17 March 2005

Daniel R. Lucey, MD, MPH

Anthrax: Key Reminders and Updates for Clinicians

Events this week regarding apparently false-positive tests for anthrax warrant a brief update on key issues related to anthrax.  The relevant CDC Health Advisory on March 15 and CDC Health Update on March 16 reported the following: on March 10th routine samples from an air sampling device at the Pentagon Remote Delivery Facility were collected and initial tests indicated possible anthrax, with the Department of Defense (DoD) being notified four days later, on March 14th.  This initial sample “was tested by a non-Laboratory Response Network (LRN) lab, and found to be positive by PCR and culture. Repeat PCR testing of this same sample at the DHS Laboratory at Ft. Detrick was also positive. Testing of a second portion of the original sample by the DHS Laboratory was negative by PCR and culture”. 

By apparent coincidence an alarm at a second DoD mailroom in a separate facility, away from the Pentagon, in the Skyline complex, Virginia occurred on March 14th. However, this alarm “proved to be from a particle counter rather than a biological sensor, and no testing indicated B. anthracis”, according to the CDC update March 16. Employees at these two DoD facilities as well as the civilian V-street postal facility in Washington, DC were initially placed on antibiotics prophylactically. No results of antibiotic susceptibility testing were given in the CDC documents for the initial sample that was found to be positive “by PRC and in culture” at the non-LRN lab. Being able to grow the Bacillus anthracis bacteria in culture, however, should prove critical in helping to subtype it, determine its susceptibility to multiple antibiotics, and possibly help identify its source.

A few of the salient points regarding anthrax “lessons identified”/”lessons learned” from 2001 and since could include:

1. Always draw blood cultures before giving any antibiotics to a person suspected of having anthrax. Blood cultures typically grow the Bacillus anthracis rapidly in <24 hours, and become sterile after even  1 or 2 doses of an antibiotic to which it is susceptible.

2. Either doxycycline or ciprofloxacin are recommended as equal initial choices for prophylaxis against inhalational anthrax, in the absence of known antibiotic susceptibility testing results.

3. It is critical that such antibiotic susceptibility testing is performed immediately once the first possible anthrax cultures are growing, as part of the standard operating procedure in either DoD-related labs, or non-DoD labs. In order to appropriately prophylax and treat persons for inhalational anthrax within the first hours to days after recognizing that an attack with anthrax has occurred, the antibiotic susceptibility of a broad array of drugs must already have been determined in the lab.

4. A search for symptomatic patients should be initiated immediately if a ‘reasonable threat’ of an attack has occurred, before final confirmation of multiple environmental samples has been completed.  This search for symptomatic patients should include looking for skin manifestations of anthrax as well as respiratory, intestinal, and meningeal manifestations. In 2004, the WHO published updated guidelines on biological and chemical threats that included two tables listing the date of onset of symptoms for all 22 patients with anthrax in the 2001 attack in the USA. The 8th patient listed by date of onset of symptoms was the man who presented with anthrax meningitis in Florida, often thought of as the first case in 2001. However, 7 patients had onset of symptoms before this patient, and 6 of these 7 had anthrax of the skin, although understandably not recognized at the time.

5. Hemorrhagic pleural effusions, sometimes rapidly accumulating and recurrent, were the rule with the patients in 2001. These effusions sometimes required repeated needle drainage or chest tube placement. 

6. Chest CT scans, without contrast, are more sensitive than chest x-ray at revealing the typical hemorrhagic mediastinal adenopathy that is highly suggestive of inhalational anthrax. This finding can occur before the patient is overwhelming ill.

7. Patients with mediastinal adenopathy, bloody pleural effusions (or “empyema” by definition when the Bacillus anthracis is found in the effusion), and positive blood cultures growing the organism CAN STILL BE CURED at this “intermediate-progressive” stage of inhalational anthrax.

8. The CDC recommends (unlike in 2001) investigational new drug (IND) use of anthrax vaccine, in conjunction with 60 days of antibiotics, after an aerosol release of Bacillus anthracis spores. This recommendation was posted on their website Sept 9, 2004 and again in 2005. The November 15, 2002 update on anthrax vaccine suggested that antibiotics be given for 7-14 days after the third dose of the anthrax vaccine. The 3 doses of vaccine are to be given over the course of one month (spaced apart at time 0, 2 weeks, and 4 weeks). 

9. There is no FDA-licensed antitoxin against anthrax at this time. Several investigational products have been tested, including monoclonal and polyclonal antibodies, as well as antisera from persons vaccinated with the FDA-licensed vaccine (that is primarily composed of “Protective Antigen (PA),” the one common component of the anthrax binary toxins, named lethal toxin and edema toxin). Whether any of these investigational anthrax antitoxin products will have a role to play as either a prophylactic or therapeutic agent is still unclear.

March 30, 2005

Daniel R. Lucey, MD, MPH

Marburg Outbreak Worsens: International Response Invited

The death toll due to Marburg Hemorrhagic Fever virus in Angola has climbed to at least 117 persons with the highest-ever-reported Marburg virus case fatality rate of 95% (117/124 cases), according to an update on the outbreak by the WHO March 29. Reports on ProMed-mail cite over 120 fatalities and quote Angolan health officials as asking for assistance from the international community to control the Marburg outbreak. 

To date all patients have been infected in the northern Uige province of Angola, although several of these patients have later been to other parts of Angola (Luanda and Cabinda).  Two travelers from Angola to Portugal who were ill have tested negative for Marburg in the WHO Reference Lab in Hamburg, Germany. However, the potential for spread of this virus to other parts of Africa, particularly Angola’s neighbor to the north, the Democratic Republic of the Congo (DRC), or to other nations and continents via plane travel is clear. 

A rapidly growing international response effort is underway in collaboration with Angolan public officials, the Ministry of Health, and health care workers. UNICEF is assisting with a social mobilization, communication, and education program working with 5,000 Scouts of Angola to disseminate information across the nation about Marburg virus.  An interdisciplinary team from WHO is supporting the contact tracing and active surveillance efforts of the Angolan Ministry of Health. 

Experts in Infectious Disease from England and South Africa are helping Angolan colleagues to organize infection control training in Luanda that will be available for health care workers from all provinces across the country. At the same time, in Uige province, infection control and isolation facilities are being optimized by Angolan officials and “Doctors Without Borders” based in multiple European nations. The US CDC laboratory confirmed the Marburg virus as the cause of death in at least 10 of the initial patients. 

​​March 31, 2005

Daniel R. Lucey, MD, MPH

H5N1 flu virus toll rises to 74 patients with 49 dead:  Pandemic Prodrome?

Today the WHO updated the total number of lab-confirmed persons with H5N1 infection to 74 of whom 49 (66%) have died. These figures include 2 patients in Cambodia, both of whom have died, 55 patients in Vietnam of whom 35 have died, and 17 patients in Thailand, of whom 12 have died. Yesterday the WHO confirmed bird flu “outbreaks involving large numbers of poultry… including one in Pyongyang Province”, North Korea. Confirmatory testing for H5N1 is still pending. WHO has volunteered to send the anti-influenza drug, oseltamivir to North Korea, since H5N1 as well as other strains of influenza are susceptible to this drug.

Today’s South China Morning Post (SCMP) newspaper (www.scmp.com) reports that North Korea has killed hundreds of thousands of chickens in an attempt to control the bird flu outbreak and that no human cases have been reported. They also report that influenza experts from China, Australia, and the veterinary expert from the UN/WHO will arrive in North Korea soon.  A Reuters Alertnews article March 28^th cited South Korean officials offering to help control the bird flu outbreak in the North Korean capital of Pyongyang if asked to do so, as well as taking precautions to prevent spread of the disease into South Korea. 

This SCMP article also commented on recent reports of clusters of patients in Vietnam with proven or suspected H5N1 infection. A WHO report March 29 also cited the ongoing investigations into these clusters in Vietnam to determine the epidemiologic risk factors for infection. Analysis of the virus genetic sequence can assist in determining whether or not mutations have occurred that could increase the risk of sustained person-to-person transmission.

The true case fatality rate of H5N1 is likely lower than 66% because of the fact that only the most ill, usually hospitalized, patients have been tested and reported to the WHO. Vietnam recently reported two asymptomatic patients infected with H5N1. Enserink and Normile  (Science 2005 (March 25); 307:1865) discuss in detail the issues surrounding the lack of data on the actual spread of H5N1.  This situation is due in part to the lack of large-scale testing of asymptomatic contacts of patients, as was done in 1997 in Hong Kong during their H5N1 outbreak involving 18 symptomatic patients and six fatalities.  

Until sustained transmission of H5N1 from person-to-person is proven we will not know for sure whether the month-by-month increase in H5N1 cases represents the prodrome of the next influenza pandemic. Having more data from expanded testing for H5N1 would surely increase the odds of identifying the start of the pandemic, however, and accelerate the global response.  The effect that the first H5N1-infected returning travelers from Vietnam, Thailand, or Cambodia will have in the USA or European countries can be anticipated, even if the route of transmission is linked to poultry rather than human contact. 

April 13, 2005

Daniel R. Lucey, MD, MPH

H2N2 influenza virus, similar to the 1957-58 pandemic, mistakenly sent for lab testing in 18 nations

Today multiple media reports and statements on the WHO and CDC websites confirmed that at least one US laboratory sent laboratory proficiency testing samples that contained the H2N2 influenza virus, similar to the one that caused the 1957-58 human pandemic, to more than 3,747 labs in 18 nations.  These countries included: Singapore, Hong Kong, Taiwan, Japan, The Republic of Korea, Saudi Arabia, Israel, Lebanon, France, Germany, Italy, Belgium, Chile, Brazil, Mexico, Canada, Bermuda, and the USA.  Most of the samples went to labs in the US and Canada, with 61 of the 3,747 labs located in the other 16 nations. 

The shipments that included the H2N2 virus were made between October 2004 and February 2005 as part of a routine panel of influenza A and B viruses distributed by the College of American Pathologists to be used by labs for proficiency testing and lab quality control.  Normally, H3N2 and H1N1 influenza A viruses are distributed for lab proficiency testing, according to the WHO.

