed-mail. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:5629139836179426979::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32553. Accessed April 18, 2006.
7. Dengue/DHF update 2006 (16). ProMed-mail. 2006. Available at: http://www.promedmail.org/pls/promed/f?p=2400:1202:12018940092736001950::NO::F2400_P1202_CHECK_DISPLAY,F2400_P1202_PUB_MAIL_ID:X,32680 . Accessed April 19, 2006.
8. Taiwanese Government Advisory. MyEGov. 2006. Available at: http://english.www.gov.tw/TaiwanHeadlines/index.jsp?categid=10&recordid=93740. Accessed April 19, 2006.
9. Zhou H, Deem MW. Sculpting the immunological response to dengue fever by polytopic vaccination. Vaccine. 2006 Mar 24;24(14):2451-9. Epub 2005 Dec 28.
Deepu Alex, Carlene Gong, Chelsea Johnson, Cheryl King, Anthony Ho, Katarro Rountree, and Lisa Sani
Graduate students in the Georgetown Medical School MICB-524 course on Emerging Infectious Diseases: the Past as Prologue (Instructor, Daniel R. Lucey, MD, MPH), Master of Science Program in Biohazardous Threat Agents and Emerging Infectious Diseases.
May 2, 2006
Daniel R. Lucey, MD, MPH
Will persons who recover from pandemic flu be immune (protected) from re-infection, and thus able to return to work even without vaccination or antiviral prophylaxis?
As truly terrible as the worst flu pandemic of the 20th century was, from 1918-1920, over 97% of infected persons survived, considering that the case-fatality rate (CFR) was ~2.5%.
Influenza is not a chronic infection, unlike other viruses such as HIV. If infection with one specific influenza virus, including the world’s next pandemic influenza virus, confers immune–protection in the vast majority of people who survive, then they may be able to return to work even during the pandemic when neither pandemic vaccine nor sufficient prophylactic antiviral drugs are available.
Given that influenza virus causes non-specific “influenza-like-illness (ILI)” of fever and cough, like many other viruses or bacteria, it would be important to have a rapid, reliable, and affordable diagnostic test to verify that a person has been infected with the future pandemic flu virus.
Development of such a diagnostic-immunity lab test should be a priority for the US government’s pandemic flu preparedness effort. R & D for such a lab test could be supported by a public-private partnership involving government (perhaps HHS, DHS, DARPA or others) and commercial companies with expertise in developing diagnostic tests.
Ideally, this pandemic flu diagnostic-immunity lab test would be both qualitative (proving that at least some form of an immune response developed to the specific pandemic flu virus) and quantitative (e.g., proving that an immune response thought to be protective to the flu virus has been made).
Reasoning by analogy to such immunity tests for current influenza viruses in persons who have been infected, or who have received an influenza vaccine, would provide a roadmap for adapting such assays to the future pandemic flu virus. For example, use of a 1:40 titre of neutralizing antibody was used as a quantitative threshold for protection against H5N1 in the US clade 1 prototype H5N1 vaccine study published in the March 30, 2006 New England Journal of Medicine).
Lastly, the Washington Post editorial April 21, 2006 appropriately called attention to the severe lack of hospital preparedness and the dire shortage of health care workers during the predictable surge in medical needs with the next flu pandemic. In a letter to the Post, published April 29th and written in response to this editorial, I raised the same issue of whether persons who recover from the next pandemic flu virus might be immune-protected from re-infection and thus may not require vaccination or antiviral prophylaxis. Such persons might provide significant mitigation of the certain shortage of health workers, and other critical societal infrastructure workers (e.g., Fire/EMS, police, truck drivers, IT persons, military, and many others).
Even so, given current pandemic preparedness efforts, health care workers will NOT will be able to “handle the pandemic” (in reference to a quote taken from the title of this April 29th letter that was independently added by the Washington Post). Pandemic flu modeling should explore the effect of health care and other workers reentering the work force after recovering from pandemic flu infection, both in their local communities and in more distant communities, in response to the contemporaneous, but not always simultaneous “wave” of pandemic flu as it spreads across the US and the world.
5 May 2006
Daniel R. Lucey, MD, MPH
“The center of gravity of the pandemic response, however, will be in communities”: The jewel in the lotus of the new USPandemic Flu Plan, or a football team with no defensive line?
On Wednesday, May 3 the US Homeland Security Council posted online (www.pandemicflu.gov) a new 227-page “Implementation Plan” for Pandemic Influenza that builds on the foundation of the November, 2005 US “National Strategy for Pandemic Influenza”. The authors’ state that this function-based implementation plan “provides a “playbook” and algorithm that the Federal Government will follow in its response to a pandemic” (page 181, Appendix A).
In fact, this plan is a significant improvement on the November 2005, and a vast improvement over the August 2004 US plan. Additional critical plays and players, however, are needed for this US “playbook”. To continue the sports analogy, the football defensive line, consisting of hospitals and public health outreach to communities at the neighborhood level, will not be operational under the current national “playbook” plan. The pandemic flu virus offensive will quickly overwhelm current hospital “surge” preparedness in the absence of this initial defensive line and quickly find itself in the defensive secondary of national pandemic defenses.
A similar lack of essential operational details for hospital preparedness occurred in the smallpox vaccination campaign of 2002-2003, as we experienced first-hand in Washington,DC-National Capitol Region hospitals. What lessons were learned, and even more importantly implemented, from that precedent for pandemic influenza preparedness?
If civil unrest does occur during the next pandemic it will likely be related to the perception, and quite possibly the reality, that communities are not able to access the essential health care they expected and believe they deserve. This health care access is not initially expected from Federal sources, but from the communities’ own hospitals and public health care system.
In chapter 8 of the nine chapters in the new US Plan, titled “Law Enforcement, Public Safety, and Security” the basis for involving the National Guard and the Armed Forces is articulated: “Consistent with State law, the Governor may deploy National Guard as needed to prevent or respond to civil disturbances”. Furthermore, “The Federal Government may assist a State in maintaining order at the request of a Governor when State and local resources are overwhelmed and not capable of an effective response. There are two primary ways the Federal Government can provide such assistance: (1) providing Federal law enforcement personnel; and (2) pursuant to exceptions to the Posse Comitatus Act, 18 U.S.C 1385, when civilian law enforcement resources are inadequate, by the President directing the Armed Forces to assist with civilian law enforcement functions.” (Page 157).
8 May 2006
Daniel R. Lucey, MD, MPH
Department of Defense (DOD) Health Care Actions and Expectations in the New US Pandemic Flu Plan
Chapter 6 “Protecting Human Health” in the new US Pandemic Flu “Implementation Plan” released May 3, 2006 lists multiple actions and expectations, to be completed within specific time frames, for both the Department of Defense (DOD) and Veterans Administration (VA). Some of the most notable ones include:
- “DOD shall establish stockpiles of vaccine against H5N1 and other influenza subtypes determined to represent a pandemic threat adequate to immunize approximately 1.35 million persons for military use within 18 months of availability” (page 120).
- “DOD shall procure 2.4 million treatment courses of antiviral medications and position them at locations worldwide within 18 months” (page 121).
