2004 Center for Biologic Counter-terrorism and Emerging Diseases Forum Updates

January 27, 2004

Daniel R. Lucey, MD, MPH

Avian Influenza updates since January 23rd

Colleagues:

Key updates (6) on avian influenza (bird flu) include:

(1) A report of drug (Rimantadine/Amantadine) resistance by at least one human and one animal isolate of avian influenza (H5N1) A.

(2) Ongoing rapid spread in the number (11) of Asian nations, now including China, reporting avian influenza. Most are H5N1, one is H5N2, and several are not subtyped yet.

(3) The World Health Organization (WHO) today (Jan 27) called for “international assistance” for “Unprecedented spread of avian influenza requires broad collaboration”. A multination conference on avian influenza begins tomorrow in Bangkok.

(4) Fortunately still no person-to-person transmission of avian influenza, or any avian-human influenza A virus reassortment has been found.

(5) The number of patients with lab-confirmed H5N1 infection has increased to 7 (6 deaths) in Vietnam, and 3 (2 deaths) in Thailand. Further lab testing of patients is also occurring in Cambodia as well as Vietnam and Thailand.

(6) The US CDC today expanded their geographic (Asia) recommendations for “enhanced surveillance efforts by health departments, hospitals, and clinicians to identify patients who have been hospitalized with unexplained pneumonia, ARDS, or severe respiratory illness AND who have traveled to countries in Asia with documented H5N1 outbreak.” In this same two page CDC document 8 such Asian nations are listed: “Outbreaks of avian influenza (H5N1) have been reported among poultry in Vietnam, South Korea, Thailand, Japan, Indonesia, Myanmar, Cambodia, and China”. (Today’s South China Morning Post (www.scmp.com) also reports that Laos has an avian flu outbreak, subtype pending. In Pakistan preliminary reports are of avian influenza in poultry in Karachi, but that it is not an H5 strain. Taiwan has an H5N2 outbreak).

Brief comments:

1. The preliminary report of H5N1 resistance to the older and less expensive FDA-licensed anti-influenza drugs amantadine and rimantadine, but retained sensitivity in vitro to oseltamivir and zanamivir appeared in the NY Times Sunday, Jan 25 on page A8 by Lawrence K. Altman. He quoted Dr. Klaus Stohr of the WHO. Thus, further testing is ongoing to confirm this finding and to determine how widespread and common (or rare) this resistance pattern is. (Having just returned from Hong Kong I was able to confirm from a colleague that at least one 2004 patient isolate of H5N1 and one animal isolate of H5N1 have been found to be resistant in vitro to rimantadine and amantadine).

2. A map and a list of nations that have reported avian influenza (H5N1, H5N2 (Taiwan), or not-yet-confirmed subtypes is available on our website at www.bepast.orgunder the “Avian Flu” IMAGES section. Updated references from WHO, CDC, and news reports and medical literature on avian flu (e.g. the 1997 H5N1 outbreak in Hong Kong) are also listed at the top of this website homepage.

3. Items 3-6 are referenced and available on the WHO homepage under avian influenza (9 updates) and under their influenza section is a 60+ page pandemic influenza plan, with a one page executive summary) at www.who.int; other references are on the CDC homepage www.cdc.gov under “Influenza”.

In closing:

1. Consensus US clinical guidelines for evaluation and management of patients with possible or proven H5N1 infection should be developed and disseminated. Practical issues will include type of personal protective equipment (PPE), type of isolation (e.g., cohorting of patients with droplet precautions OR single patient rooms e.g., to decrease both risk of spread to other patients of H5N1, AND also to decrease the risk of one person becoming infected with BOTH H5N1 avian influenza A and a human influenza A (such as H3N2 or H1N1) that could lead to a “reassortment virus” with increased person-to-person transmission.

2. Recommendations for possible selective use of prophylactic and/or therapeutic use of anti-influenza drugs (? the newer, more expensive neuraminidase inhibitors oseltamivir (oral) or zanamivir (inhaled)).