The WHO reported on their website, in a document dated April 12, 2005, that the US Department of Health and Human Services (HHS) “has recently learnt that other proficiency testing providers have sent additional H2N2 samples to further laboratories in the USA. HHS is taking steps to ensure the rapid destruction of this material.”

A large debt of gratitude is owed to the Canadian scientists who first identified the presence of this H2N2 influenza A virus. On March 26, 2005 the Public Health Agency of Canada (PHC) notified the WHO of this H2N2 virus, similar to the virus found at the beginning of the 1957 human pandemic. They then worked to identify the source of this H2N2 virus, and found that it came from the American College of Pathologists panel of lab proficiency samples.  On April 8 the WHO, HHS, and CDC were notified by Canada of the source of the virus.

Fortunately, not a single human infection has been found as a result of this H2N2 virus having been shipped to over 3, 700 labs.  

The H2N2 virus circulated in the human population from 1957-1968. Then, it went out of circulation when the H3N2 influenza pandemic hit in 1968. Thus, importantly, persons born after 1968 have little or no immunity to H2N2 influenza. Moreover, there is no vaccine currently available against this H2N2 virus.  

The theoretical potential to trigger a new pandemic due to H2N2 influenza is evident, although the current risk to the public is considered low by the WHO. Another theoretical risk is that a severe pandemic could be triggered if this H2N2 virus, capable already of spreading in a sustained manner from person-to-person, combined with another virus such as the H5N1 avian influenza virus that has killed 50/80 laboratory-confirmed cases in Asia in the past 15 months.

On April 1, 2005 US President Bush issued an Executive Order amending the prior order of April 4, 2003 (during SARS) regarding quarantinable communicable diseases to include “Influenza caused by novel or reemergent influenza viruses that are causing, or have the potential to cause, a pandemic” (source: www.cdc.gov/ncidod/dq/). 

International vigilance is warranted to certify that all laboratories worldwide that received this H2N2 virus destroy all samples, and that outbreaks of influenza A are tested for H2N2, as well as H5N1, if they are not identified as the usual H3N2 or H1N1 influenza A viruses.  Review and optimization of laboratory biosafety protocols for handling influenza virus samples to protect lab workers (and their families and other contacts) is warranted on a global basis.  In addition, safeguards to ensure that no further errors regarding shipment of routine proficiency testing samples containing H2N2 influenza virus are needed.

April 28, 2005

Daniel R. Lucey, MD, MPH

Oseltamivir, Influenza, and the Media

Oseltamivir (commercial trade name “Tamiflu”) is an antiviral drug licensed by the Food and Drug Administration (FDA) for the prevention and treatment of influenza A and B.  On April 26 the Washington Post editorial page carried an article titled “Flu Prevention” in which it was stated that the USA has fallen behind other countries in stockpiling oseltamivir for potential use against the H5N1 influenza virus that may trigger the next flu pandemic. 

This high-visibility involvement in influenza pandemic preparedness by a major US newspaper could be a catalyst to accelerate action to mitigate what will be an acute international health crisis when this pandemic occurs.  The Post and other major print and electronic media could contribute more to global preparedness by publishing at regular intervals updates on pandemic influenza preparedness (or lack thereof) based on the weekly-monthly updates from international sources, the World Health Organization (WHO), and the US Department of Health and Human Services, including the CDC, NIH, and FDA. Such updates would form a “Pandemic Watch” that could serve to enhance pandemic preparedness and prevent the pandemic panic that is likely to occur with this respiratory disease starts to spread from person-to-person. 

The Post compares Britain’s purchase of 15 million courses of this drug, enough for one-quarter of their population, with the purchase of only 2.3 million doses by the USA. The editorial page goes on to state “A part of the problem may also be overall reluctance in Washington to recognize the danger that a flu epidemic poses.” They contrast this lack of a large stockpile of oseltamivir with the “U.S. government’s early recognition of the danger and its investment in vaccines” against the H5N1 virus and the “almost daily reports” on the spread of this virus in Asia, (by the WHO and other sources). 

The Post acknowledges that “U.S. officials point out that the drug is not perfect”, but the media would provide a service to the population-at-large by additional articles, part of a “Pandemic Watch” type educational campaign about pandemic influenza by delineating some of the potential problems with oseltamivir. For example, the drug is much more costly that older anti-influenza drugs such as amantadine and rimantadine, but the H5N1 virus now in Asia is resistant to these latter two drugs. Indeed, this H5N1 virus, or its pandemic-causing descendants will predictably develop some degree of resistance to oseltamivir. 

For now, however, oseltamivir is the only anti-influenza drug that can be taken by mouth that is proven to kill the H5N1 virus in laboratory tests. A clinical study has not yet been done to answer how effective oseltamivir is at preventing or treating H5N1 infection.  Such a study needs to be designed and ready for implementation long before the first major outbreaks of the early pandemic, a hard-learned lesson from the SARS outbreak of 2003. 

Another issue with oseltamivir is that for prevention (“prophylaxis”) the drug is not approved for children ages 1-12 years. And the dose of this drug varies by weight for the treatment of children 1-12 years of age who are already ill. Thus, a liquid suspension is needed for children as well as capsules for persons 13 years of age and older.  In this regard the shelf life of oseltamivir capsules is relatively long, namely 4 years (48 months), while the shelf life of the oral suspension (as a dry powder) is 18 months, according to an announcement January 6, 2004 by the European-based drug manufacturer, Roche Laboratories. 

17 June 2005

Daniel R. Lucey, MD, MPH

H5N1 in Thailand: Public Health and Political Response Temporally Linked with Lack of New Human Cases since October 2004.

Since the first human infections with the H5N1 avian influenza virus in Thailand 18 months ago, in January  2004, Thailand has organized an admirable high-level public health and political campaign against the virus in poultry and humans.  This intense nation-wide effort to control H5N1, publicly announced in October 2004 by the upper high levels of the Thai government, has been temporally linked with the absence of any human cases of H5N1 since October 8, 2004.  Webster and Hulse (“Controlling avian flu at the source.” Nature May 26, 2005;435:415-16) commented that “the culling of ducks in Thailand (with farmer compensation) has reduced the flocks of ducks that were positive for H5N1 from almost 40% infected in October 2004 to almost undetectable levels in March 2005. Thus, reducing H5N1 infection in poultry clearly reduces the threat to humans.”

On the website of the Thailand Ministry of Public Health (MOPH) Bureau of General Communicable Diseases, Department of Disease Control, is both a daily update on human surveillance for avian influenza and an archive of key documents and information regarding the national response over the past 18 months. For example, on November 8, 2004 the MOPH published detailed guidance on “Avian Influenza: Prevention and Control Measures in Humans”.  Village Health Volunteers were directed to monitor nationwide for ill or dead birds, and for patients with flu-like symptoms. Evidence of either ill poultry or humans was to be reported immediately for prompt evaluation. All hospitals and health care facilities were directed to follow a specific algorithm for  standardizing the epidemiologic exposure history for H5N1, the clinical specimens to be obtained and specific diagnostic tests to be performed,  infection control measures including use of single patient rooms for protective isolation, x-rays to be performed, and rapid treatment,  including  use of anti-influenza drug even prior to final results of H5N1 testing if the patient is ill. 

Medical evaluation and monitoring for fever or flu-like symptoms for family members and health care workers who had contact with possible H5N1 patients was also specified in this November 2004 guidance. Surveillance and Rapid Response Teams (SRRT) were mandated for Provincial Health Offices in both provinces and districts across Thailand. These teams were to be on-call 7 days a week to respond to possible H5N1 single cases or outbreaks. Prompt lines of communication were mandated from the level of the SRRT having mobile phones, to the Provincial Health Office(s), to the Bangkok Metropolis Administration.  Possible outbreaks in poultry were to be reported immediately to the appropriate corresponding government organizations related to livestock. 

By November 10, 2004 a “Standard Operating Protocol” for evaluating patients with suspected avian influenza was published, and a clinical management guideline for such patients in both an outpatient and inpatient setting was revised on December 2, 2004 by the MOPH Department of Medical Services working group on medical management. H5N1 patient case definitions were listed on the Thai MOPH website and the WHO Thailand website  for “suspect”, “probable”, “confirmed”, “excluded” and “on investigation”. Between 1 January 2005 and 9 June 2005 the MOPH Bureau of Epidemiology daily H5N1 surveillance online reporting cited 587 persons having been evaluated for H5N1 infection, with 583 excluded and four still being investigated.

On January 25, 2005 the National Cabinet of Thailand approved the “National Strategic Plan for Avian Influenza Control”.  Summaries of this plan were published on websites ranging from the FAO Animal Production and Health Division Avian Influenza Emergency subsection, to the Tourism Authority of Thailand. The plan is for the three years from 2005-2007. It contains six strategies and five specific targets. For example, targets for the control of H5N1 include no spread of avian influenza in economic poultry within 2 years, and no spread from animals to humans within 2 years, as well as efficient pandemic preparedness for influenza within 1 year.  The high level coordination for the “war” on avian influenza in Thailand was summarized in  slides presented May 18, 2005 at the World Health Assembly in Geneva regarding “technical briefing on strengthening pandemic preparedness and response” by Dr. Kumnuan Ungchusak, Director, Bureau of Epidemiology, Department of Diseases Control, Ministry of Health, Thailand.  His slides, posted on the WHO website, portray the involvement of the Cabinet of Thailand via the National Avian Influenza response committee, which in turn interacts with the Ministry of Agriculture/Department of Livestock Development (DLD), the Ministry of Health, other ministries and the private sector.  The National response committee in turn oversees the Government’s Avian Influenza Operation Center and coordinates with both the DLD and MOPH operation centers that oversees the animal and human H5N1 issues, respectively.  The budget for the National Strategic Plan on Avian Influenza and Plan for Pandemic Preparedness is $105 million.

With regard to vaccines against H5N1, Webster and Hulse (Nature May 26, 2005. p. 416) observed that “Thailand is now investigating the use of flu vaccines for backyard poultry, free-ranging ducks and fighting cocks (not commercial poultry). This decision represents a major shift in policy. The use of H5N1 vaccines for such ‘open range’ poultry is a prudent step, and should be encouraged in other countries in the region”. No H5N1 vaccine studies in humans have been initiated to date in Thailand, although key discussions have been reported.

