2009 Center for Biologic Counter-terrorism and Emerging Diseases Forum Updates

January 9, 2009

Daniel R. Lucey, MD, MPH

No Statistically Significant Clinical Differences Seen with Oseltamivir-Resistant Influenza A (H1N1) in Norway in 2007-2008

Several media reports in the past week have commented on a possible increase in pneumonia and/or sinusitis in patients from Norway with the new oseltamivir (Tamiflu)-resistant influenza A (H1N1) virus. For example, today’s NY Times article (page A10/A17, January 9th) cites a well-known biochemist stating that “Preliminary data out of Norway…suggested that the new strain was more likely to cause pneumonia”. This study from Norway was published early online in the February issue of Emerging Infectious Diseases (EID) journal on the CDC website (Hauge SH et al. Osetamivir-Resistant influenza A (H1N1, Norway, 2007-08. Emerg Infect Dis. 2009 February). Of note, this study did not find a statistically significant increase in either pneumonia or sinusitis in persons infected with oseltamivir-resistant influenza A (H1N1).

Specifically, this study from Norway reported the following:

“Overall, the observed clinical manifestations associated with influenza viruses A (H1N1) in this study were as expected for seasonal influenza. No differences were noted for virus shedding, primary symptoms, or overall complication and hospitalization rates caused by oseltamivir-resistant and –susceptible viruses. We did find, although not a statistically significant finding, that patients infected with a resistant virus appeared to be more likely than those infected with a susceptible virus to have pneumonia or sinusitis…Because of our limited sample size, the precision of our estimates is low, but they do indicate findings that warrant further.”

Certainly, further study is warranted of these preliminary findings. At the same time, however, it should be emphasized that no statistically significant differences have been reported in the clinical manifestations of patients with oseltamivir-resistant and oseltamivir–susceptible influenza A (H1N1) infection.

12 January 2009

Daniel R. Lucey, MD, MPH

White House issues Executive Order to Strengthen Laboratory Biosecurity in the USA

On Friday, January 9, President George W. Bush issued an Executive Order: “Strengthening Laboratory Biosecurity in the United States”.

By this order the White House “hereby established, within the Department of Defense for administrative purposes only, the Working Group on Strengthening the Biosecurity of the United States”. The Co-Chairs of the Working Group include the Secretary of Defense and the Secretary of Health and Human Services (HHS).

This Working Group is required to “submit a report to the President, through the Co-Chairs, not later than 180 days after the date of this order that is unclassified, with a classified annex as required…The Working Group shall terminate 60 days after the date of the report…”

Additional members of this Working Group include, but are not limited to, the Secretary of State, the Attorney General, the Director of National Intelligence, the Director of the National Science Foundation, and the Secretaries of Agriculture, Commerce, Transportation, Energy, and Homeland Security.

The full White House press release from 9 January is posted online at: www.whitehouse.gov/news/releases/2009/01/20090109-6.html

16 January 2009

Daniel R. Lucey, MD, MPH

CDC Announces Guidance on Smallpox Revaccination of Eligible Persons on an “Out-The Door” As-Needed Basis

On January 14 the CDC posted on their website a documented titled “Interim Guidance for Revaccination of Eligible Persons who participated in the US Civilian Smallpox Preparedness and Response Program”.

The summary of their guidance is stated on page 6 of the 9 page document (http://emergency.cdc.gov/agents/smallpox/revaxmemo.asp

“After consideration of available scientific evidence and the practical issues relevant to pre-event vaccination, CDC recommends revaccination of volunteer responders from the pre-event smallpox program on an as-needed, ‘out-the-door’ basis.”Out-the-door basis is defined as receiving revaccination only after there is determination of a credible threat to public health and prior to engaging in activities involving a risk of exposure to smallpox virus…”

19 January 2009

Daniel R. Lucey, MD, MPH

Salmonella Outbreak in 43 US States appears linked to Peanut Butter and Paste

On Saturday and Sunday, January 17-18, the CDC and FDA posted updates on their websites (www.cdc.gov and www.fda.gov) of the ongoing investigations into a nation-wide outbreak of Salmonella Typhimurium that initially appears linked to peanut butter and foods (e.g., cookies, ice cream, crackers) containing peanut paste.

CDC reported in their Health Advisory of Saturday, January 17th that 474 persons from 43 states were reported to be infected with the outbreak strain of Salmonella Typhimurium. At least 107 of these persons have been hospitalized, and 6 have died. The states with the largest number of patients as of January 16th are: Ohio (64), California (60), Massachusetts (40), Minnesota (35), Michigan (25), and Virginia (20).

The CDC case definition is “illness in a person with a Salmonella typhimurium infection with illness onset (or isolation, if onset date unknown) on or after September 1, 2008, and with an isolate matching an outbreak PFGE pattern.” Diarrhea, abdominal pain, and fever typically occur 12- 72 hours after Salmonella infection and the illness usually lasts 4-7 days.