July 6, 2004

Daniel R. Lucey, MD, MPH

Evolving H5N1 Influenza: Avian Epidemic to Human Pandemic?

This past influenza season in the northern hemisphere recorded 23 deaths among the 34 persons infected with H5N1 “avian influenza”, and over 100 million birds and poultry infected or culled over the past seven months due to this subtype of influenza A.

The reported human cases, with a 68% mortality rate, were from Vietnam (15/22 deaths) and Thailand (8/12 deaths). Six other Asian nations, including China, Korea, Japan, Cambodia, Laos, and Indonesia, also had extensive bird and poultry infections with H5N1 influenza A. Never before has avian influenza, of any subtype, caused such widespread veterinary disease, and human deaths. Will the H5N1 virus evolve into a new influenza virus that is spread readily from person-to-person and thus trigger the next major global influenza epidemic, or “pandemic”?

H5N1 influenza virus has already evolved through mutations from its initial appearance in humans in 1997 when it killed 6 of the 18 persons who were symptomatic enough to receive medical attention. It also caused additional asymptomatic infections in humans. In 1997 this H5N1 virus was limited to poultry in only Hong Kong, which courageously chose to cull all poultry over three days rather than risk the start of an H5N1 pandemic. By February 2003, a biologically distinct H5N1 virus had evolved and infected at least two persons in Asia.

By January 2004, at least 10 patients with H5N1 avian influenza had been confirmed in Vietnam as reported by Hien et al., in the N Engl J Med March 18, 2004. Notably, the virus had evolved for the first time to become resistant to the two less-expensive, older oral anti-influenza drugs amantadine and rimantadine. It remained sensitive to the newer and more expensive drugs, of which oseltamivir is the only oral formulation. This virus had evolved through mutation so much that the early human vaccine effort begun using prior H5N1 virus isolates had to be restarted using the 2004 H5N1 strain. Thus, no human vaccine against H5N1 is currently licensed.

In the July 13, 2004 issue of the Proceedings of the National Academy of Science (PNAS) volume 101; p. 10452-10457) Chen et al., reported that different H5N1 influenza viruses isolated from seemingly healthy domestic ducks in mainland China from 1999-2002 caused influenza illness in chickens, and increasingly in mice. The evolution of mutations in the H5N1 neuraminidase and nonstructural genes from H5N1 was linked with increasing ability to infect mice, a mammalian host, and raises concern that further mutations could result in increased human infections.

The World Health Organization (www.who.int) and Centers for Disease Control and Prevention (www.cdc.gov) have posted extensive information on H5N1 influenza on their websites including a chronology of events, veterinary and human infection control measures, human pandemic influenza planning steps, and advice for travelers. Further summaries on human and avian influenza will appear here, at www.bepast.org, in the weeks and months ahead.

July 26, 2004

Daniel R. Lucey, MD, MPH

Cities Readiness Initiative (CRI): 8 Key Quotes

The Centers for Disease Control and Prevention (CDC) posted on their website in June 2004 information about the new and critically important Cities Readiness Initiative (CRI) involving 21 US cities. This CRI is closely linked with the US Strategic National Stockpile (SNS). As an overview of the key points of this new initiative, cited below are 8 quotes from one of the CRI documents posted by the CDC titled “Continuance Guidance-Budget Year Five Attachment K”. The complete “Cities Readiness Initiative -Attachment K” document can be found at: www.bt.cdc.gov/planning/continuationguidance/index.asp