29 June 2005

Daniel R. Lucey, MD, MPH

Public Use of Masks in Hong Kong during SARS 2003

Use of masks by the public in Hong Kong, and not in Toronto, during the SARS epidemic of 2003 is understandable and rational given the different contexts in which SARS occurred in these two locations. Criticism of the use of masks by the Hong Kong public as a ‘fashion statement’ or ‘window dressing’, is unfounded and counterproductive. Such criticism demonstrates a lack of understanding regarding the context of the initial SARS outbreak in Hong Kong ,and the fact that a similar disease in the USA, such as SARS, pandemic influenza, or plague pneumonia could elicit the same mask-wearing response by the American public in affected cities.

According to the World Health Organization (WHO), a total of 251 “probable SARS cases” were reported from Canada, and 1,755 probable SARS cases were reported form Hong Kong. In Canada the vast majority of patients were from the Greater Toronto Area, and nearly all were related to hospital exposure to the SARS coronavirus. The one major exception was a community outbreak involving a funeral and a group of 31 persons belonging to the same religious group who became infected with the SARS virus. Thus, it is understandable and rational that the general public in Toronto did not perceive a significant risk of becoming infected with the SARS virus and did not wear masks in public.  As a visiting physician who worked in a Toronto SARS-designated hospital (Scarborough General) in late June and early July 2003, and lived in a downtown hotel, it was obvious that there was no widespread sense of fear that transmission of SARS was occurring outside of the health-care facilities.

In contrast, the SARS outbreak in Hong Kong began from room 911 of a large, well-known hotel (“M”), where a physician visiting Hong Kong from Guangdong province, China, stayed for one night on February 21, 2003.  Persons infected at this Hong Kong hotel, and their secondary contacts, soon were admitted to hospitals in Hong Kong and other places abroad. In Hong Kong, however, unlike Toronto, SARS was transmitted to a relatively large number of persons in community settings early during the outbreak (March 2003) before the name “SARS” had even been adopted and when this new disease was still  referred to as an “atypical pneumonia”.  

An informative description of the epidemiology of all 1,755 SARS patients in  Hong Kong was published in November 2004 by Gabriel Leung and colleagues from Hong Kong (Annals Internal Medicine 2004;141:662-673). Notably, only half (49.3%) of SARS patients in Hong Kong were infected in hospitals, clinics, or elderly or nursing homes.  Of note, an additional ~ 26.1% of SARS patients (totaling 458 persons) were infected in large residential buildings in Hong Kong, mstly in Block E of the Amoy Gardens apartment complex (330 person or ~18.8% of the  1,755 total) and “nearby Amoy Gardens” residential buildings where relatives, friends and other contacts lived (128 person or ~7.3%). Another 47 persons (2.7%) were infected in residential buildings other than those near Amoy Gardens. 

Notably, a further 152 persons (8.7% of the 1,755 total) also had community-acquired SARS infection.  “Of this community transmission, 64%  (97 of 152 cases) could be attributed to intrafamilial or within-house-hold spread, defined as transmission from 1 household or family member to another with no known sources of infectious contact” (page 665). Thus, at least 657 persons (330+128+47+152) had community-acquired SARS virus infection in Hong Kong, most  during March 2003 when this novel respiratory disease was still being defined and named, and public health-infection control countermeasures were still being developed in health care facilities, such as the use of surgical mask and N-95 respirators. 

A 2^nd highly informative publication from Hong Kong presents data from ten (10) telephone surveys performed between 21 March 2003 and 12 May 2003 involving 1,397 Hong Kong residents that  documents the perceptions, concerns, and behaviours of the general public regarding the unfolding SARS outbreak (Lau JTF and colleagues. J Epidemiology and Community Health 2003;57:864-870).  In these surveys, the perceived efficacy of wearing a mask to prevent SARS infection increased from only 11.5% on March 21^st to a striking 84.3% on April 1^st.  What changed? 

This behavior is understandable and rational when examined in the context of the timeline of the SARS outbreak in Hong Kong.  On or about March 26 the  large (e.g., more than the total number of probable SARS cases in all of Canada) SARS outbreak involving the Amoy Gardens residential building area, and especially the Block E section, became widely known. On March 29 “all classes in all schools in Hong Kong were suspended. On March 31, all block E residents of the Amoy Gardens estate were quarantined at home and all close contacts of SARS patients were required to be examined in designated clinics. On April 1, all block E Amoy Gardens estate residents were further moved to two quarantine camps” (page 864).  From these facts, as well as from visiting Hong Kong in May 2003, I conclude that use of masks by  a large part of the  public in Hong Kong during the SARS outbreak was as understandable and rational as was not wearing masks in Toronto, given the respective contexts of SARS-transmission in these two places.

22 July 2005

Daniel R. Lucey, MD, MPH

Indonesia: H5N1 now in Humans in addition to Poultry and Pigs

The Indonesian Ministry of Health and World Health Organization reported this week Indonesia’s first laboratory-confirmed H5N1 avian influenza virus infection in a 38-year-old man who died of pneumonia this month. Yesterday (July 21) the WHO reported that lab tests for H5N1 were still pending on the limited samples available from the man’s two daughters, ages 1 and 8 years, who also died after becoming ill with fever and diarrhea followed by cough and pneumonia. 

No exposure to poultry or pigs near the family’s home close to the Jakarta metropolis has been linked to the H5N1 infections. Thus the source of the virus is yet unknown, and the potential exists that person-to-person transmission occurred. Fortunately, 315 close contacts of these three family members are under observation for any evidence of H5N1 symptoms, and so far none are reported ill.

A senior official of the Indonesian Ministry of Agriculture was cited 21 July on ProMED reporting that bird flu had been found at some time point in 21 of 30 provinces in the nation, accounting for the deaths of 9.5 million chickens. Earlier this year confirmed reports of H5N1 in a small number of pigs in Indonesia had also been reported (e.g., May 26, 2005 issue of Nature focusing on H5N1 influenza).  Pigs can be infected both by avian influenza viruses such as H5N1, and human influenza viruses, such as H3N2 because their respiratory epithelium contains the appropriate receptors for both types of influenza viruses. Therefore, pigs are considered a potential “mixing vessel” for dual infection with both avian and human influenza viruses that could result in a new influenza virus that shares the high mortality and novel hemagglutinin (e.g., “H5”) of H5N1 viruses, and the ability to spread readily from person-to-person typical of human influenza viruses (e.g., H3N1 or H1N1). Such a virus could trigger a human pandemic and likely require a new vaccine based on that specific avian H5N1-human influenza hybrid or “reassortant” virus.

On July 20 the WHO announced that currently there have no evidence to recommend a change in H5N1 vaccine strain selection for prototypic vaccines against H5N1 viruses that have infected humans so far. The official scientific report of the sequence of the H5N1 virus isolated from the 38-year-old gentleman in Indonesia is awaited to see if any significant mutations occurred that could increase the risk of person-to-person transmission. The H5N1 confirmation tests were performed in the WHO H5 reference lab at the University of Hong Kong Department of Microbiology, and the US CDC in Atlanta.

Currently, human vaccine studies with a prototypic H5N1 vaccine are continuing since April 2005 at three sites in the USA (Rochester, New York, Los Angeles, and Baltimore) sponsored by the NIH, at NIAID Vaccine Treatment and Evaluation Units. An inactivated H5N1 vaccine antigen, without adjuvant, is being studied in 450 volunteers, in a dose-ranging study.

29 July 2005

Daniel R. Lucey, MD, MPH

H5N1: Hypercytokinemia and Hemophagocytosis?

What is the mechanism of the high case fatality rate of influenza A virus H5N1 in humans both in the initial outbreak in 1997 in Hong Kong and in the ongoing outbreak that since 2004 has killed 55 of the 109 lab-confirmed cases in Vietnam, Thailand, Cambodia, and Indonesia?  Answers to this question could influence anti-H5N1 therapies, and potentially impact development of a safe and effective vaccine.  

One hypothesis is that that the H5N1 virus stimulates much higher amounts of proinflammatory cytokines including Tumor Necrosis Factor alpha (TNF-alpha), interleukin 6 (IL-6), and Interferon Induced Protein 10 (IP-10). In severe cases these cytokines trigger the reactive hemophagocytic syndrome (RHPS), which in other diseases is linked with multiorgan damage (e.g., to the bone marrow, liver, kidneys, and blood clotting system) and death. 

Hemophagocytosis refers to the pathological process whereby human macrophage white blood cells ingest (“phagocytose”) other white blood cells (such as neutrophils), red blood cells, and platelets (that normally help blood to clot). A review of the literature reveals that the “reactive” form has been reported to occur in response to over 20 infectious diseases ranging from viruses (e.g., EBV), to bacteria (e.g., brucella), to fungi (e.g., histoplasmosis) to rickettsia (e.g., Q-fever). 

The common denominator for the reactive hemophagocytic syndrome appears to be marked overproduction of proinflammatory cytokines such as TNF-alpha by monocyte-macrophage white blood cells. The ideal therapy is to treat and cure the underlying cause, namely the inciting infectious disease. In practice, however, potent anti-inflammatory medications, such as corticosteroids, are sometimes given, particularly when the infection is not identified, a specific anti-microbial drug is unavailable, or the patient is very ill.

Evidence to support the H5N1 virus link to hypercytokinemia and hemophagocytic syndrome is limited due to the small number of patients with cytokine studies, tissue biopsies, and autopsies. In the initial 1997 H5N1 outbreak in humans in Hong Kong  6/18 symptomatic patients died and 2/6 had autopsies performed. Both showed striking reactive hemophagocytic syndrome (To KF et al. J Med Virol 2001;63:242-46). A third patient had a bone marrow aspirate that showed occasional hemophagocytic activity. In retrospect, cytokine levels were measured on stored serum samples and showed increased TNF-alpha, IL-6, and soluble IL-2 receptor (Chan PKS. Clin Infect  Dis 2002;34 (suppl):558-564). 