- “DOD shall enhance influenza surveillance efforts within 6 months by: (1) ensuring that medical treatment facilities (MTFs) monitor the Electronic Surveillance System for Early Notification of Community-based Epidemics (ESSENCE)…(2) ensuring that Public Health Emergency Officers (PHEOs) report all suspected or actual cases through appropriate DOD reporting channels, as well as to CDC, State public health authorities, and host nations; and (3) posting results of aggregated surveillance on the DOD Pandemic Influenza Watchboard; all within 18 months…”(page 128).
- “As appropriate, DOD, in consultation with its Combat Commanders (COCOM), shall implement movement restrictions and individual protection and social distancing strategies (including unit shielding, ship sortie, cancellation of public gatherings…DOD personnel and beneficiaries living off-base should comply with local community containment guidance with respect to activities not directly related to the installation. DOD shall be prepared to initiate within 18 months.” (page 131).
- “DOD shall enhance its public health response capabilities by: (1): continuing to assign epidemiologists and preventive medicine physicians within key operational settings; (2) expanding ongoing DOD participation in CDC’s EIS Program; and (3) within 18 months fielding specific training programs for PHEOs that address their roles and responsibilities during a public health emergency.” (page 133).
- “DOD and VA assets and capabilities shall be postured to provide care for military personnel and eligible civilians, contractors, dependants, other beneficiaries, and veterans and shall be prepared to augment the medical response of State, territorial, tribal, or local governments and other Federal agencies consistent with their ESF # 8 support roles, within 3 months. (page 134).
- “VA shall develop, test, and implement protocols and policies allowing VA personnel and resources to be used for the treatment of non-veteran patients during health emergencies, within 3 months. (page 134).
- “VA shall develop draft emergency policies and directives allowing VA personnel and resources to be used for the treatment of non-veteran patients with pandemic influenza within 3 months (page 134).
- “DOD shall develop and implement guidelines defining conditions under which Reserve Component medical personnel providing health care in non-military health care facilities should be mobilized and deployed, within 18 months” (page 135).
- “DOD and VA, in coordination with HHS, shall develop and disseminate educational materials, coordinated with and complementary to messages developed by HHS but tailored for their respective departments, within 6 months”.(page 135).
Implementation of these timed actions as part of the integration of civilian, military (DOD), and VA health care resources and personnel into pandemic influenza preparedness is a welcome advance in US and international planning.
12 May 2006
Daniel R. Lucey, MD, MPH
H5N1 in the Horn of Africa: First human infection in Djibouti and new poultry infections in Sudan confirmed.
The WHO reported May 12 the first confirmed patient with H5N1 infection in the Horn of Africa. A 2 year old girl from a rural village in the district of Arta became ill April 23, was tested for H5N1 virus on May 10 at the NAMRU-3 reference lab in Cairo, apparently after the deaths of some chickens resulted in increased surveillance for this virus. At least three chickens in Djibouti have also tested positive for H5N1. Fortunately, the child is alive and still under medical care. Djibouti is working with the WHO to expand their response to this H5N1 outbreak.
Djibouti is now the 8th African nation to report avian infections with the H5N1 virus. These 8 nations are: Nigeria, Egypt, Niger, Cameroon, Burkina Faso, Cote d’Ivoire, Sudan, and Djibouti.
Sudan confirmed on May 8, 2006 the presence of H5N1 avian influenza virus in poultry in its first follow-up report to the OIE (world Animal Health Organization in Paris). The initial report April 19 was of an H5 virus (Neuraminidase undetermined) in the states of Khartoum and Gezira. The May 8 report to OIE reported two new outbreaks, in Atabara in River Nile state, 250 km north of Khartoum and in Gezira state, ~ 45 km south of Khartoum. The H5N1 virus was confirmed at the OIE/FAO avian influenza lab in Padova, Italy by virus isolation and RT-PCR sequencing to prove the characteristic amino acid sequence in the cleavage site of the H5 protein seen with highly pathogenic avian influenza (HPAI).
The Horn of Africa includes Sudan, Djibouti, Eritrea, Ethiopia, and Kenya. Earlier in 2006 the WHO called attention to the ongoing health crisis in the Horn of Africa. This crisis is related to multiple factors including drought, malnutrition, economic and political instability, and increased infectious diseases, including HIV/AIDS and other communicable diseases (see: www.who.int/hac/crises/international/hoafrica/en/index.html
The addition of H5N1 avian influenza to the ongoing health crises in the Horn of Africa will worsen matters considerably if it is not controlled as soon as possible. Increased surveillance for H5N1 in both avian and human populations is needed to determine the extent of spread of this virus. International assistance should be provided when requested by member nations of this region, such as that being provided by the WHO at the recent invitation of Djibouti.
14 May 2006
Daniel R. Lucey, MD, MPH
New highly active anti-malarial Artemisinin-based Combination Therapy (ACT) protected by phase-out of marketing single-drug artemisinin malaria pills
On May 11 the World Health Organization (WHO) announced that their recommendation to stop marketing single-drug artemisinin malaria pills has been agreed to by 13 pharmaceutical companies. This phase-out of single-drug artemisinin monotherapy for the oral treatment of malaria is a major advance in maximizing the probability that Artemisinin-based Combination Therapies (ACTs) currently recommended as the drugs of choice by WHO for uncomplicated falciparum malaria will remain highly active and effective.
Earlier in 2006 the WHO posted online new “Guidelines for the Treatment of Malaria”. This 240-page document contained clear advice on the diagnosis and treatment of all four types of malaria: Plasmodium falciparum (“uncomplicated” and “severe”), Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
WHO listed alphabetically the following specific Artemisinin-based Combination therapies (ACTs) (page 21):
A. Artemether-lumefantrine (already available as co-formulated tablets containing 20 mg of artmether plus 120 mg of lumefantrine. The total recommended therapy course is a 6-dose regimen with one tablet being taken orally twice a day for three (3) days.
b. Artesunate plus amodiaquine
c. Artesunate plus mefloquine
d. Artesunate plus sulfadoxine-pyrimethamine
The choice of ACT for uncomplicated falciparum malaria depends on the level of resistance of the partner medicine in the combination. For example, in Africa (page 23) WHO recommends artemether-lumefantrine, OR artesunate plus amodiaquine, OR artesunate plus sulfadoxine-pyrimethamine. In areas of multidrug resistance malaria, such as SE Asia, WHO recommends artemether-lumefantrine OR artesunate and mefloquine.
In Africa WHO notes (page 22) concerns about “insufficient safety and tolerability data on artesunate and mefloquine at the recommended dose of 25mg/kg in African children to support its recommendation there. Trials with mefloquine monotherapy (25mg/kg) have raised concerns of tolerability in African children. Countries may therefore opt instead to use artesunate plus amodiaquine, OR artesunate plus sulfadoxine-pyrimethamine which may have lower cure rates because of resistance”.
Monotherapy with amodiaquine, or montherapy with sulfadoxipine-pyrimethamine are widely available and provide continued selection pressure for the P. falciparum malaria parasite to develop resistance.
Lumefantrine has never been available as a monotherapy. Instead, it is only available as a co-formulated tablet with artemether and thus resistance is less likely.
Remarkably, “artemisinin and its derivatives (artesunate, artemether, artemotil, dihydroartemisinin) produce rapid clearance of parasitemia and rapid resolution of symptoms. They reduce parasite numbers by a factor of approximately 10,000 in each asexual cycle, which is more than other current antimalarials (which reduce parasites numbers 100-1,000-fold per cycle)” (page 17).