“Of foremost concern is the ability to respond in a timely manner to a bioterrorism attack over a large geographic area with an agent such as Bacillus anthracis, the organism that causes anthrax. In this case, antibiotics must reach the population within 24-48 hours to have the greatest life-saving effect.” (CRI document page 1 of 7).
“To this end, CDC is providing special funding targeted to 21 selected entities for fiscal year (FY) 2004 cooperative agreement on public health preparedness and response for bioterrorism.” (Page 1 of 7).
“The targeted funding is to ensure that these selected cities are prepared to provide oral medications during an event to 100 percent of their affected populations. This generally will entail enhancing each city’s capability to establish a network of points of dispensing (PODs) staffed with trained/exercised paid and volunteer staff.” (Page 2 of 7).
“In the wake of a catastrophic bio-terrorism event, even the largest POD network that the jurisdiction is capable of mounting on its own may be insufficient to protect its citizens—in which case, the grantee may elect to request staff and other resources from the Federal Government to augment the POD network or to deploy elements of the United States Postal Service to complement the POD network with direct delivery of antibiotics to residences.” (Page 2 of 7).
Recipients must coordinate planning and program implementation activities to ensure that state and local health departments, hospitals, other health care entities, and State and local public safety and emergency management agencies are able to mount a collective response featuring seamless interaction of their event-specific capabilities ion the following areas:
1. Oral Dispensing of Medications at the PODs
2. Providing Oral Medications to First Responders & Critical Infrastructure Personnel
3. Public Information and Communications
4. Dispensing of Medical Material to Treatment Centers
5. Tactical Communications between Command and Control Elements (page 3 of 7).

“Specifically, the Cities Readiness Initiative is designed to significantly improve the operational capability of 21 large metropolitan areas to receive, distribute, and dispense SNS assets”. (Page 4 of 7).
“Within 6 months following the application of the SNS Assessment Tool…each designated city should be able, in the wake of a bioterrorism event for which antibiotics are an appropriate countermeasure, to provide such prophylaxis to the known and potentially affected population within 48 hours of the time of the decision to do so.” (Page 4 of 7).
“With a view to catastrophic incidents that may overwhelm even the largest POD network the city can establish, the assessment also will seek to determine whether the local plan is structured adequately to accommodate the deployment of complementary federal government assets such as the United States Postal Service for direct residential delivery of antibiotics.” (Page 7 of 7).

31 August 2004

Daniel R. Lucey, MD, MPH

The US Pandemic Influenza Plan: Just in Time?

On August 26 the US Department of Health and Human Services released the draft Pandemic Influenza Preparedness and Response Plan. This plan is timely. Only the next few years will determine how timely.

Reports confirmed by the World Health Organization (WHO) in the past two months document that the avian influenza A H5N1 virus has killed at least three more persons in Vietnam, has been found in poultry in at least five nations in Asia, and was detected in pigs in China in 2003-2004.

The significance of pigs being infected with H5N1 is that in the past other pigs have also been shown to be infected with human influenza A virus H3N2. Thus, the risk is evident of a novel hybrid, or reassortant influenza virus forming in pigs that are infected both with an avian influenza (such as H5N1) and a human influenza virus (such as H3N2). If such a novel virus spreads readily from person-to-person and was so different that the human population had no prior immunity from past similar infections or similar vaccines, then by definition a “pandemic influenza” crisis could occur.

The timeliness of this new Pandemic Influenza Plan is not related only to the evolving avian influenza H5N1 virus. In fact, “bird flu” H5N1 is only one of several candidate pandemic influenza viruses, along with H9N2, H7N7, and H7N2 that have been reported within the past two years to infect humans. These infections of humans have been in small numbers due to little or no person-to-person spread. Thus, no pandemic influenza has occurred.

The widespread infection of poultry in 2004 by avian influenza H5N1 in some parts of Asia is unprecedented and unlikely to be eradicated in the immediate future. Thus, preparing in earnest now for pandemic influenza in humans is critical, even though no pandemic has begun yet. The past century saw three pandemics: 1918, 1957, and 1968.