The H5N1 virus from Hong Kong in 1997 was also shown to induce high levels of  the proinflammatory cytokines TNF-alpha, IL-6, and interferon-gamma when used to infect cultures of primary human macrophages (Cheung CY et al. Lancet 2002;360:1831-37).  However, this 1997 virus appeared to be protected against the antiviral effect of TNF-alpha, at least in part by a change in the Non-Structural (NS) gene that required a glutamic acid residue at position 92 in the NS1 molecule (Seo SH et al. Nature Med 2002;8:950-954. Lipatov AS et al. J Gen Virol 2005;86:1121-1130. Virus Research2004;103:107-113).  Overproduction of TNF-alpha by laboratory-cultured macrophages infected with this 1997 H5N1 virus could be blocked by inhibitors of  p38 MAPK (Mitogen Activated Protein Kinase) (Lee DC et al. J Virol 2005;79:10147-54).

Similarly, in 2003 two patients were diagnosed with H5N1 pneumonia after travel to Fujian province, China (Shinya K et al. J Virol 2005;79:9926-9932).  Their viruses were reported to stimulate TNF-alpha and IP-10 in human macrophage cultures (Guan Y et al. PNAS 2004;101:8156-61).  They also had elevated serum levels of TNF-alpha and IP-10, and monokine induced by interferon gamma (MIG) (Peiris JS et al. Lancet 2004; 363:582-83). 

In the current H5N1 outbreak of 2004-2005 serum cytokine levels of IP-10 were strikingly high (37,000pg/ml on day 5 of illness) in one 6 year old child from Thailand, although his autopsy did not show RHPS, possibly due to treatment with methylprednisolone (Uiprasertkul M et al. Influenza A H5N1 replication sites in humans. Emerg Infect Dis 2005; 11:1036-1041). A 2^nd patient who died had a limited exam of tissues and hemophagocytic activity was seen in the liver (Ungchusak K et al. N Engl J Med 2005;352:333-340). No cytokine data has been reported from this patient. 

Continuing research is needed to look for hypercytokinemia and stimulation of p38 MAPK, hemphagocytosis, and mutations in the virus’ NS1 molecule as well as the hemagglutinin (HA) gene, to understand better how H5N1 causes its high mortality rate. Development of a safe and effective vaccine against H5N1, as well as new therapies based on inhibition of TNF-alpha and other cytokines, may benefit from such integrated research.

31 July 2005

Daniel R. Lucey, MD, MPH

Outbreak in Sichuan: Is Strep Suis the only infection?

This month an outbreak of a rapidly progressive, sometimes fatal disease has been reported in Sichuan, China primarily in persons in contact with pigs and pork products. The cause has been preliminarily identified as the gram-positive bacteria “Streptococcus (Strep) suis“. Certain characteristics, however, raise the possibility that in addition to Strep suis a 2nd infectious disease agent could be present and thus further laboratory testing and clinical information is needed.

Prior reports of Strep suis causing human illness have been small in size and often focused clinically on patients who develop meningitis, sometimes with secondary hearing loss. Some patients in the literature have also been reported to have toxic shock syndrome, which can cause desquamation of large parts of the skin. In the current outbreak in several cities in Sichuan province, however, meningitis is reportedly rare and skin changes are most striking for subcutaneous hemorrhage, not a typical skin finding for Strep suis infection. 

Conceivably, the strep bacteria has mutated and now causes a cutaneous hemorrhagic disease, but preliminary reports form China on the genetic sequencing of this organism are reported in the media (South China Morning Post and China Daily) a snot demonstrating any mutations.

To date, there is no report of person-to-person spread of this apparent Strep suis infection. Most cases are suspected to be due to direct contact with pigs and pork products. In addition, there is no report of multidrug antibiotic resistance. However, a few patients have now been reported outside Sichuan province, such as in Hong Kong and Guangdong province, and thus constant vigilance and more detailed epidemiologic surveillance is needed. 

If H5N1 avian influenza were a co-infection with the Strep suis, then one would expect many more cases to have occurred by now, and the identification of this now-familiar virus by Chinese laboratory researchers to have been reported. The involvement of the WHO in the investigation of this outbreak is welcomed.

8 August 2005

Daniel R. Lucey, MD, MPH

H5N1 Flu Virus Confirmed in Russia; Is Mongolia Next?

Russia has now officially confirmed to the OIE that the poultry outbreaks in the Novosibirsk region (Oblast) of Siberia that began in  July 18-July 22 was due to the avian influenza H5N1.  In addition, Mongolia has reported deaths of waterfowl due to an avian influenza A virus with definitive identification of whether the virus is H5N1 or not expected by August 12.

Initial reports of the outbreak in Russia suggested the virus might be H5N2 rather than H5N1. The August 5^th report on the OIE website, however, has proved that the virus is H5N1 based on tests performed in at least four (4) laboratories (www.oie.int/eng/info/hebdo/a_current.htm . The tests included ELISA for antigen and antibody, PCR for the M-protein gene and a hemagglutinin test. 

At least 13 villages in Novosibirsk were found to have evidence of H5N1 infection, either by virus isolation or antibody to H5N1. Infected species included ducks, chicken, turkeys and geese. The disease in these species was attributed to contact with wild waterfowl at water reservoirs, in particular lakes frequented by both wild waterfowl and domestic birds. Of note, there was no evidence of H5N1 infeciton oin any of 14 commercial poultry farms tested.

Meanwhile, on August 8^th the OIE published an “Alert Message” from the Ministry of Food and Agriculture in Ulaanbaator (www.oie.int/messages/050808MNG.htm)  Mongolia that 80 dead birds, including wild ducks, geese, and swan (migratory birds) had died on Erhel lake in Huvsugel province.  The cause was an avianinfluenza virus, but the precise type is pending further testing and is expected this Friday, 12 August 2005.

Sequencing of the H5N1 virus in Russia and of the avian influenza in Mongolia will help to determine the origin and degree of relatedness to the H5N1 avian influenza virus reported in June from two locations from two locations in western China and to the H5 virus found in  Kazakhstan. If the same virus is found in all these locations then it is likely that wild migratory birds are transporting the infection across thousands of kilometers.

New infections should then be anticipated in south Asia, Europe, and the Americas as these birds continue in their long-established and well-mapped migratory routes.  Infection of poultry, pigs, and humans should also be anticipated along these international migratory bird flypaths.

24 August 2005

Daniel R. Lucey, MD, MPH

WHO to receive 3 million treatment courses (30 million capsules) of the only oral anti-H5N1 drug (oseltamivir) by mid-2006 as outbreaks spread to Kazakhstan, Russia and Tibet.

Today the WHO announced that the manufacturer (Roche) of the only oral drug (oseltamivir) active against the H5N1 influenza virus will donate 3 million treatment courses (at 10 capsules/course a total of 30 million capsules) beginning in early 2006 and ending by mid-2006. 

The Director-General of the WHO, Dr. LEE Jong-wook, signed the agreement with Roche and noted in a media briefing that “New outbreaks have recently been confirmed in birds in Kazakhstan, Mongolia, and the Russia Federation…An influenza pandemic will not discriminate between those who live in mansions and those who live in slums”.

Modeling use of antiviral medications to attempt to control an H5N1-like pandemic in Asia two groups (Longini IM et al., in Science Express Aug. 3, and Ferguson N et al. in Nature) recently reported that antiviral stockpiles of oseltamivir such as those being donated next year to the WHO would be needed for rapid delivery and distribution after sustained person-to-person spread began of a pandemic influenza strain. 

Of note, a treatment course of oseltamivir is usually considered to require 10 capsules, two given every 12 hours for 5 days.  A prophylactic course of oseltamivir given after each exposure to an influenza virus has been defined as also 10 capsules, one given each day for 10 days. 

Unfortunately, a person does not always know when they have been exposed to an influenza virus and therefore a longer term (weeks-months) prophylactic course, requiring many more capsules of oseltamivir may be needed. For example a two month prophylactic course, given for repeated H5N1 influenza exposures, would require 60 capsules, taken one each day, rather than 10 capsules.

In addition, a recent study in the Journal of Infectious Diseases involving mice infected with H5N1 suggested that eight days of oseltamivir therapy, rather than 5 days of treatment (not prophylaxis) might improve outcome. 

Meanwhile, H5N1 has been found in two locations in western China, Tibet (Lhasa), Kazakhstan, Mongolia, and at least six areas in Russia.  Moreover, in the August 5  (Vol 18-No. 31) report on the World Animal Health Organization (“OIE”) website (www.oie.int) additional pigs tested positive by PCR for H5N1 in Indonesia (Panongan subdistrict, Tangerang district, near Jakarta). 

Potential spread of H5N1 by migratory birds across the Ural mountains into Europe or to SW Asia, India, or the Middle East is recognized, although one writer (Hon S. Ip, Diagnostic Virology Laboratory in Wisconsin, USA) today questioned the causal role of migratory birds as transmitters of the virus in a ProMEDmail letter titled “Dead birds don’t migrate”. 

Progress on human H5N1 vaccines, cited recently from the initial US study using a non-adjuvanted vaccine, different doses of vaccine, and two immunizations is welcome (NY Times front page 7 August). Further testing of new vaccines in multiple nations of the world is still needed, including testing of vaccines that would decrease the amount of H5N1 antigen needed, with the ideal being only one immunization to confer protection and less than or equal to the usual 15ug of influenza antigen per shot use din annual flu vaccines. 

Such an “antigen–sparing” vaccine may require use of a vaccine adjuvant (e.g., the FDA-licensed vaccine adjuvant “alum”; on the other hand, researchers announced this week a planned study by Chiron and supported by the US NIH that will use the adjuvant MF-59 with an experimental H9N2 avian influenza vaccine). 

Another potential “antigen-sparing” strategy could be alternative routes of immunization (e.g., SQ vs IM), perhaps compared with or without an adjuvant, i.e., proceeding with vaccine studies “in parallel” rather than “in series”.

The need for vaccine safety is paramount, for the sake of each vaccinee, well as from the vaccine regulatory body perspective  (e.g., the US FDA). If, however, the next winter brings the first wave of a pandemic influenza “Pacific Storm,” then a safe and effective vaccine will be in extremely high demand worldwide. 

14 September 2005

Daniel R. Lucey, MD, MPH

WHO issues new H5N1 pandemic flu recommendations for policy-makers

At the beginning of this month the World Health Organization (WHO) posted on their website (www.who.int) an 18-page document addressed to policy-makers titled: Responding to the avian influenza pandemic threat: Recommended strategic actions.  Several of the highlights of this key document warrant emphasis.