Artemisinin drugs are eliminated rapidly from the body. Thus, when given in combination with other rapidly eliminated antimalarial compounds (tetracyclines or clindamycin) seven (7) days of the artemisinin medication are required. When given in combination with slowly eliminated antimalarial medications, however, shorter courses of only three (3) days of the artemisinin compounds are required (page 17, WHO 2006).
This important step announced May 11 by the WHO of the phase-out of marketing single-drug artemisinin malaria pills should help preserve Artemisinin-based Combination Therapies (ACTs) as highly effective treatment for uncomplicated falciparum malaria. Combination therapy with several effective medications against the malaria parasite is analogous to combination therapy with highly active antiretroviral drugs for the human immunodeficiency virus, and combination therapy with multiple antibiotics against tuberculosis. In parts of the world where all three infections (malaria, HIV. and TB) can occur in the same patient such combination therapies can increase the probability of successful treatment.
29 May 2006
Daniel R. Lucey, MD, MPH
Four criteria in the WHO decision to launch an influenza containment operation once a change occurs from Pandemic Alert Phase 3 to Phase 4
Much concern has been generated over the past two weeks regarding a family cluster in Sumatra, Indonesia of up to eight persons with H5N1 avian influenza. This is not the first such cluster, but it is the largest to date. Nor will this be the last such cluster. Thus, it is worthwhile looking again at the four (4) criteria integral to the decision to launch a containment operation that the WHO articulated in their March 17, 2006 document titled, “WHO pandemic influenza draft protocol for rapid response and containment”.
WHO states (pages 8-9): “An attempt to contain an emerging pandemic virus at its source is a demanding exercise and a resource-intensive operation. Moreover, supplies of antiviral drugs reserved for use to support an operation are finite and not easily replenished, and must therefore be used judiciously. For these reasons the decision to initiate activities aimed at rapid containment should be triggered by compelling evidence that the situation represents a transition in the behavior of the virus likely to result in efficient and sustained human-to-human transmission. Such evidence will derive from a combination of clinical, epidemiological, and virological findings as guided by the following criteria:
- Moderate-to-severe respiratory illness (or deaths) in three or more health care workers who have no known exposure other than contact with ill patients, and laboratory confirmation of H5N1 infection in at least one of these workers.
- Moderate-to-severe respiratory illness (or deaths) in 5 to 10 persons with evidence of human-to-human transmission in at least some, and laboratory confirmation of H5N1 infection in more than 2 of these persons.
- Compelling evidence that more than one generation of human-to-human transmission of the virus has occurred.
- Isolation of a novel virus combining avian and human material or a virus with an increased number of mutations not seen in avian isolates from one or more persons with moderate-to-severe respiratory illness(acute onset), supported by epidemiological evidence that transmission patterns have changed.
In the current family cluster in Indonesia, criteria # 1 and # 4 are definitely NOT met. Criteria # 2 is probably met, unless a common environmental source (e.g., chickens with H5N1) is identified by the ongoing investigation. Criteria # 3 is only possibly met by the one person who might represent a single instance of a second generation of human-to-human transmission.
IF a containment operation is launched, then WHO delineates a two-phase strategy:
- Immediate implementation of standard measures aimed at reducing further transmission. In this phase, active case finding and contact tracing are undertaken and antiviral drugs are administered, in a targeted way, to treat persons identified during these activities.
- Implementation of exceptional measures, including wider prophylactic administration of antiviral drugs, quarantine, and (possibly) the introduction of social distancing measures.
Moreover, WHO emphasizes that throughout these two sequential phases of the containment response “enhanced surveillance at national and international levels is important to guide the continuation of measures and monitor their impact.
These WHO criteria could be updated with future drafts of this protocol that first appeared earlier this year. Room for interpretation and application to specific conditions and epidemiological, clinical, and virological findings for the current cluster in Indonesia and for the highly predictable future clusters in the same and other regions of the world, including Africa, are allowed within the WHO wording of the factors influencing the decision to launch or not launch a containment operation. This is as it should be.
Future media, public health, and political concern about the beginning of the next human flu pandemic should reflexively look back at these four WHO criteria integral to the decision-making process of whether to launch a containment strategy, and thereby declare the transition from the current Phase 3 Pandemic Alert to a Phase 4 (“small clusters”) or Phase 5 (“larger clusters” of persons).
26 June 2006
Daniel Lucey MD, MPH
Indonesia Hosts Avian Flu Expert WHO Consultation:
No Pandemic Virus Found In Single Family 8-Person Outbreak
From June 21-23 Indonesia held an international conference on H5N1 avian influenza to discuss multiple issues including the 8-person single-family outbreak of H5N1, with 7 fatalities, in north Sumatra last month and “to provide an authoritative risk assessment of avian influenza in Indonesia in both humans and animals”.
The Jakarta Post newspaper reported on June 26th that although the H5N1 virus had “mutated somewhat” in the last two members of the single family cluster, a son who transmitted the virus to his father, the WHO emphasized that the virus did NOT mutate into a new influenza virus that could be spread in either a sustained or efficient manner from person-to-person-to-person. The wife of the man infected by his son did not develop any influenza-like-illness, nor did any other close contacts outside of this single family.
On Sunday, June 25th, Australia pledged a grant of a$10million (Rp 68.5 billion) to Indonesia to help fight H5N1 avian influenza. In particular, this funding will strengthen a two-year emergency avian influenza program that focuses on both animal and human aspects.
The three-day international conference included Indonesia Ministry of Health and Agriculture officials, Indonesian hospitals and university researchers, as well as global partners including WHO, FAO, Hong Kong University, Japan’s National Institute for Infectious Diseases, France’s Epicentre, and the US CDC and NAMRU-2 (based in Jakarta).
On May 30, 2006 the WHO updated their evolving ‘Rapid Response and Containment Protocol for Avian Influenza’. The decision to launch a containment operation has now been revised to include consideration of the following three criteria that form an integral of clinical, epidemiological, and virological data:
- Clustering of cases of moderate-to-severe respiratory illness (or deaths) with two generations of transmission in a health care facility, and laboratory confirmation of H5N1 infection in at least one of them. The cases could be three or more health care workers who have no known exposure other than contact with ill patients, or just one health care worker and additional patients with evidence of nosocomial transmissions.
- Moderate-to-severe respiratory illness (or deaths) in 5 to 10 persons with evidence of human-to-human transmission in at least some as determined by temporal sequencing of onset dates of cases and opportunity among cases for exposures to one another consistent with respective infectiousness and incubation period. At least 2 of these persons should have a laboratory-confirmed H5N1 infection.
- Isolation of a novel virus combining avian and human genetic material or a virus with an increased number of mutations not seen in avian isolates from one or more persons with moderate-to-severe respiratory illness (acute onset), supported by epidemiological evidence that transmission patterns have changed”.
More information is anticipated from the WHO in follow-ups to the June 21-23 conference late last week in Jakarta, including specific information about the mutations detected and the evidence of person-to-person transmission, albeit limited to a single family and not signifying the emergence of a new human pandemic flu virus. In addition, further refinement of the WHO definitions of Phase 4 and 5 of the Pandemic Alert period, and new operational details of the evolving implementation plan for the WHO-international host nation(s) rapid response and containment protocol are likely.