The FDA has also provided a very informative and comprehensive update on its investigation and a list of company product recalls (13) on its website at: www.fda.gov/oc/opacom/hottopics/salmonellatyphi.html This FDA website also includes a useful list of frequently asked questions (FAQs) for consumers.

The CDC Health Advisory of January 17 made the following recommendations for consumers:

—“Do not eat products that have been recalled and throw them away in a manner that prevents others from eating them.

—Postpone eating other peanut butter containing products (such as cooking, crackers, cereal, candy, and ice cream) until information becomes available about whether that product may be affected.”

23 January 2009

Daniel R. Lucey, MD, MPH

US CDC Announces New Acting Director:

Richard Besser, MD

On Thursday, January 22, the US Centers for Disease Control and Prevention (CDC) announced that Dr. Richard E. Besser is now the Acting Director of the CDC and Acting Administrator of the Agency for Toxic Substance and Disease Registry (ATSDR). Dr. Besser replaces Dr. Julie Gerberding, head of the CDC and ATSDR since 2002.

Most recently, Dr. Besser served as the Director of the CDC’s Coordinating Office for Terrorism Preparedness and Emergency Response (COPTER). According to the CDC Press release posted on their website Dr. Besser received his BA degree in economics at Wiliams College, his MD from the University of Pennsylvania, and completed a pediatrics residency and chief residency at Johns Hopkins.

He began at CDC in the Epidemic Intelligence Service (EIS) studying food-borne diseases. Subsequently his work has included epidemiology section chief in the Respiratory Diseases Branch, and acting chief of the Meningitis and Special Pathogens Branch. In addition he served as the medical director of “Get Smart: Know When Antibiotics Work”, CDC’s campaign to foster appropriate antibiotic usage, prior to his position as Director of COPTER.

Dr. Besser is quoted on this website press release as stating: “Preparedness is a continuum rather than a state of being”. From that perspective and with his prior experience, numerous publications, and distinguished training, Dr. Besser should be welcomed by emergency planners, public health officials, and clinicians in his new position during an especially challenging time in America and the world.

25 January 2009

Daniel R. Lucey, MD, MPH

Pearls from the online WHO “Smallpox and its Eradication” (I): Development and Use of the WHO Smallpox Recognition Card in Indonesia 1970-71.

Smallpox is the only human infectious disease that has been eradicated from the world. The definitive description of this immense accomplishment appears in the 1,460-page, 31-chapter pdf book posted on the World Health Organization (WHO) website at: http://whqlibdoc.who.int/smallpox/9241561106.pdf

The original book was published in 1988 by the WHO (Geneva) and was titled “Smallpox and its Eradication”. The five authors are: Frank Fenner (Australia), Donald Ainslie (DA) Henderson (USA), Isao Arita (Japan), Zdenek Jezek (former Czechoslovakia), and Ivan Danilovich Ladnyi (former USSR). Smallpox was officially declared eradicated in 1980 by the WHO.

While reading this book one is struck by multiple lessons learned, as well as by many poignant public health and clinical stories (“pearls”). As such, renewed recognition may benefit current and future human disease eradication, elimination, and control efforts. Thus, succinct excerpts of such examples will be cited periodically in this forum as www.BePast.org “newsletters”. Some of these examples can also stand alone as literature regarding the human condition itself, beyond the specific context of smallpox and its eradication.

Chapter 13 Indonesia

“The Development and Use of the WHO Smallpox Recognition Card”

“Events which led to the development of the WHO smallpox recognition card and the use of schools in the search for cases in Indonesia occurred in Bandung. Among the many vaccinators engaged in search activities, there was one who recorded exceptional success in detecting outbreaks. Supervisors noted that, paradoxically, this vaccinator was considered to be one of the laziest workers—the last to leave for the field and the first to return home. When asked how he was so successful, he admitted that instead of visiting all the houses in a village, as instructed, he was only visiting the schools. There he showed children and teachers pictures of smallpox cases which appeared in a WHO teaching folder on smallpox diagnosis that had been prepared for Africa. Numerous case notifications were obtained with the minimum of effort.

The teaching folder contained many different pictures of smallpox in African children. The photographs were small and the smallpox rash on a black skin appeared to differ somewhat from the rash on the skin of Indonesians, which was lighter in colour. Nevertheless, most children had recognized the disease. Programme staff suggested the preparation of a single large picture of an Asian child with smallpox for use as a recognition card. Thus, the WHO smallpox recognition card was first prepared, encased in plastic for durability, and widely distributed around the world.” (page 651).

Comment: One of the observations that could be made on this example is the importance of disease surveillance. The WHO smallpox recognition card and the use of schools in the search for cases contributed significantly to the “Surveillance-Containment Strategy” of the WHO “Intensified Smallpox Eradication Programme, 1967-1980” that culminated in the global eradication of smallpox.

26 January 2009

Daniel R. Lucey, MD, MPH

WHO 2003-2009: Cumulative Number of H5N1 Flu Patients reaches 400, with sporadic cases this month in China, Egypt, Indonesia, and Vietnam.