The opening page reiterates the official WHO position that “In view of the immediacy of the threat, the WHO recommends that all countries undertake urgent action to prepare for a pandemic.” The real-world difficulty of pandemic flu preparedness is captured by the WHO description of the situation today as “characterized by both urgency and uncertainty” (italics added for emphasis). 

Six points are discussed in assessing the current potential pandemic situation:

1. The risk of a pandemic is great.
2. The risk will persist
3. Evolution of the threat cannot be predicted
4. The early warning system is weak
5. Preventive intervention is possible, but untested
6. Reduction of morbidity and mortality during a pandemic will be impeded by inadequate medical supplies.

WHO then discusses three (3) phases of a pandemic ((1) pre-pandemic; (2) emergence of a pandemic virus; (3) and when a pandemic is declared)) and what the objectives are for each phase and what strategic actions are recommended to achieve each objective within the three phases of the pandemic The example of the two objectives for the current pre-pandemic phase, and their strategic actions, are summarized below:

The first of two objectives for the pre-pandemic phase is: “Reduce opportunities for human infection”. The four strategic actions recommended to achieve this objective are:

1. Support the FAO/OIE (international animal health) control strategy
2. Intensify collaboration between the animal and public health sectors
3. Strengthen risk communication to rural residents
4. Improve approaches to environmental detection of the virus

The second objective of this pre-pandemic phase is: “Strengthen the early warning system”. The seven strategic actions to achieve this objective are:

1. Improve the detection of human cases
2. Combine detection of new outbreaks in animals with active searches for human cases.
3. Support epidemiological investigation
4. Coordinate clinical research in Asia
5. Strengthen risk assessment
6. Strengthen existing national influenza centres throughout the risk-prone region
7. Give risk-prone countries an incentive to collaborate internationally.

In addition to these recommended actions, WHO emphasizes several sobering facts about international (lack of) preparedness:

1. Only one-fifth (1/5) of the nations in the world have any form of a pandemic flu response plan, and these vary widely in detail and stage of completeness.
2. Twenty-three (23) nations have ordered anti-influenza drugs for national stockpiles, but these orders cannot be filled for at least one year.
3. Less than 10 nations have one or more domestic vaccine manufacturers working on a pandemic flu vaccine.
4. Given this current vaccine situation, the majority of developing nations “would have no access to a vaccine during the first wave of a pandemic and possibly throughout its duration”.
5. “The best opportunity for international collaboration—in the interest of all countries—is now, before a pandemic begins”. 

Whether policy-makers, in developed or developing nations, act now on these WHO recommendations will certainly influence the severity of the coming pandemic, whenever it arrives. 

At its best, working together internationally now on such a difficult and momentous health issue as pandemic influenza would also strengthen global efforts against other infectious diseases such as HIV/AIDS, tuberculosis, malaria and other parasitic diseases, the next SARS-like disease, and bioterrorism. 

17 September 2005

Daniel R. Lucey, MD, MPH

US to stockpile second drug (zanamivir) to treat H5N1 influenza, add $100 million worth of H5N1 vaccine, and travel to SE Asia in October.

The Secretary of the US Health and Human Services (HHS), Mike Leavitt, announced in a news release September 15that the US will augment the Strategic National Stockpile (SNS) with both drug and vaccine countermeasures for the H5N1 influenza virus spreading across Asia (www.hhs.gov/news/press/2005pres/20050915.html).

So far, the oral (capsule for adults, liquid for children) anti-influenza drug oseltamivir (“Tamiflu”) has been added to the SNS in quantities sufficient to treat 2.3 million persons (i.e., two capsules each day for 5 days as standard regimen for any type of influenza). Now the US will add a 2nd anti-H5N1 influenza drug, zanamivir (“Relenza”), to the SNS by awarding a $2.8 million contract to purchase quantities sufficient to treat 84,300 persons.

Importantly, however, no oral form of zanamivir exists and it is not FDA-licensed for prophylaxis of persons of any age. Instead, zanamivir is FDA-licensed only as a treatment for active influenza disease, and comes in an inhaled preparation only. The drug is given twice each day for five (5) days via a breath-activated plastic device called a Diskhaler (according to the FDA website description of the drug at www.fda.gov/cder/news/relenza/default.htm). Like oseltamivir, zanamivir acts as a neuraminidase inhibitor of influenza viruses.

Of note, persons with asthma and chronic lung diseases should generally not use zanamivir due to the risk of exacerbating breathing problems (according to the FDA). Zanamivir is FDA-licensed for persons down to the age of seven (7) years.

The other neuraminidase inhibitor anti-flu drug, oseltamivir (“Tamiflu”) is FDA-licensed as an early (within 48 hours of symptoms) therapy for influenza down to the age of one (1) year, and for prophylaxis in persons down to the age of 13 years. Thus, no drug is FDA-licensed for the prophylaxis of influenza in persons less than 13 years of age.

The other countermeasure against H5N1 that was purchased is an investigational vaccine to be made by the company Sarnoff Pasteur, according to the HHS news release. Exactly how many persons can be vaccinated with this $100 million worth of vaccine is unclear, because the final amount of vaccine antigen in each dose has yet to be determined. So far clinical trials in the USA (U. of Maryland, U. of Rochester, and UCLA), funded by the NIAID/NIH, have shown presumably protective levels of an immune response against the H5N1 virus currently circulating in Asia only at the highest dose tested, namely 90 micrograms, and even then only after two (2) shots of the vaccine several weeks apart. In contrast, the usual annual flu vaccine requires only 15 micrograms, and only one shot, to achieve a protective immune response.

This current H5N1 vaccine does not contain a “vaccine adjuvant”, i.e., a chemical substance such as the FDA-licensed adjuvant called “alum” (e.g., aluminum hydroxide) that stimulates a stronger immune response (in the case of alum more antibody-based immunity than cell-mediated immunity) for a given level of vaccine antigen.

Future vaccines against H5N1 might study at least two “antigen-sparing” approaches to increase the amount of H5N1 antigen available to vaccinate more people. One “antigen-sparing” approach is to add a vaccine adjuvant such as alum or investigational adjuvants such as MF-59 or other candidate adjuvants, to the H5N1 vaccine. A second approach could be to give the vaccine under the skin (“subcutaneously”) rather than into the muscle (e.g., of the upper arm or “deltoid” muscle) to see if a stronger immune response is induced against H5N1 when the vaccine is introduced to the immune system sentinel cells (“antigen-processing cells”) under the skin than in the muscle tissue. Some precedent for this approach exists with influenza virus strains other than H5N1.

In addition, HHS Secretary Leavitt also announced on September 15th at the UN General Assembly US participation in the International Partnership on Avian and Pandemic Influenza. He will be leading a delegation from the US to Vietnam, Thailand, Cambodia, and Laos next month (October) to meet with Heads of State and Ministers of Health. He has invited the WHO Director-General, Dr. Lee, the Heads of the UN Food and Agricultural Organization (FAO) and the World Animal Health Organization (OIE—French acronym), and the US State Department Under Secretary Dobriansky to join him. The US Congress has approved funding to assist with H5N1 surveillance and other efforts in some affected parts of Asia.

Secretary Leavitt stated in his presentation to the UN General Assembly: “Here in the United States, we have adopted a simple rule for our preparedness: prepare as if the pandemic strikes tomorrow…We’ve all learned in the past few weeks, that bad things can happen very fast. This is why the new International Partnership on Avian and Pandemic Influenza is so critical. We simply must improve global readiness in an unprecedented way.” (www.hhs.gov/news/press/2005pres/20050915a.html).

20 September 2005

Daniel R. Lucey, MD, MPH

Bird Flu closes Jakarta Zoo, H5N1 human case(s) confirmed

The Jakarta Post reported September 19th and 20th that the Ragunan Zoo in south Jakarta has been closed down for 21 days beginning Monday, September 19th, after multiple bird species were found to be infected with bird flu. The Minister of Agriculture was cited as reporting that the infected species included eagles, herons, peacocks, mynahs, pigmy chickens, and wild ducks. This striking discovery likely means that H5N1 is more widespread in the avian population inside and outside Jakarta than previously known, and thus the risk for more human infections may be higher than appreciated.

Two persons who work in the Jakarta zoo have been hospitalized. One of these individuals is described as an employee and another as a vendor, and both are reported to have an influenza-like illness that warrants being evaluated for H5N1 influenza infection. All 500 of the zoo employees are to be offered testing for H5N1 avian influenza virus. So far no official report has been made public as to whether the type of avian influenza virus in the zoo has been proven to be the H5N1 virus.

Other zoos in Indonesia are being evaluated for the presence of avian influenza. 19 of 27 samples from the Ragunan zoo in Jakarta have been reported positive for avian influenza. The source of the infection within the zoo is not certain at this time. H5N1 virus infection of poultry, pigs, and humans has previously been reported in Indonesia earlier in 2005.

The WHO confirmed on 16 September the death of another person in Indonesia due to lab-proven H5N1 virus infection. This 37 year-old woman was reported by the Jakarta Post today to be a resident of Petukangan Utara, south Jakarta. She apparently lived near a chicken slaughterhouse in a south Jakarta suburb, according to today’s paper, while the WHO reported that she also had opportunities for exposures to ducks.

In July, 2005 a government worker died of H5N1 infection, close to the time of the death of his two daughters, ages 8 and 1, of a similar respiratory disease. This family lived in Tangerang, Banten province, in a western suburb of Jakarta. The epidemiological link to a known H5N1 virus exposure was never established for this family.

Currently there are at least six (6) persons in hospital in Jakarta being evaluated for H5N1 infection. At least two are young persons, ages 7 and 9 years. Their samples are being tested for H5N1 virus in the renowned virology referral lab in Hong Kong. One child lives in Tangeran and the other child is a “close relative”, according to the Jakarta Post, of the 37 year old woman who died two weeks ago and was confirmed by the WHO September 16th.

On Monday, September 19th the Indonesia declared the avian influenza outbreak an “extraordinary situation”. The Health Minister, Siti Fadila Supari, was reported in an AP article today (written by Niniek Karmini) as declaring that 44 state-owned hospitals had been assigned to treat avian flu patients, including with free medications. Person with influenza-like illness suggesting H5N1 infection “could be forcibly admitted to hospitals”.