In short, what is slowly evolving worldwide, and is explicitly needed for global preparedness are “Waves of Pandemic Preparedness” at the local, regional, national, and international levels.
8 July 2006
Daniel R. Lucey, MD, MPH
US Pandemic Flu Stockpile Plans: “As Is” vs. “To Be”
On June 29, 2006 US Health and Human Services (HHS) Secretary Michael Leavitt posted a 12-page “Pandemic Planning Update II” that contained valuable information on the chronology of the spreading avian H5N1 pandemic and of US preparedness countermeasures. Subheadings of this second update, posted at www.pandemicflu.gov include: “Monitoring and Surveillance”, Vaccines and Vaccine Production Capacity, Antiviral Drugs, State and Local Preparedness, and Communications.
Multiple key points were made in this update. For example, it was reported that “In May, the United States shipped an amount of the antiviral drug Tamiflu to a secure location in an Asian country. The Tamiflu could be used as part of the international community’s efforts to contain a pandemic.” Also, the successful effort of Thailand and Vietnam to control the outbreak of H5N1 in their human population was emphasized: “Up to now, the disease appears to be successfully contained through culling in Vietnam and Thailand.” This statement, however, does not include a major difference between the control measures of these two nations, namely that Vietnam has extensively used veterinary vaccines against H5N1 in their poultry, while Thailand has not.
Information provided in the text of this updated plan has been used (by this writer) to create the following table summarizing the current US stockpile of key items (termed “AS IS”) with plans to increase the stockpile in the future (termed “TO BE”).
Item AS IS (today) TO BE (in the future)
N-95 respirators 20.2 million 100 million (9/2007)
Surgical masks 12.3 million 50 million (9/2006)
Tamiflu (oseltamivir) 6.2 million regimens 21.6 million (12/2006)
(10 Capsule regimens)
Relenza (zanamivir) 84,000 regimens 3.984 million (12/2006)
Liquid Tamiflu 8,600 regimens not stated
(e.g., for small children)
Clade 1 H5N1 Vaccine ~ 8 million doses not stated in this update
Clade 2 H5N1 vaccine “toward development” not stated
Ventilators not stated 6,000 more (in 2006)
27 July 2006
Daniel R. Lucey, MD, MPH
Inhaled Zanamivir (Relenza) for Anti-Influenza Drug Stockpiling Available to 50 States, DC, and 8 other Jurisdictions at Subsidized Cost.
On 20 July the US Secretary of Health and Human Services (HHS) announced that all US states, the District of Columbia, and five other U.S. territories and three Freely Associated States of the Pacific are able to purchase Zanamivir (“Relenza”), at a federally negotiated price and with a 25% federal subsidy for a specific number of treatment courses. The expense for these 59 jurisdictions may still be significant and could impact the rate of full compliance in purchasing anti-flu drugs.
The overall HHS goal is to stockpile enough anti-influenza medications (including the oral drug oseltamivir (“Tamiflu”) and the inhaled drug Zanamivir (“Relenza”)) to stockpile for 25% of the US population (75 million doses). The federal government will purchase 44 million of these medication courses and keep them centrally in the Strategic National Stockpile (SNS). The remaining 31 million courses are currently anticipated to come from the state-purchased, federally subsidized, program and to be kept in the 50 states and nine other jurisdictions.
On March 29, 2006 the US Food and Drug Administration (FDA)announced approval of inhaled Zanamivir (Relenza) for prophylaxis (prevention) of influenza A and B for children 5 years of age and older. This drug had previously been FDA-licensed for treatment of actual influenza illness.
Due to severe and sometimes fatal respiratory side effects of the drug in persons with underlying lung disease, Zanamivir is NOT recommended for treatment or prophylaxis of seasonal influenza in persons with lung diseases such as asthma or chronic obstructive pulmonary (lung) disease (COPD).
Of note, influenza viruses that are resistant to the other neuraminidase inhibitor drug oseltamivir (“Tamiflu”) are still susceptible to Zanamivir (“Relenza”). This fact could become important as increasing amounts of “Tamiflu” are used around the world due to high rates of resistance emerging now among influenza viruses (such as H3N2, H1N1, and H5N1) to the older anti-flu drugs “amantadine” and “rimantadine”
29 July 2006
Daniel R. Lucey, MD, MPH
Anthrax Antitoxin Antibody: Second Source to be Added to US Stockpile
On 28 July 2006 the U.S. Department of Health and Human Services (HSS) announced a contract with a Canadian company, Cangene Corporation, for 10,000 courses of therapy with anthrax antitoxin antibody, termed “Anthrax Immune Globulin (AIG)”. Delivery to the U.S. Strategic National Stockpile (SNS) will begin in 2007. A full description of the HHS press release describing agreement can be found on the HHS website at: http://www.hhs.gov/news/press/2006pres/20060728.html
Once in the stockpile the anthrax immune globulin (AIG) could be used to treat patients, under specific conditions, even prior to the Food and Drug Administration (FDA) licensure for marketing. Such specific regulatory conditions could include the FDA’s Emergency Use Authorization (EUA) or Investigational New Drug (IND) protocols. Of note, however, full payment to Cangene is contingent on AIG receiving FDA approval for marketing. AIG is a hyperimmune product prepared by purification of blood plasma.
Last month, on June 20, HHS announced a contract with Human Genome Sciences, for 20,000 treatment courses of a different anthrax antitoxin, the monoclonal antibody termed “ABthrax”. Delivery to the SNS is anticipated to begin in 2009. As with AIG, full payment is contingent on gaining approval from the FDA for licensure to market this product. A full description of the HHS press release can be found at: http://www.hhs.gov/news/press/2006pres/20060620.html
Antibiotics remain the initial countermeasure against anthrax. In the event of an aerosol attack with anthrax (e.g., as one scenario in the Cities Readiness Initiative (CRI), the CDC has recommended for prophylaxis of exposed persons (but not for those with active disease) since September 2004 adding three doses over one month of post-exposure anthrax vaccination (under an FDA IND). A preventive immune response requires weeks to acquire via this post-exposure “active immunization”.
The stockpiling of two types of an anthrax antitoxin, one plasma derived and the other a monoclonal antibody, will hopefully provide clinicians with yet another countermeasure for the actual treatment of inhalational anthrax, a disease that is now usually fatal if not treated with appropriate antibiotics in the “early-prodromal” or “intermediate-progressive” stages.
Treatment with antibiotics alone during the third and final stage of inhalational anthrax, the “late-fulminant” stage, when anthrax toxin levels are likely at their highest, was not successful during the anthrax attacks in 2001. It should not be assumed, however, that either of the above anthrax toxin inhibitors (AIG or ABthrax) will be highly effective at preventing death in patients with advanced inhalational anthrax. The design of animal experiments to test this hypothesis should be examined closely. Timing is likely to be crucial. Exactly when the antitoxin is given during the three-stage course of inhalational anthrax, and whether the bacteria is susceptible to readily available antibiotics, might be major determinants of how helpful these anthrax antitoxins are to patients.
With Multi-Drug Resistant (MDR) anthrax, such “passive immunization” with anthrax antitoxins such as ABthrax and AIG, should provide at least some significant degree of immediate neutralization of toxin, buying critical time to find some uncommon or still investigational antibiotic(s) to be added as treatment to kill the anthrax toxin-producing bacteria.