Four key points, of many, that can be emphasized from an initial reading of the 55 page core draft plan and 12 additional annexes include:

The six pandemic phases of the plan (see annex 1, page 21) are the same as the WHO pandemic staging system. These phases range from “Phase 0” (the current inter-pandemic phase) to “Phase 5” (confirmation that the pandemic waves have ended). We are currently in “Level 2” of Phase 0 defined by the recognition of novel influenza viruses (such as H5N1 and others above) that infect humans without causing widespread person-to-person spread.
Unlike the SARS or smallpox viruses, which usually do not spread from person-to-person before symptoms occur, humans infected with influenza virus can shed virus and potentially infect other people before becoming asymptomatic, as well as during asymptomatic influenza infections. This fact, along with others, will likely make infection control, isolation, and quarantine more difficult during pandemic influenza (annex 8, page 7).
Unlike the yearly human flu vaccines that require only one dose for adults, the new vaccines that would be required to protect against a pandemic influenza virus might need two (2) doses, spaced several weeks apart. Thus, a computerized tracking system and ability to give the 2^nd dose on time would be critical (annex 6, page 7). A 2^nd dose of vaccine might be required since there may be no prior human immunity, due to either infection or vaccination, against such a novel virus.
Of the two classes of anti-influenza drugs, the adamantines (amantadine and rimantadine) “may be the preferred choice for prophylaxis if the pandemic strain is susceptible”. The second class of drugs, the neuraminidase inhibitors (oseltamivir (oral) and zanamivir (inhaled) “may be the preferred choice for treatment (annex 7, page 8). However, only limited amounts of oseltamivir are available. In addition, H5N1 viral isolates from patients in early 2004 in Vietnam were resistant to amantadine and rimantadine, the older and less expensive anti-influenza drugs, but still sensitive to oseltamivir, the only oral neuraminidase inhibitor.

14 September, 2004

Daniel R. Lucey, MD, MPH

Anthrax Vaccine After Exposure to Aerosolized Anthrax Spores

On September 9, 2004, the US Centers for Disease Control and Prevention (CDC) provided updated information on anthrax that emphasizes a role for three (3) shots of the anthrax vaccine in the event persons are exposed to “potentially aerosolized Bacillus anthracis spores.”. In this potential situation of aerosol release of anthrax the CDC will recommend “60 days of selected antibiotics in conjunction with a 3-dose regimen (0, 2, 4 weeks) of anthrax vaccine (BioThrax, formerly known as AVA) as an emergency public health intervention…Biothrax is not licensed for post-exposure prophylaxis for prevention of inhalation anthrax, or for use in a 3-dose regimen. Therefore, this program would be considered under an Investigational New Drug (IND) application.”

The CDC guidelines go on to make explicit that two antibiotics are FDA-approved for post-exposure prophylaxis (PEP) against anthrax, and these two drugs are doxycycline and ciprofloxacin. Initial therapy with either “Cipro” or “Doxy” is recommended for adults and children when no information is available about the antimicrobial susceptibility of the implicated strain of Bacillus anthracis, while awaiting sensitivity testing.

These recommendations, focusing on aerosolized anthrax, deserve careful attention by medical and public health personnel. In particular, use of the anthrax vaccine in an IND setting should be communicated and discussed prior to any further anthrax attacks.

September 29, 2004

Daniel R. Lucey, MD, MPH

Probable Case of Human-to-Human H5N1 Transmission: Thailand

On September 28^th, the WHO reported that the Thailand Ministry of Public Health has concluded that the death on September 20th of a 26-year-old woman due to H5N1 avian influenza virus “represents a probable case of human-to-human transmission” of the virus.

The index case of the H5N1 transmission appears to have been the 11-year-old daughter of the 26-year-old woman. This child died of an influenza-like illness on September 8. The 11-year-old girl lived with her 32-year-old aunt, who has also been diagnosed with lab-confirmed H5N1 infection and has been hospitalized. A fourth ill family member is a 6-year-old son of the aunt. He is also hospitalized and is being tested for H5N1 infection. The WHO Influenza Laboratory Network is currently sequencing these H5N1 isolates to see if they have mutated in some way that might facilitate human-to-human spread.