Neighboring Malayasia is reported to have gone on heightened bird flu alert, checking poultry farms near the border with Indonesia. The WHO Director-General, Mr. Lee Jong-wook was quoted in an Agence France-Presse article September 20th while addressing the WHO’s regional committee for the western Pacific, to say that “It’s obvious a pandemic will occur, all the conditions are in place. The problem now is time”.

Models published last month in Science and Nature on how to control a nascent influenza pandemic, in part by rapid deployment of an antiviral stockpile by the WHO in partnership with the affected country have been base don a rural, rather than urban, area being the initial site of the pandemic. Any delay or mitigation of a nascent pandemic by such WHO-lead interventions would be significantly, and perhaps overwhelmingly, much more difficult if the pandemic began in a major metropolis such as Bangkok (as stated explicitly in one of the models), Jakarta, or other international travel hubs in Asia, Europe, or the Americas.

29 September 2005

Daniel R. Lucey, MD, MPH

UN Director General appoints WHO Expert to Lead Avian Flu Efforts, New WHO paper on H5N1, and more cases in Indonesia

On September 29 the UN Secretary General Kofi Annan appointed Dr. David Nabarro, a senior WHO official, to coordinate the fight against H5N1 avian influenza and catalyze pandemic flu international planning across all UN agencies and the private sector.  The Director-General of the WHO, Dr. Lee  Jong-wook reiterated yesterday that “the WHO has been very clear about the imminent threat of a human influenza pandemic”.

In the Jakarta Post of 29 September Indonesia was reported to be evaluating at least 63 persons with suspected H5N1 avian influenza infection.  On Sept 22 and Sept 29 the WHO reported two more lab-confirmed patients with H5N1 infection in Indonesia.  This brings the official lab-confirmed number of persons with H5N1 infection to four, with three being fatal, and other tests still pending. Worldwide, the WHO total number of lab-confirmed patients and deaths is now 116 persons/60 fatalities (52% fatality rate).

In the 29 September issue of the New England Journal of Medicine (NEJM) two articles related to avian influenza and the pandemic threat were published. The first was a detailed review article on the two drugs (“neuraminidase inhibitors’ ‘), one oral and one inhaled, that are effective against this H5N1 virus now circulating in Asia.  This article is an excellent resource for information about these drugs, their limitations, side effects, and potential role in the ongoing avian H5N1 outbreak and in the potential coming human pandemic if and when the current H5N1 virus changes in a way that allows it to spread from person-to-person in a sustained and efficient manner.

The second article is a “Current Concepts” detailed review of human H5N1 avian influenza infections (NEJM 2005;353:1374-1384). It was published by the WHO “Writing Committee” on” Human Influenza A/H5” comprised of multiple influenza experts from around the world, including from affected nations in Asia.  This paper is the one best comprehensive paper now in print and complements that by Yuen and Wong in the June 2005 issue of the Hong Kong Medical Journal on the same topic.

The NEJM review paper on H5N1 human infections includes detailed sections on transmission, clinical symptoms, signs, lab diagnosis, pathogenesis, antiviral drugs for prophylaxis and therapy, vaccine development, infection control issues and ways to lessen the risk of infections in a nonpandemic situation (Table 5, page 1382).  Specific mention is made of using “High efficiency masks” (N-95 or equivalent) as part of personal protective equipment (PPE) by health care workers under isolation precautions in health care facilities, and as a consideration for household contacts of persons with H5N1 influenza virus infection.

The timing of this detailed paper from the WHO is welcomed, as was the WHO Pandemic Influenza plan posted last April on the WHO website.  The revised US pandemic influenza plan that will update the August 26, 2004 draft plan is anticipated to be released later this autumn.

October 1st, 2005 – Washington, DC

Daniel R. Lucey, MD, MPH

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

See also: Tularemia Identification Flowchart

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 1st. 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 9, 2005

October 4-8: The 100-Hour “Tipping Point” in US Pandemic Flu Awareness

This past week marked the tipping point in public awareness of pandemic influenza preparedness in the United States of America.

In his press conference Tuesday, October 4, President Bush mentioned a book he had read recently on the devastating 1918 pandemic flu, and discussions he has had with Dr. Anthony Fauci at the National Institutes of Health about influenza. He also referred to the need for discussion about potential use of the military if the current potential threat of a severe flu pandemic were to occur.  Media interest in pandemic influenza was accelerated as this story was reported Tuesday and Wednesday, October 4-5.

On Thursday, October 6, the renowned basic science journal, Nature, published online a landmark medical paper regarding the sequence of the final three genes (polymerase) of the 1918 pandemic influenza virus.  Notably, it appeared that this 1918 pandemic flu virus may have originated entirely from an avian source (“bird flu”) without having exchanged genes (“reassorted”) with another virus as occurred in the less devastating pandemics of 1957-58 and 1968-69.  The actual avian source of such a flu virus that gave rise to the 1918 human pandemic, however, was not identified. 

The media noted the potential similarity between this H1N1 influenza A “avian flu” virus that caused the human pandemic in 1918-1919, and the current H5N1 influenza A “avian flu” virus that President Bush, HHS Secretary Michael Leavitt, and many in the global medical and scientific community emphasized may cause the next human flu pandemic. The Secretary of the Department of Health and Human Service, Michael Leavitt, was shown on CBS Evening News Thursday evening clearly stating that the US was not adequately prepared for a human flu pandemic. 

This work on the 1918 flu virus marked the culmination of ten years of sustained effort by a team of researchers lead by the first author of this publication, Dr. Jeffery Taubenberger of the Armed Forces Institute of Pathology (AFIP) in Rockville, Maryland.

By Friday, October 7, the equally renowned journal, Science, published another landmark paper in which the 1918 pandemic influenza virus had been reconstructed and studied in a high biosecurity containment laboratory at the CDC in Atlanta. This virus was shown to be highly lethal in mice (Balb/c) after only 3-4 days, and in embryonated chicken eggs. It caused swelling and hemorrhage in the lungs of the mice, and also produced very high amounts of virus in tissue culture of human lung (bronchial) epithelial cells.

These experiments were done only at the CDC under strict safety conditions primarily by the first author of the paper Dr. Terrence Tumpey of the CDC.  At the same time, many collaborators from other institutions contributed significantly and were co-authors on the paper, including Dr. Peter Palese from Mt. Sinai School of Medicine in NY City, David Swayne from the US Department of Agriculture, and Dr. Taubenberger.

             In addition, on Friday, October 7, the US hosted a meeting on avian influenza and the human pandemic threat for 80 nations in Washington, DC, and President Bush met with vaccine manufacturers regarding ways to increase influenza vaccine production.   By Saturday, October 8^th, HHS Secretary Leavitt was leading a high-level delegation to SE Asia from the USA, with key partners from the WHO and other global organizations in the new international alliance against avian and pandemic influenza.  The delegation will visit four nations affected by bird flu since 2004: Thailand, Vietnam, Laos, and Cambodia.  

             In the course of 100 hours, between October 4 and October 8, the tipping point had been reached in the US media and the US Public’s awareness of H5N1 avian influenza and its potential human pandemic threat.

 Although the current H5N1 avian flu has not spread in a sustained manner from person-to-person, this virus has infected 117 people, killing 60 (51%). If this avian flu virus ever does mutate and acquire the ability to spread in a sustained manner from person-to-person, then a human pandemic will begin. The policy and actions of national and international planners now should be “Preparedness not Panic”.

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism and Emerging Diseases

ER One Institutes, Washington Hospital Center

Adjunct Professor, Department of Microbiology and Immunology

Georgetown University School of Medicine, Washington, DC

October 13, 2005

Avian H5N1 Influenza Virus Confirmed in Europe Today

At a press conference in Brussels today the European Union Health Commissioner Markos Kyprianou announced that the avian influenza A virus H5N1 has been confirmed in Europe for the first time, after investigation of animal deaths in Turkey.  No human infections have occurred. The story has been carried online this morning by Reuters, the Washington Post, the NY Times, and other news sources.

He also noted that, in Romania, testing of ducks has so far only revealed an “H5” virus. Whether it is H5N1, H5N2, H5N3 or another virus is not yet known. The final viral identification is expected by October 14^th.  The EU has therefore banned imports of live poultry and birds from Romania.

Turkey reported the bird flu deaths promptly, and identified an “H5” avian flu virus to the OIE on October 9, and undertook culling and quarantine response measures.  On October 10, the EU banned all imports of live poultry from Turkey. On October 11^th  the Chairman of the Turkish Veterinarians’ Union cited the Manyas region in the NW city of Balikesir as the location of the bird flu cases, but as a precaution noted that surveillance for other outbreaks, and educating the public, are among additional necessary measures.

Yesterday, October 12, Iran reported to the Paris-based OIE World Animal Health Organization that 3, 673 wild waterfowl (wild ducks) had died at Poldasht, on the coast of Arras, West Azerbaijan province. No etiological agent for these deaths of wild ducks has been identified yet, and thus it is unknown whether an avian influenza virus is even present here. The date of onset of this event was listed as October 2^nd. The area has been quarantined.

Emergency meetings of the EU are scheduled for today and tomorrow regarding this news that the H5N1 influenza virus has now entered Europe. How the virus arrived is relevant for several reasons, both in terms of mitigating further such events, and in predicting where this virus may appear next. 

For example, will H5N1 follow migratory wild bird flyways further into Europe or toward North Africa, or is there a human-associated element involved with transport of infected wild birds or poultry, across somewhat long distances from Asia? Both possibilities have been cited previously to account for the spread of the virus in Asia, and they are not necessarily mutually exclusive.

National and international preparedness for both H5N1 influenza outbreaks in avians, and pandemic influenza preparedness in humans will hopefully be catalyzed further in an interactive and linked manner by these developing events.

Daniel R. Lucey MD, MPH

Director, Center for Biodefense and Emerging Diseases

ER One Institutes, Washington Hospital Center

Georgetown University School of Medicine

Department of Microbiology and Immunology

Washington DC

​​October 21, 2005

New H5N1 infections in Avians in Romania, Russia, China, Thailand, and in birds smuggled into Taipei, China; First new human infection in Thailand in 12 months; No evidence of “P2P” or “P5P” transmission

The Paris-based World Organization for Animal Health (OIE) reported on 21 October that H5N1 influenza virus had been confirmed in avians (not humans) in multiple new locations in European and Asian Nations where it has previously been found, emphasizing the tenacity of the virus and the ongoing risk of avian-to-human infection as the flu season approaches north of the equator.