One should anticipate that the next anthrax attack (s) will be with a strain of the Bacillus anthracis bacteria that is resistant to one or more of the antibiotics that were used as prophylaxis and therapy after the 2001 attacks. September 18, 2006 will be the five-year mark for the initial anthrax letters for which a postmark date is known. Hopefully this date, and the date of later mailings in October 2001, will pass uneventfully.
31 July 2006
Daniel R. Lucey, MD, MPH
Domestic Cats in Iraq with H5N1 Clade 2 Avian Flu
In the August 2006 issue of Emerging Infectious Diseases Yingst, Saad, and Felt from the Naval Medical Research Unit (NAMRU-3) in Cairo, Egypt reported finding domestic cats with fatal H5N1 avian flu infection in February 2006 in the Erbil governate of Kurdish northern Iraq. The infection of the cats occurred near the time of the outbreak of H5N1 in northern Iraq (Sulymaniyeh and Erbil Governates).
The authors reported that the cats had the more recent “clade 2” H5N1 virus, unlike earlier infections of tigers and leopards in Thailand with the “clade 1” H5N1 viruses. Specifically, this clade 2 virus is very similar to the H5N1 clade 2 viruses found at Qinghai Lake in the western China in the spring of 2005 associated with the deaths of several thousand migratory birds. In addition, the authors reported the unusual finding of severe hemorrhagic pancreatitis in the two cats that underwent necropsy. Their brief report can be found online on the CDC website at www.cdc.gov/eid.
The outbreak study was performed after the government of Iraq requested a World Health Organization (WHO) investigation. The NAMRU-3 team also participated in the H5N1 avian flu investigation in Azerbaijan, using the innovative PCR diagnostic equipment that had been adapted by them for use in the field, thereby shortening the time required to make the diagnosis of H5N1 by avoiding the need to transport specimens to a distant reference laboratory.
In the Iraq study of domestic cats, the H5N1 virus was found in the large intestine, pancreas, and lungs of both cats, and in the feces of the one cat in which it was looked for. The route of infection of the cats was not proven, but might have occurred by consumption of H5N1-infected chickens or geese given that such species were also found to be infected with H5N1 at the same time as the cats. No evidence of cat-to-cat transmission was established, as likely occurred between tigers in a zoo in Thailand (Emerg Infect Dis (EID) 2005; 5:699-701).
Clade 2 H5N1 infections, antigenically distinct from the clade 1 H5N1 viruses that appeared in 2003-2004 in Vietnam and Thailand, are now found in multiple nations inside and outside Asia. These clade 2 viruses have recently lead to the announcement that WHO is providing clade 2 H5N1 viruses for candidate vaccine development, in addition to the earlier clade 1 H5N1 viruses. A color map of the early geographical distinction between clade 1 and clade 2 H5N1 viruses in Asia can be found in the paper published by the WHO Global Influenza Program Surveillance Network in October 2005 in this same journal (Emerging Infectious Diseases (EID) volume 11: pages 1515-1521.
18 August 2006
Daniel R. Lucey, MD, MPH
H5N1 outbreak investigation begins in remote village of West Java, Indonesia
The WHO posted on their website (www.who.int) August 17th that the Indonesian Ministry of Health reported the death of a 9 year-old girl from a remote village in West Java province (Garut District) due to H5N1 avian influenza virus. Indonesia and the WHO have launched an investigation into the three hamlets within the one village where the 9 year-old child died because of an additional laboratory-confirmed H5N1 infection in a 17 year-old young man in a second hamlet in this village, and the death of his 20 year-old male cousin (neighbor) of a respiratory disease “strongly suspected” to be H5N, but for whom no samples were obtained laboratory testing.
Of note, the WHO reports that the 17 year-old and 20 year-old young men both developed symptoms on 26 July and this “makes human-to-human transmission between the two highly improbable”. The two cousins are assumed to have “acquired their infection from a shared environmental source”, according to yesterday’s WHO situation update 27. Their remote village in West Java was reported to have recent die-offs of poultry and all three of the patients “documented exposure to diseased chickens”. The 9 year-old girl developed symptoms on August 1st, was hospitalized nearly two weeks later (August 14th), and died the next day.
Rumors of other patients with respiratory disease in the three hamlets of this village during this time frame since late July are being investigated. In parallel, animal health experts are investigating the poultry deaths in this village.
As with the single family-related cluster of H5N1 infections in north Sumatra, Indonesia, in May 2006 one can anticipate further information in the days and weeks ahead. Such information will likely include the results of human epidemiological studies to assess how the infections occurred, and analyses to determine the genetic sequences of the H5N1 viruses from both humans and poultry to assess any evidence of either recombination with human influenza viruses or significant mutations in the H5N1 virus.
Indonesia’s declaration within the past month that they will share such H5N1 viral sequences with the global community is a welcome event in this regard. Indonesia has now reported 58 laboratory-confirmed patients with H5N1 virus infection since the first Indonesian patient was diagnosed in 2005. Of these 58 persons, 45 have died (78%). Indonesia has recently surpassed Vietnam (42 deaths) with the highest number of laboratory-confirmed deaths due to H5N1 virus infection. According to the H5N1 table of confirmed cases on the WHO website, Vietnam has reported zero deaths due to H5N1 virus infection in 2006, while Indonesia has reported 34 deaths this year.
Most importantly, as of today there is NO indication that any evidence warrants consideration of changing the WHO pandemic alert from the current Phase 3 to Phase 4 (i.e., small clusters of human-to-human transmission), or trigger a WHO-partnered rapid response and containment protocol.
Readers interested in considering what would be involved at some future time should Phase 4 develop in any nation(s) in the world should review the latest WHO version (May 30) of this protocol at: http://www.who.int/csr/disease/avian_influenza/guidelines/draftprotocol/en/index.html
August 25, 2006
WHO: Three Clade 2 H5N1 Candidate Pre-Pandemic Vaccines Added to Current Clade 1 Vaccine
Pre-Pandemic H5N1 avian flu vaccine development has become more complex due to the continuing evolution of the H5N1 virus over the past three years. On August 18th the World Health Organization (WHO) posted on their website a detailed update from their May and June 2006 postings on new H5N1 prototype strains for vaccine development. Whereas current clinical trials with the pre-pandemic H5N1 vaccine all use Clade 1 (“genetic group 1”) H5N1 viruses isolated in 2004 from Vietnam, the WHO now recommends use of three (3) more candidate H5N1 vaccines, all of which are Clade 2 H5N1 viruses, specified as “subclades” 1, 2, and 3.
WHO reports that of the six (6) known subclades of Clade 2 H5N1 viruses, three (3) differ in geographical location and have caused most human infections in the latter part of 2005 and in 2006. The 18 August WHO document provides a helpful figure, grouping by name each of these three subclades of Clade 2 H5N1, as well as Clade 1 viruses, termed “Evolution of the H5N1 haemagglutinin gene”.
This document also contains a very useful table that illustrates the very limited cross-reactivity between the antibodies induced in the standard influenza model (the ferret) by the Clade 1 and Clade 2 (subclades 1-3) H5N1 viruses, thus explaining the rationale for developing candidate vaccines against all four of these different H5N1 viruses. This table comparing the antigenic differences in the evolving H5N1 viruses is titled “Haemagglutination Inhibition Reactions of H5N1 viruses”.