That limited, non-sustained transmission of H5N1 from person-to-person would occur in 2004 is not surprising given that transmission resulting in antibody-positive, asymptomatic infection occurred with the initial H5N1 outbreak in 1997 in Hong Kong. Of much greater public health concern would be the unprecedented person-to-person transmission of H5N1 that is sustained, especially if it begins to approach the efficient transmission seen during the yearly outbreaks of human influenza A H3N2 or H1N1. So far, this has not happened.

The Thailand Ministry of Public Health has responded admirably to the recent H5N1 situation, opening an avian influenza Operational Center to respond to questions and address all aspects of avian influenza. Moreover, nationwide they have instituted a very large and coordinated response effort involving thousands of workers to provide surveillance for H5N1 and testing for anyone with influenza-like disease. A very informative and detailed listing of case definitions (suspect, probable, confirmed) and individual case evaluations, by location across the country, is provided daily on the Ministry of Public Health website at http://eng.moph.go.th

October 1^st, 2005 – Washington, DC

Key Questions to Help Identify the First High-Risk Patients with Tularemia

I. Are there any clinical findings of an illness associated with tularemia such as:

A. Fever

B. Cough, shortness of break, difficulty breathing on exertion

C. Pharyngitis or conjunctivitis, cervical or pre-auricular adenopathy

D. Unexplained skin ulcers or other lesions

E. Chest X-ray or Chest CT scan: Key findings include hilar

adenopathy that sometimes can cause mediastinal widening, and pleural

effusions, in addition to pneumonia.

If “Yes” to the above question, then:

II. Is there an Epidemiological Linkto the reported detection zone of the tularemia-causing bacteria close to the Mall on September 24-25, “in and near the area between the US Capitol and Lincoln Memorial”? (Wash Post Saturday, Oct 1^st. p. B01)?

III. Were cultures obtained before antibiotics and was a commercial identification

system used by the microbiology lab to identify any bacteria growing in culture?

A. All cultures (blood, sputum, pleural fluid, skin lesions, other) should be done BEFORE any antibiotics are given. If antibiotics are given before cultures, then notify the microbiology lab so they can keep the cultures for 7 days instead of the usual 5 days that CDC recommends allowing the fastidious Francisella tularensis organism to grow. (P.6 of 13. CDC Basic Protocols for Level A Labs for the presumptive identification of F. tularensis.)

B. “Identification of F. tularensis should not be attempted with commercial identification systems because of the potential for generating aerosols and the high probability of misidentification” (CDC Basic Protocol as above). The two bacteria typically misidentified by commercial microbiology lab systems when Francisella tularensis is actually present are Actinobacillus actinomycetemcomitans and Haemophilus influenza.

“High Risk” Patients with Tularemia could be defined as those with:

A. A positive Epidemiological-Link to the known detection zone of tularemia September 24-25, AND any one of the following

1. Pneumonia with hilar adenopathy (including “mediastinal widening”) or

pleural effusions, or other clinical syndromes caused by tularemia as listed.

2. A gram-negative bacteria growing from blood, sputum, pleural effusion, skin

lesion or other site that has been identified as either:

a. Actinobacillus actinomycetemcomitansor

b. Haemophilus influenza.

Conclusion:

The rationale for rapidly identifying and reporting the first patient with tularemia is to establish that an infectious exposure did in fact occur. Thus, there may be additional patients. These patients may already be in hospitals (EDs, ICUs, ward units, or morgues, in outpatient clinics, or they may enter the healthcare system in the coming hours-days.

Recognition and notification of the appropriate authorities of the first patients with tularemia will facilitate the rapid medical care and public health management of other patients.

October 14, 2004

Daniel R. Lucey, MD, MPH

UK details smallpox response plan

The United Kingdom (UK) Department of Health has provided a detailed and very useful update online of their “Interim Guidelines for Smallpox Response and Management in the Post-Eradication Era (Smallpox Plan)”. The 59 page core document ranges from training and planning for smallpox, to management of initial cases and their contacts, to vaccination strategies, to communication with the media and the public. The document is found on the website of the UK Department of Health at www.dh.gov.uk by entering the search term “smallpox” on the homepage.