In Romania, the OIE reported H5N1 in the villages of Maliuc and Vulturu in addition to the original outbreak diagnosed in Ceamurlia-de-jos.  The avians include chickens, ducks, and a swan. The hemagglutinin and neuraminidase genes have been sequenced and found to be same as the recent H5N1 isolate from Turkey and Central Asia.  All H5N1 tests were confirmed at the OIE Reference Lab in VLA Weybridge, United Kingdom.

In Russia H5N1 virus was confirmed in Jandovka village, Efremov district, in the Tula region.  Ducks, geese, turkeys, chickens, and Muscovy ducks in backyard farms had mortality rates ranging from > 4% for ducks to 100% for turkeys. A lake bordering the village with migratory ducks (probably mallard) were linked to this outbreak.  The date of the start of this outbreak was reported as 14 October.

In Inner Mongolia, China H5N1 was confirmed in Tnegjiaying village, Huhehot municipality division, starting on 14 October. Chickens and ducks were infected. Migrating birds are noted to pass or congregate at a nearby lake. A monovalent H5N2 vaccine was administered to 166,177 birds as part of the response to the outbreak.

In Thailand, new H5N1 outbreaks were reported in several villages in the province of KamphaengPhet involving native poultry and fighting cocks (in village No. 4 only).   No vaccinations were given (prohibited).  OIE reports that in this third wave of avian outbreaks (the 2^nd wave ended April 12^th) there have been 59 confirmed outbreaks in 7 provinces, all in the Central Poultry Zone of Thailand. The animals involved were reported to OIE as having been farm-raised poultry or free-range poultry with traditional husbandry practices including poor sanitation and inadequate biosecurity. 

On October 14 the Taipei China Coast Guard intercepted a cargo boat from the People’s Republic of China and found smuggled birds (and mice and turtles). 46 samples were obtained from the 1,037 birds, and some tested positive for H5N1 virus. All the smuggled animals were killed on 15 October.

Dead birds in multiple other locations have been or are still being tested for H5N1. These locations include Kosovo, Croatia, Greece, Macedonia, and Nepal. In Macedonia, Newcastle disease was reported by the OIE October 21^st, although “one serum gave a positive result to the serological test” for the 16 different avian influenza viruses tested. Samples were then sent to the OIE reference lab in VLA Weybridge, UK, and are pending.

Not surprisingly, with the ongoing outbreaks in avians in Europe and Asia, the risk of avian-to-human infection continues.  Thus, the risk of dual infection with both an avian and a human influenza virus is increased as the human influenza season begins now in the northern hemisphere. 

The WHO reported on 20 October that the Ministry of Public Health (MOPH) in Thailand confirmed the first human infection with H5N1 in more than one year (since October 8, 2004). The 48-year-old man died after slaughtering diseased poultry in Kanchanaburi province in the Central Poultry Zone of Thailand.  This man, the 18^th confirmed human infection in Thailand and the 13^th fatal infection, had a 7-year-old son who was also reported hospitalized with an influenza-like illness.  Preliminary reports suggested that the son had also been infected during close contact with infected poultry and not by person-to-person spread. 

We should anticipate more avian infections as the virus spreads further in Europe and into Africa and the Middle East, as well as recurring in Asia. More human infections from avians and non-sustained person-to-person (“P2P”) infections in small clusters in humans are predictable this winter.  

Surveillance for more extensive, sustained, person-to-person-to-person-to-person-to-person (“P5P”) transmission is essential if any realistic hope is to be maintained that a nascent pandemic can be identified and mitigated by public health intervention by national and WHO response partners.

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism and Emerging Diseases

ER One Institutes, Washington Hospital Center

Adjunct Professor, Department of Microbiology and Immunology

Georgetown University School of Medicine

Washington, DC                                 

29 October 2005

Africa and the Threat of Avian and Pandemic Flu: The US Should Act Now

In a candid “Risk assessment for Africa” the World Health Organization (WHO) October 28^th made explicit what can be anticipated if and when H5N1 avian influenza, and its attendant human pandemic threat, arrives in Africa.  The time for the US and other nations to act to prevent, or at least mitigate, the following readily predictable avian influenza events in Africa is now, even though not so stated by the WHO.  Such preemptive action by the USA would be both the right thing to do from a humanitarian perspective and from a national self-interest perspective. HHS Secretary Leavitt returned this month from an admirable five-nation tour of H5N1-affected nations in SE Asia.  A similar tour is warranted within the next few months to nations in North and East Africa that can be predicted to be affected soon by H5N1 by virtue of migratory bird flyways from Europe and Asia.

Key avian influenza-related issues the WHO noted with regard to Africa include:

1.  Large numbers of households keep backyard flocks of poultry, as in parts of Asia, affording many opportunities for transmission of avian influenza via close contact with humans, including children. 
2.   Surveillance for avian influenza is, with few exceptions, non-existent. Moreover, mortality of nutrition-poor birds is high at baseline, therefore missing the initial outbreak of bird flu easily occur.
3. Farmers are unlikely to be adequately compensated by economically challenged governments for culling of avian-flu infected poultry, thus discouraging compliance with reporting and culling requirements.
4.  Late diagnosis of avian flu outbreaks increases the probability that viruses like H5N1 will become endemic in parts of Africa, as this virus has in parts of Asia.
5. A critical source of nutritional protein for human populations of Africa will be removed if large numbers of poultry are killed by avian flu and subsequent culling in an attempt to limit its spread.
6.  Avian-to-human infection with H5N1 virus in Africa is likely to occur as it has in Asia, partly due to similar traditional culinary practices. 
7. Human infections with H5N1 virus would be an immense superimposed burden on the health care system of Africa already overwhelmed by HIV/AIDS/SIDA, TB, malaria, parasitic and other diseases, 
8.  Adequate resources are not generally available for the rapid diagnosis of H5N1 virus, a non-specific mimic of other respiratory and influenza-like-illness, nor are large stockpiles of affordable and effective antiviral drugs for H5N1 therapy.
9.   Infection control to prevent spread to other patients and health care providers would be difficult to sustain in most hospitals. How would the needed large amounts of personal protective equipment become available?
10. Surveillance for clusters of human disease due to H5N1 and related viruses in Africa would be difficult. The excellent reference laboratories in Africa could be overburdened by a surge in demands for testing.  Early warning signs of a nascent human pandemic in Africa could be readily missed. Thus, there is a national and international self-interest in preventing and mitigating H5N1 influenza in Africa, in addition to the immense humanitarian value.
11.  Indeed, on October 28^th the WHO also posted online the information that “the H5 hemagglutinins (HA) genes of viruses from birds in China, Indonesia, Japan, Mongolia, Russia, South Korea, and Turkey, as well as 3 viruses from humans in Indonesia are genetically distinguishable from the prototype strains selected last year for influenza pandemic vaccine development. There is also evidence of antigenic variation among the HA of recent viruses. However, their geographical spread and pathogenicity in human populations remain unclear.”
12. Thus, “for vaccine research purposes, the WHO H5 Reference Laboratory Network, which undertakes the tasks of selecting and developing the pandemic vaccine strains, has initiated the development of experimental H5N1 vaccine prototype strains from the recent viruses.” 
13. At the same time “WHO does not recommend changing the previously selected H5N1 prototype strains for ongoing pandemic vaccine development.

In my opinion, the predictable future H5N1 viruses that will occur in Africa will need to be analyzed ASAP, as do those now in Europe and Asia, to understand and act on their evolving antigenic relationships. Significant changes in how the human immune system perceives these evolving H5N1 viruses (ie, “antigenic relationships”) could have a direct and immediate impact on the probability that current pre-pandemic prototypic human vaccines against H5N1 will even partially protect humans if an H5N1-related virus triggers the next human influenza pandemic.

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism and Emerging Diseases

ER One Institutes, Washington Hospital Center

Co-Director, Master of Science (MS) Graduate Program in

“Biohazardous Threat Agents and Emerging Diseases”

Georgetown University School of Medicine, Washington, DC

11 November 2005

WHO Reference Labs developing new experimental H5N1 vaccine prototype strains

The World Health Organization (WHO) posted online an important 3-paragraph milestone October 28^th that reported H5N1 viruses from both birds and humans are “genetically distinguishable from the prototype strains selected last year for influenza pandemic strain development”. Thus “the WHO H5 Reference Laboratory Network, which undertakes the tasks of selecting and developing the pandemic vaccine strains, has initiated the development of experimental H5N1 vaccine prototype strains from the recent viruses”. WHO also reported “evidence of antigenic variation among the HA (hemagglutinin) of recent viruses”.

At the same time WHO stated in the title of this article that they “recommend H5N1 prototype strains for influenza pandemic vaccine development remain the same” referring to “ongoing pandemic vaccine development”, but not for “vaccine research purposes” in which the newer H5N1 viruses will be used to develop experimental H5N1 vaccines. 

Notably, WHO stated that “H5 hemagglutinins (HA) genes of viruses from birds in China, Indonesia, Japan, Mongolia, Russia, South Korea, and Turkey, and 3 viruses from humans in Indonesia are genetically distinguishable from the prototype strains selected last year for influenza vaccine development. There is also evidence of antigenic variation among the HA of recent viruses. However, their geographical spread and pathogenicity in human populations remain unclear.”  

Clicking on the link to  “WHO H5 Reference laboratory Network” cited in this document takes the reader to a 23 March 2004 WHO list of “WHO reference laboratories for diagnosis of influenza A/H5 infection”. These 8 labs are located in Hong Kong (2), France, Japan, the United Kingdom, USA (2), and Australia.

This critical WHO October 28^th update on genetic changes and antigenic variation in the immunologically-dominant hemagglutinin (HA) molecule of the H5N1 virus is a new milestone marking the continued evolution of this potentially pre-pandemic H5N1 virus from 1997 to 2002-2003 to 2004-2005.  