Geographically, the WHO notes that human infections with Clade 1 H5N1 viruses (of which there are currently no “subclades”) occurred primarily in 2004-2005 in “Cambodia, Thailand, and Vietnam”.
Although not stated explicitly by WHO, a shorthand nomenclature for these viruses could be: “Clade 1”, “Clade 2.1” (Clade2/subclade 1), “Clade 2.2” (Clade 2/subclade 2.2) and Clade “2.3” (Clade 2/subclade 3).
Geographically, the WHO notes that human infections with H5N1 were caused mainly by clade 1 viruses (of which there are currently no “subclades”) in 2004-12005 in “Cambodia, Thailand and Vietnam”.
In contrast, in later 2005 and 2006 most human infections with H5N1 have been due to Clade 2 viruses, primarily “subclade 1” in Indonesia, “subclade 2 in countries in the Middle East, Europe, and Africa, and “subclade 3” in China. The one exception noted by the WHO is that the H5N1 viruses from the Karo cluster in rural north Sumatra, Indonesia in May 2006 appear “antigencically more closely related to H5N1 viruses in subclade 2” whereas most H5N1 viruses are Clade 2/subclade 1 (“2.1”).
In this 18 August document WHO names for the first time a Clade 2/subclade 3 (“2.3”) candidate vaccine virus, namely A/Anhui/1/2005-like virus.
The impact of this new and evolving WHO information for stockpiling of pre-pandemic H5N1 vaccines appears to be that more than one, and possibly multiple, such vaccines are needed, with all the associated public health, economic, and ethical implications.
5 September 2006
Daniel R. Lucey, MD, MPH
“XDR-TB” (Extensive (Extreme) Drug Resistant-Tuberculosis): WHO describes as “Virtually Untreatable”
On September 5th the World Health Organization (WHO) posted on their website an article titled “Emergence of XDR-TB”. This form of “extensive (or “extreme”) drug resistant tuberculosis” is “virtually untreatable” and may be associated with a very high mortality (e.g., 52/53 patients with XDR-TB died in a recent study of HIV-positive patients from Kwazulu-Natal, South Africa. The brief summary from the WHO and news of a conference in South Africa this September 7-8, supported by WHO and CDC, can be found online at: www.who.int/mediacentre/news/notes/2006/np23/en/index.html
XDR-TB is defined by WHO as Multidrug–Resistant TB (MDR-TB) “that is also resistant to three or more of the six classes of second line drugs” against TB. MDR-TB is defined as strains of TB that are resistant to at least the two main first-line TB drugs isoniazid and rifampicin. WHO guidelines for “programmatic Management of Drug-Resistant Tuberculosis” are provided in a 186-page document, with four Editor-in-Chiefs, on the WHO website at: www.who.int/tb/dots/dotsplus/en/index.html
Who reports that XDR-TB was first described earlier this year after a WHO-US CDC survey that found this TB strain in all parts of the world. For example, it was most frequent in nations of the former Soviet Union, such as Latvia (19% of MDR-TB cases are also XDR-TB), and Asia. In the USA 4% of MDR-TB patients also had XDR-TB.
A potential link with HIV is noted in the WHO document and also in a September 5th entry on ProMed mail. As noted by the ProMed commentator (LM) today, the development of XDR-TB, and its apparent very high mortality rate, as cited in the study from South Africa, is likely to be multifactorial.
WHO cites potential contributing factors in TB drug-resistance as “incorrect drug prescribing practices by providers, poor quality drugs, or erratic supply of drugs, and also patient non-adherance”. WHO goes on to state that “Given the underlying HIV epidemic, drug-resistant TB could have a severe impact on mortality in Africa and requires urgent preventative action”.
All in all, this is bad news in the long global war against tuberculosis and the ongoing human pandemic of HIV/AIDS.
15 September 2006
Daniel R. Lucey, MD, MPH
WHO Recommends Indoor Spraying with DDT or other Insecticides to fight Malaria, in addition to Insecticide-Treated Mosquito Nets and Artemesinin Combination Therapies
Today the World Health Organization (WHO) announced (http://www.who.int/mediacentre/news/releases/2006/pr50/en/index.html) they are giving “indoor use of DDT a clean bill of health for controlling malaria”. Unlike widespread policy of the past quarter century, the WHO will now promote “indoor residual spraying (IRS)” with insecticides, including DDT, as one of three main interventions against malaria, joining insecticide-treated bed nets and artmesinin combination therapies (ACTs) in what could be termed the new “triad against malaria (TAM)”.
Indoor residual spraying (IRS) is defined by WHO as “the application of long-acting insecticides on the walls and roofs of houses and domestic animal shelters in order to kill malaria-carrying mosquitoes that land on these surfaces”.
In terms of safety, focusing on indoor (not outdoor) use of DDT, the WHO states that “DDT presents no health risk when used properly.” Since WHO stopped advocating use of DDT in the early 1980’s due to health and environmental concerns, “extensive research and testing has since demonstrated that well-managed indoor residual spraying programmes using DDT pose no harm to wildlife or to humans”.
In terms of efficacy, WHO states that of the 12 insecticides they have approved as safe for house spraying, “the most effective is DDT”, according to Dr. Arata Kochi, Director of WHO’s Global Malaria Programme.
More than 500 million persons become ill with acute malaria every year. Over 1 million people die, with more than 860,000 deaths in Sub-Saharan Africa, each year. These deaths are primarily in children and infants, with WHO estimating that 3,000 deaths occur each day. A second high-risk group for death due to malaria is pregnant women, of whom 10,000 die in Africa alone each year, according to the WHO. Understandingly therefore, WHO is now recommending use of IRS “throughout Africa”, including areas with not only epidemic, but also high and constant malaria transmission.
WHO cites supports for indoor spraying with DDT from organizations such as the Sierra Club, the Endangered Wildlife Trust, Environmental Defense, and the President’s Malaria Initiative (PMI). The PMI includes 15 country programs in President Bush’s $1.2 billion commitment to decrease malaria deaths by 50%. WHO also cites dramatic success by India and South Africa in use of IRS, including DDT, to cut malaria transmission and deaths. In fact, WHO notes that already today “14 countries n Sub-Saharan Africa are using IRS and 10 of those are using DDT”.
This new policy by WHO is admirable in that it is based on data supporting the safety record for both humans and wildlife of indoor use of DDT. With sufficient funding to provide safe application of IRS, combined with prevention of malaria by insecticide-treated bed nets, and artemisinin-combination therapy for patients with malaria infection, the number of infections and deaths could dramatically drop over the coming years.
In addition, killing of mosquitoes by IRS, including use of DDT might result in a significant drop in other mosquito-borne diseases that co-exist in malarious parts of the world.
17 October 2006
Daniel R. Lucey, MD, MPH
Additives or Not: The Anthrax Mailed in October 2001 Could Form an Aerosol and Could Reaerosolize.