Appendix 1-17 follows with further specific guidelines including algorithmic flow diagrams on management of initial suspected cases when they occur: at home, in the Emergency Department, in the Intensive Care Unit, on the Medical, Surgical, or Infectious Disease wards or clinics, or at a Port Health Control Unit.

In the text of the plan, pages 44-47, there are six “Alert Levels” listed, and specific preparedness measures defined for each level. The levels are:

Level 0: No credible threat of a smallpox release.

Level 1: At least one case of smallpox outside the UK.

Level 2: At least one case inside the UK.

Level 3: A smallpox outbreak in the UK.

Level 4: A large outbreak of smallpox not controlled by “ring vaccination”

Level 5: Outbreak controlled and no further cases.

Guidelines for these UK “alert levels” are very helpful when considering and comparing with the four general smallpox “scenarios” described for the USA by the Institute of Medicine (IOM) of the National Academies Committee on Smallpox Vaccination Program Implementation in their letter # 5 to the US Centers for Disease Control (http://books.nap.edu/catalog/10875.html)

The UK smallpox containment strategy begins with the same measures as the USA and the WHO strategy recommendations including: isolation of cases, tracing-surveillance of contacts, quarantine of contacts and “ring vaccination” of cases and cases. In the UK plan, however, there is also an Alert Level 4 defined (page 46 of 59) as when a large outbreak occurs that is not controlled by the traditional and field-proven “ring vaccination” strategy. Such hypothetical “circumstances may arise when mass vaccination may be required to raise the level of immunity to smallpox such as when:

A large number of cases occur simultaneously all over the country
Uncontrolled spread resulting from larger or multiple deliberate release
Many secondary cases occurring without identifiable contact with a primary case, implying that contact tracing and enhanced surveillance for cases has been ineffective”.

29 October 2004

Daniel R. Lucey, MD, MPH

WHO: New Public Health advice from data on H5N1 flu virus in ducks

On 29 October the World Health Organization (WHO) posted on the avian influenza section of their website (www.who.int) findings of a new study of H5N1 bird flu in domestic ducks resulting in new Public Health recommendations.

In a laboratory study performed at the WHO collaborating centre for animal influenza viruses in Memphis, Tennessee at St Jude’s Children’s Research Hospital, and reported by WHO prior to publication due to its importance researchers found:

Most domestic ducks infected with H5N1 avian influenza virus in the laboratory study had no symptoms, and yet excreted large amounts of H5N1 virus in both the feces and from the respiratory route. In contrast, H5N1 causes illness and often death in chickens, and humans.
Such apparently healthy, H5N1-infected, domestic ducks could transmit the H5N1 virus to chickens.
All infected ducks in this study excreted the 2004 strain of the H5N1 virus for 11 days or longer. In contrast, the H5N1 virus from one year ago (2003), when used to infect ducks in this lab study, was excreted for a maximum of 10 days.
The H5N1 virus from 2004 appeared to survive for three times longer in the environment than the H5N1 virus strain from 1997 (6 days vs 2 days, at 37 C).

Based on these soon-to-be published findings, the WHO Public Health recommendations for H5N1-affected nations included:

“Ducks should not be kept as pets or allowed to enter households”.
“Water supplies for human use should not be drawn from open ponds used by domestic ducks and should always be stored in ways that prevent contact with ducks”.
“Significant exposure can occur during home slaughtering and preparation prior to cooking, and these risks need to be addressed”.
‘Research on the prevalence of asymptomatic infection in ducks in Asia is urgently needed…to allow a focused approach to the prevention of human cases arising from exposure to apparently healthy domestic ducks.”

Given the widespread interaction between domestic ducks, chickens, humans and other species in some parts of Asia affected by H5N1, these laboratory findings should be confirmed in the field. The potential impact of these WHO Public Health recommendations is very large when seen from health, nutrition, lifestyle, and economic perspectives.