Once again the tenacious and timely monitoring and decision to take action based on the evolution of the H5N1 virus by initiating new research vaccine development by the WHO is to be appreciated worldwide.  Such WHO action, however, would not be possible without the “rapid sharing of avian influenza virus isolates/specimens from affected Member States with the WHO H5 Reference Laboratory Network”. 

26 November 2006

New H5N1 Patients in China, Vietnam, Indonesia and Thailand as Winter Nears

The total number of WHO-laboratory confirmed cases of H5N1 infection has now reached 132 as four nations have had additional patients reported on the WHO website November 14-25. The cases fatality rate is 68/132 (52%). 

China has now had three laboratory-confirmed patients, with two deaths. Two have occurred in Anhui province, in SE China, and one in Hunan province in southern China. On November 24^th WHO reported the death of a 35-year-old farmer in Anhui province and announced that China has invited the WHO to join them in a joint mission to investigate H5N1 issues in Anhui province. 

On November 25 the WHO reported the 93^rd patient in Vietnam with H5N1 infection, of whom 42 have died.  Notably, however, the case fatality rate has decreased to 33% (22 deaths/66 patients) since December 2004.  During the preceding year, from December 2003, the case fatality rate had been 74% (20 deaths/27 patients). The average age of the patients in Vietnam increased in 2005 compared with 2004, according to Dr. Bui Ba Bong, Vice-Minister, Ministry of Agriculture and Rural Development, at the WHO conference on H5N1 held in Geneva November 7-9. He noted that the average age of fatal cases increased from 16.0 years in 2004 to 24.0 years in 2005. His presentation can be found on the WHO website, along with those from Kenya, China, Netherlands, Indonesia, and Japan.

Indonesia reported on 17 November new H5N1 infections in two women in Jakarta, 16 and 20 years old. The fulminant nature of this virus was reiterated by the fact that the 16 year old developed symptoms on 4 November, was hospitalized on 6 November, and died on 8 November. Similarly, the 20-year-old woman had symptom onset on 5 November, was hospitalized on 9 November, and died on 12 November.  Clinical research studies are urgently needed to define better the pathogenesis of H5N1 influenza, and potential additional therapies, such as cytokine modulators and parenteral neuraminidase inhibitors. 

Recent work implicating “cytokine storm” as a key cause of the rapid and severe illness due to H5N1 was strengthened by the publication this month online 11 November in Respiratory Research, a BioMed Central journal by M CW Chan and colleagues from Hong Kong and Hanoi, Vietnam (http://respiratory-research.com/content/6/1/135).   They reported that H5N1 virus from both Vietnam in 2004 and Hong Kong in 1997 induced much higher amounts of proinflammatory cytokines and chemokines than did a comparison H1N1 influenza virus from human respiratory epithelial cells in vitro. These findings were similar to those reported from Hong Kong using human macrophages in vitro (Lancet2002; 360:1831-1837).  Therapeutic interventions designed to decrease inflammatory cytokines and chemokines would be important to test the proof-of-concept that hyperinduction of inflammatory cytokines contribute causally to the pathogenesis of H5N1 influenza disease and mortality.

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism and Emerging Diseases

ER One Institutes, Washington Hospital Center

Co-Director, Master of Science Graduate Program in Biohazardous Threat Agents and

Emerging Infectious Diseases, Georgetown University Medical School

Washington, DC.

  28 November 2005

  Three types of Influenza Vaccines: (1) The Yearly Human Flu Vaccine, (2) The Avian Flu H5N1 Vaccine, and (3) A Future Pandemic Flu Vaccine

30 November 2005

 N-95 Respirator Protection against TB, SARS, or Flu:     An Analogy to Automobile Seat Belts

	N-95 RESPIRATOR	SEAT BELT
If not worn correctly:	NO BENEFIT	NO BENEFIT
Only one part of a total safety package?	YES	YES
IF worn correctly will  protect most of the time	YES	YES

12 December 2005

WHO: Review of Data on Influenza Virus Transmission 

Early online publication of two papers from the WHO slated for the January 2006 edition of the Emerging Infectious Diseases (EID) CDC  journal (www.cdc.govhome page) provide useful literature and policy reviews for “nonpharmaceutical interventions for pandemic influenza”.  The first paper addresses international measures and the second national and community measures.

A selection of key points emphasized relevant to data review on influenza virus transmission in these WHO documents follows.  Later discussion will focus on the extrapolation of these data to recommendations by WHO regarding nonpharmaceutical interventions. 

During the incubation period of influenza persons with asymptomatic (or “presymptomatic”) infection “shed virus at lower titers than persons with symptoms; however, the infectiousness of those with presymptomatic infection has not been studied”.  They cite one study of adults that occurred in 1991 as “apparently the only published report implicating transmission during the incubation period”; it involved 26 adults in New Zealand and was published in the journal Communicable Disease New Zealand 1992; 92:18-19.  

In healthy adults, titers of infectious influenza virus peak during the first 24-72 hours of illness and decline within several days with low or undetectable titers by day 5. However, shedding in severely immunocompromised adults “may last weeks to months”. Children also shed the highest amount of virus for 1-3 days after symptoms start and the “median duration of virus detection is typically 7-8 days after illness onset, but shedding up to 21 days has been noted”.  “In both children and adults, shedding does not usually continue once illness has resolved. Serologic testing indicates that ~ 30%-50% of seasonal influenza infections may not result in illness”. 

The predominant mode of influenza transmission is via virus-laden large particles when persons cough or sneeze, but evidence also exists for aerosol transmission by smaller particles. “The precise proportion of infections transmitted by large droplets versus aerosols is difficult to assess and likely depends on the setting but is relevant when developing recommendations on mask use. Data do not exist to quantify the relative efficacy of surgical masks versus respirators in preventing influenza infections in exposed persons, but surgical masks should protect against large droplets, believed to be the major mode of transmission. 

“Transmission of influenza viruses by contaminated hands, other surfaces, or fomites has not been extensively documented but is believed to occur…In an environmental study, influenza virus placed on hard, nonporous surfaces (steel and plastic) could be cultured from the surfaces at diminishing titer for < 24 to 48 hours and from cloth, paper, and tissue for < 8 to 12 hours”…Virus on nonporous surfaces could be transferred to hands 24 hours after the surface was contaminated, while tissues could transfer virus to hands for 15 minutes after the tissue was contaminated. On hands, virus concentration fell by 100 to 1000-fold within 5 minutes after transfer.” 

“The mean incubation period for influenza averages 2 days (range 1-4 days), and the serial interval (the mean interval between onset of illness in 2 successive patients in a chain of transmission) is 2-4 days. Also, viral excretion peaks early in illness. These factors enable influenza to spread rapidly through communities. By contrast, SARS has a serial interval of 8 to 10 days, and peak infectivity does not occur until week 2 of the illness, which allows more time to effectively implement isolation and quarantine measures.” 

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism and Emerging Diseases

ER One Institutes, Washington Hospital Center

Co-Director, Masters of Science Program in Biohazardous Threat Agents and 

Emerging Infectious Diseases, Georgetown Medical School, Washington, DC.

22 December 2005

FDA Approves Oseltamivir (Tamiflu) as Prevention against Influenza A and B for Children Over the Age of One (1) Year

Today the FDA posted on their website (www.fda.gov) the announcement of the FDA’s approval of the oral antiviral drug oseltamivir (Roche Pharmaceuticals drug name “Tamiflu”) for the prevention of both influenza A and influenza B in children 1-12 years of age. 

Previously, this drug had only been approved for prevention purposes down to the age of 13 years.  At the same time, oseltamivir (Tamiflu) had already been FDA-approved for treatment of actual symptomatic influenza illness down to the age of one (1) year.  Now the age restrictions for children are identical for both prevention and treatment purposes of influenza A and B, namely all children over the age of one (1) year.

The clinical study on which FDA-approval for ages 1-12 years was based included 222 children in that age range out of a total of over 1100 people. Prophylactic doses of Tamiflu were given once daily for 10 days when someone in the household was diagnosed with the typical seasonal human influenza (this was NOT a study of avian H5N1 influenza A since that virus still does not spread easily from person-to-person).

 The FDA reported that “The rate of children developing fever and other symptoms confirmed to be flu was reduced from 17% in the group receiving no preventive treatment to 3% in the group that received Tamiflu as a preventative measure”. 

The most common side effects in this study were nausea, vomiting, headache and fatigue. Importantly, the FDA has requested further safety data post-marketing to evaluate the long-term safety of this drug. An FDA Pediatric Advisory Committee met on November 18, 2005 and the FDA required that the Tamiflu product label now include additional language regarding serious skin/hypersensitivity reactions.

Although not specifically mentioned by the FDA as playing a role in this new approval of Tamiflu for prevention of influenza in young children, this FDA approval calls to mind the October 24, 2005 FDA news release on their website titled “FDA Announces Rapid Response Team to Combat Pandemic (Avian) Flu”.  Quoting the Acting FDA commissioner, Dr. Andrew von Eschenbach: ”Americans can be certain that FDA has the best scientific minds working together to ensure we have enough Tamiflu and other medications and to quickly get it to doctors and patients, if ever necessary”. 

The October 24^th FDA announcement regarding the Rapid Response Team for Pandemic (Avian) Influenza also stated that new medications for avian influenza could be made available under the FDA’s Emergency Use Authorization (EUA) provision. In addition, this team “will facilitate the development and availability of safe and effective vaccines that could help protect Americans against a future pandemic, including from avian flu”.

The FDA has made an important contribution by reviewing the safety and efficacy data for Tamiflu prophylaxis against influenza in children 1-12 years of age and approving the drug for this indication based on their review. In addition, the FDA Rapid Response Team to Combat Pandemic (Avian) Flu is also a welcome addition to optimize the options for accelerated preparedness against pandemic flu, both in terms of antiviral drugs as well as avian and pandemic flu vaccines. 

May this potential for influenza preparedness FDA-regulatory agency partnerships with scientists, academics, pharmaceutical companies, and other US Federal agencies outside the FDA, be realized in practice in the months and years ahead.

Daniel R. Lucey, MD, MPH

Director, Center for Biologic Counterterrorism & Emerging Diseases

Washington Hospital Center Department of Emergency Medicine

Co-Director, Master of Science Program

Biohazardous Threat Agents and Emerging Infectious Diseases

Georgetown University School of Medicine, Washington, DC