Five years ago this month two letters containing anthrax spores were mailed to Senators Tom Daschle and Patrick Leahy. The letters were postmarked October 9, 2001 in New Jersey. Both letters then traveled through the large postal facility in Washington DC, known at the time as Brentwood. The letter to Senator Daschle was opened on October 15, 2001 and therefore, understandably, five years later to the day, an article he writes in the Washington Post begins: “October 15, 2001 is a day I’ll never forget” (Washington Post. Page B07. Oct 15, 2006).
The FBI has also not forgotten. Two months ago they published a description of the forensic evaluation of the unopened letter to Senator Leahy, titled: ”Forensic Application of Microbiological Culture Analysis to identify Mail Intentionally Contaminated with Bacillus anthracis spores. Applied and Environmental Microbiology (2006 (August); 72 (8):5304-5310 . The single author of this paper is Douglas J. Beecher, from the FBI Laboratory in Quantico, Virginia.
Even more recently, on September 25, 2006 the Washington Post published an article on page A01 titled “FBI is Casting a Wider Net in Anthrax Attacks”, authored by Allan Lengel and Joby Warrick. This article begins, “Five years after the anthrax attacks that killed five people, the FBI is now convinced that the lethal powder sent to the Senate was far less sophisticated than originally believed, widening the pool of possible suspects in a frustratingly slow investigation. The finding, which resulted from countless scientific tests at numerous laboratories, appears to undermine the widely held belief that the attack was carried out by a government scientist or someone with access to a U.S. biodefense lab.”
Although “The FBI would not allow Beecher to be interviewed about his article”, the Washington Post writers quote from his August 2006 paper in Applied and Environmental Microbiology: “A widely circulated misconception is that spores were produced using additives and sophisticated engineering supposedly akin to military weapons productions”. In their September 25 Post article, Lengel and Warrick also quote from a former Soviet bioweapons scientist Sergei Popov, now working at George Mason University, regarding the Ames strain of anthrax found in the 2001 anthrax letters: “Ames was available in the Soviet Union…It could have come from anywhere in the world”.
The August 2006 by Beecher provides great detail on the forensic examination of the letter to Senator Leahy, including the effect of personal protective equipment (PPE) contamination while personnel were investigating the Leahy letter (Table 1, page 5307), and the anthrax contamination studies of 20 letters also postmarked October 9, 2001 in Trenton, New Jersey close in time to the “Daschle and Leahy letters” (Table 2). Of note, however, no new data is provided in the “Results” section of the paper regarding the presence or absence of any additives to the anthrax spores in the letter.
In the “Discussion” section of the paper (page 5309) however, Mr. Beecher states that ”Individuals familiar with the composition of the powders in the letters have indicated that they were comprised simply of spores purified to different extents (6)”. This single reference # 6 is from an article titled “Anthrax powder: State of the Art?” published 28 November 2003 in Science (volume 302, pages 1492-1497) by Gary Matsumoto, described at the end of the five-page article as an investigative journalist.
For this 2003 article, Matsumoto interviews many persons and discusses a spectrum of possibilities ranging from no additives being found (see page 1494 that refers to FBI scientists) to discussion of whether certain additives were present. Mention of polymerized glass, silica, and use of nanotechnology are made, for example, but no definitive data presented that any additives were found. At least one expert is cited as suggesting that the anthrax spores in the letter “could have acquired a charge from friction as the envelopes passed through mail-sorting machines” (p. 1493). These electrical charges could have helped create a “self-dispersing powder” that increased the chance of allowing the spores to reach the deepest parts of the lungs where they would cause inhalational anthrax.
A common theme from the 2006 paper by Beecher, and the 2003 article by Matsumoto is the aerosol nature of the anthrax spores in the letters postmarked October 9, 2001. This theme is supported by their publications and a December, 2002 Journal of the American Medical Association (JAMA) paper by the US Environmental Protection Agency and other government organizations involved in a study of the Hart Senate Office Building after it was closed following the anthrax attack:
- Douglas Beecher (FBI). Applied and Environmental Microbiology 2006 (August) 72 (8): 5304-531: “…physically handling the intentionally contaminated letter proved to be exceptionally hazardous, as did sorting of cross-contaminated mail which resulted in generation of hazardous aerosol and extensive contamination of protective clothing” (page 5304).
- Gary Matsumoto. Science 2003 (Nov 28); 302: 1492-97. “There is no debating that the Senate powder was exceptionally pure and highly concentrated…But what made it truly remarkable, according to biodefense specialists, was its conversion into a cutting-edge aerosol” (page 1493)
- Weis et al. Secondary Aerosolization of viable Bacillus anthracis spores in a contaminated US Senate Office. J Am Med Assn (JAMA) 2002 (Dec 11)288: 2853-58. “Viable B. Anthracis spores reaerosolized under semiquiescent conditions, with a marked increase in reaerosolization during simulated active office conditions…these findings have important implications for appropriate respiratory protection, remediation, and reoccupancy of contaminated office environments” (page 2853).
Some, but not all, studies at the Dugway Providing Ground in Utah similarly documented decades ago the ability of Bacillus subtilis, an anthrax simulant, to reaerosolize (Resnick IG et al. Evaluation of Need for Detection of Surface Biological Agent Contamination: Dugway Proving Ground, Life Sciences Division, US Dept of the Army; 1990; 1-35. Publication DPG-FR-90-711. (also cited by Inglesby et al. JAMA (May 1) 2002; 287: 2236-52. See reference 107).
Future biodefense planning for anthrax attacks, especially if aerosolized attacks as envisioned in the US Cities Readiness Initiative (CRI), should emphasize the ability of the anthrax spores to form a biohazardous aerosol, and to reaerosolize as documented in the Hart Senate Office Building.
3 November 2006
Oseltamivir (Tamiflu) now produced in United States for Pandemic Flu Preparedness…Are we safer?
Amidst fears of a bird flu pandemic, the US Department of Health and Human Services (HHS) has been adamant that the US be self-reliant in the supply of the anti-influenza drug oseltemivir (“Tamifllu”) for the American public. Now through a working partnership with Roche AG, the Swiss manufacturer of Tamiflu, and its external contractors, the US is able to make the drug entirely on US soil. The US production facility is part of Roche’s worldwide global production network capable of producing 400 million treatment courses of Tamiflu annually by the end of 2006 (Roche Pharmaceuticals Press Release, 14 September 2006, [http://www.rocheusa.com/newsroom/current/2006/pr2006091401.html]).
Oseltamivir is the generic name for Tamiflu that is used in the treatment and prophylaxis of both Influenza virus A and Influenza virus B. Oseltamivir is a neuraminidase inhibitor which prevents new viral particles from being released by infected cells. Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of infected cells. This promotes the release of progeny viruses from infected cells (FDA Information on Tamiflu, [http://www.fda.gov/cder/drug/infopage/tamiflu/default.htm] and Roche Tamiflu Fact Sheet, [http://www.roche.com/med_mbtamiflu05e.pdf]).
Roche AG (http://www.roche.com/home.html) is the primary maker of Tamiflu and in early 2005, it announced a production shortage resulting from a bottleneck due to lack of shikimic acid. Shikimic acid is a critical ingredient that is isolated from star anise, which is an ancient cooking spice. Star anise is only grown in four provinces in China and harvested between March and May, and also in Lang Son province in Vietnam. The extraction process for the shikimic acid from star anise is long, complicated, and has a low yield. Therefore, Roche is now shifting production to a fermentation process using E. coli bacteria. This will decrease, if not eliminate, reliance on limited and unpredictable agricultural resources. Reports have indicated that this new fermentation production method of shikimic acid also produces much higher amounts of this critical ingredient.
Tamiflu is hoped to be effective in combating the next flu pandemic, assuming the virus causing the next pandemic is susceptible to this neuraminidase inhibitor. In preparing for this future pandemic, many countries and health organizations, including the US and the WHO, have begun stockpiles of oseltamivir (Roche Media News, 19 April 2006, [http://www.roche.com/med-cor-2006-04-19]). Along with the US, multiple countries have begun to produce oseltamivir. Prior to 2004 all production of this medication occurred in Switzerland at the Roche company production facility in Basel.
“The ability to produce Tamiflu from start to finish on US soil is a significant milestone that will help ensure access to Tamiflu when and where it is needed,” said George Abercrombie, president and chief executive officer for Hoffman-La Roche, Inc., the company’s US pharmaceutical division (Roche Press Release, 14 September 2006). He continues, “”This most recent expansion further demonstrates Roche’s long term commitment to serving as a responsible and collaborative partner with the U.S. government on pandemic preparedness and response To date, HHS has ordered 21.3 million courses of Tamiflu for the U.S. Strategic National Stockpile, which will be delivered in full this year. The total targeted U.S. stockpile is 81 million antiviral treatment courses by the end of 2008; HHS plans to purchase 50 million treatment courses and subsidize by 25 percent the states’ purchases of 31 million courses”.
Oseltamivir is the only oral neuraminidase inhibitor licensed by the FDA to prevent and treat influenza infection. The only other FDA-licensed neuraminidase inhibitor drug for influenza prevention and therapy, zanamivir (“Relenza”) is only available commercially as an inhaled drug and not as a pill or capsule. Of note, influenza viruses that are resistant to oseltamivir (Tamiflu) are still susceptible to zanamivir (Relenza). The US Department of Health and Human Services (see their pandemic flu website: www.pandemicflu.gov) is stockpiling both oseltamivir and, to a lesser extent, zanamivir.
If the next pandemic influenza virus is susceptible to these neuraminidase inhibitor medications, then we will be better prepared and safer than in the absence of this stockpile. At the same time it is important to remember that both oseltamivir (Tamiflu) and zanamivir (Relenza) have important caveats to their use and effectiveness. In addition, antiviral drugs are only one part of overall pandemic flu preparedness and response.
Shoshana Avertick, Jordan Kanter, Stephanie Hrycaj, Igor Fogelman, Pete Harlan, and Shannon Hibbard.
Graduate students, Georgetown University Master of Science (M.S.) Program in Biohazardous Threat Agents and Emerging Infectious Diseases. Biodefense Public Health Countermeasures MICB-523.Washington, DC. Course instructor and article editor: Daniel R. Lucey, MD, MPH. Adjunct Professor of Microbiology and Immunology. Director, Center for Biologic Counterterrorism and Emerging Diseases, EROne Institute, Washington Hospital Center, Washington, DC.
29 November 2006
Daniel R. Lucey, MD, MPH
Report on H5N1 in Indonesia
Since 2005 Indonesia has diagnosed 74 lab-confirmed H5N1 avian flu patients in 9 provinces, as well as 12 probable and 187 suspected patients.
On 28 November 2006 the Indonesia National Committee for Avian Influenza Control and Pandemic Preparedness reported on the website www.komnasfbpi.org/press_november_28.html the following number of patients and fatalities due to lab-confirmed H5N1 avian flu virus in nine (9) provinces across the country:
| Province | Number of Patients | Number of Deaths |
| West Java | 25 | 20 |
| Jakarta | 18 | 16 |
| Banten | 9 | 8 |
| North Sumatra | 7 | 6 |
| East Java | 5 | 3 |
| Central Java | 4 | 3 |
| Lampung | 3 | 0 |
| West Sumatra | 2 | 0 |
| South Sulawesi | 1 | 1 |
| Total: | 74 | 57 (77% of 74) |
In addition, a total of 12 probable (with 4 deaths) and 187 suspect (with 50 deaths) diagnoses of patients with H5N1 avian flu infection have been made in Indonesia. One “exposure case” and 539 persons who have tested negative for H5N1 virus infection were also included in this report. To date, the number of provinces reporting human cases is less than the number reporting infections in avians, the latter being much more widespread across the nation.
The most recent fatality, reported 28 November, was a 35 year old woman who lived in Taman Adiyaksa, Tangerang, Banten Province. She was being treated in the Sulianti Saroso Infectious Disease Hospital in Jakarta. “A history of contact with poultry has not been established”, according to the above website posting by Dr.Lily S. Sulistyowati, Director of the Center for Public Health Communication
.
Laboratory confirmation of H5N1 virus infection was by RT-PCR performed by the Indonesian Health Ministry Research and Development Agency and the Naval Medical Research Unit (NAMRU)-2 located in Jakarta.
10 December 2006
Daniel R. Lucey, MD, MPH
International Avian Flu Conference in Mali Reports Success
Press releases on December 8th by the Food and Animal Organization (FAO, based in Rome) of the United Nations and the World Organization for Animal Health (OIE, based in Paris) reported positive outcomes of the 4th international avian influenza conference held December 6-8 in Bamako, the capital of Mali.
The OIE press release noted that co-organizers of the meeting included the African Union/Interafrican Bureau for Agricultural Resources (AU/IBAR), the European Union, and The Government of Mali. They pointed out that at the time of the prior (3rd) international avian influenza conference, in Beijing in January 2006, H5N1 avian influenza virus had not yet been found in any African nations. Since February of this year, however, the virus was found in poultry in multiple countries in Africa, as well as causing human infections in Egypt and Djibouti.
At the meeting in Bamako the OIE encourage the idea of “laboratory twinning”, matching currently certified OIE-reference laboratories with veterinary laboratories not yet designated as OIE-reference laboratories in developing and in transition nations. The outcome of this effort is intended to be enhanced rapid diagnostic capabilities to facilitate detection and response to avian flu outbreaks in animal populations.
The OIE also reported that several million doses of veterinary H5N1 vaccines have already been delivered to African nations in 2006. This effort has been linked to the creation of a “virtual vaccine bank” for Africa earlier in 2006 through a partnership between OIE, AU/IBAR, and the EU.
The FAO press release cited comments at the conference in Mali emphasizing the importance of defending against avian flu in Africa. The FAO Assistant Director General, Alexander Muller, was quoted as saying that Africa should be “a top priority for resources and technical assistance in the battle against avian flu”. Both the FAO and OIE releases reported pledges of approximately 475-500 million US$ by the third day of the conference.
In a related news story (Reuters) appearing on the front page of the print copy of the Middle East “Gulf News” (al Nisr publishing, wwwgulfnews) on December 9th, the World Bank’s lead livestock specialist for Africa, Francois Le Gall, was quoted as emphasizing that “Avian flu is just one of many diseases that are impacting the continent of Africa. The experts are telling us that other diseases are going to emerge or re-emerge”.
Indeed, it is clear that preparing well for avian influenza now, for example by enhancing veterinary and human public health laboratories and related human resource infrastructures, will strengthen preparedness for the new or resurgent “emerging” infectious diseases of the coming years and decades, in Africa, Asia, and globally.