Today the World Health Organization (WHO) announced a new patient with laboratory-confirmed H5N1 avian influenza infection. She is a 2-year-old child from Manofia Governate in Egypt who had a recent exposure to sick poultry. The cumulative number of lab-confirmed human cases of avian influenza A (H5N1) reported to the WHO from 2003 until the beginning of 2009 is now 400. The total number of deaths is 252, with a case fatality rate based on these numbers (252/400) of 63%.

So far in this month of January 2009, the WHO has reported sporadic cases of human H5N1 virus infection in China (at least 4 confirmed cases), Egypt (2 cases), Indonesia (2 cases) and Vietnam (1 case).

Both China and Vietnam have issued warnings regarding how to prevent exposure to H5N1 avian flu virus, particularly during celebrations of the Lunar New Year (Year of the Ox) that begins today. Such celebrations can be associated with increased travel, and exposure to poultry.

Vietnam and the WHO opened a new website January 16^th that includes a focus on avian influenza. A specific warning about avian influenza and its prevention during Tet, the lunar New Year, was posted January 22^nd. This website is: www.wpro.who.int/vietnam/home.htm

For Egypt, useful and timely information on H5N1 infections of both animals and humans can be found on the Strengthening Avian Influenza Detection and Response (“SAIDR”) website: www.saidr.org/index.php

For Indonesia, an updated WHO website for avian influenza information can be found at: www.who.or.id/avian. Provided on this website, for example, are the names and addresses of 100 Avian Influenza Referral hospitals in 31 provinces across the Indonesian Archipelago.

Fortunately, no instances of efficient and sustained, person-to-person transmission of H5N1 avian flu virus have ever been reported, or are known to be under investigation. Hopefully, this will remain true during 2009, and this New Year of the Ox.

28 January 2009

Daniel R. Lucey, MD, MPH

Pearls from the WHO’s “Smallpox and its Eradication”:

Lessons and Benefits, but no Template for other Disease Control Campaigns

This third (3^rd) in a series of pearls (insights) from the 1988 World Health Organization (WHO)’s Red Book on “Smallpox and its Eradication” is taken from Chapter 31 “Lessons and Benefits”.

“The rapidity with which smallpox was finally eradicated after so long a history of persistent transmission suggests that lessons may be derived from the experience of the Intensified Programme to benefit other initiatives in health and development. Most significant is the extraordinary achievement which was possible when countries throughout the world collaborated in the pursuit of a common aim, making use of the structures of an international organization and acting under its auspices. This made it possible for the necessary resources to be mobilized and applied to better effect, for improved methods of management and epidemiology to be introduced and widely applied, for vital modifications in strategy to be communicated quickly, and for new and often very simple techniques suited to a country’s capacities and characteristics to be introduced promptly. In consequence, international confidence and accord were strengthened and a foundation was laid for other community-wide health programmes.

The smallpox eradication programme, however, cannot serve as a template for other disease control or eradication campaigns. Every disease has its own epidemiological characteristics and methods for its control which require strategies and tactics specific to it. Also, the approach taken to the eradication of smallpox differed considerably from country to country and was continually modified to capitalize on an evolving understanding of smallpox epidemiology and to deal with different local conditions. It is important also to note that smallpox had a number of features which greatly facilitated eradication. Most important is the fact that its severity and ability to spread in any part of the world commanded both the attention and the concern of health authorities everywhere. It had no known animal reservoir; there were no long-term carriers of the virus; and a single attack of the disease conferred life-long immunity. The detection of cases was comparatively simple because the rash was so characteristic and the persons with subclinical infections did not transmit the disease. Finally, a highly effective, easily administered and surprisingly heat-stable vaccine, conferring long-term protection, was available by the time the Intensified Programme started. Taken together, these characteristics are unique in relation to human infections. Indeed, when the goal of eradication from all countries of the world was decided upon, its feasibility in most of the industrialized countries and some of the developing ones had already been demonstrated.” (page 1346).

Global, national efforts must be urgently intensified to control Zimbabwe cholera outbreak

Daniel R. Lucey, MD, MPH

30 JANUARY 2009 | GENEVA — Zimbabwe’s cholera outbreak, one of the world’s largest ever recorded, is far from being brought under control. An enhanced response is needed to urgently reverse an epidemic that has so far infected more than 60,000 people and killed more than 3,100 since August 2008.

Related links

WHO health action in crisis – Zimbabwe

More on cholera

“The World Health Organization and other international and local partners are supporting the Ministry of Health and Child Welfare’s (MoHCW) efforts to control the epidemic. But unless drastic action is taken by all players in this crisis, more Zimbabweans will succumb to the outbreak, and other countries in the southern African region will face the continued threat of spill over epidemics,” said Dr Eric Laroche, Assistant Director-General for WHO’s Health Action in Crises Cluster.

Urgent measures needed in Zimbabwe include:

Increasing awareness, particularly at grassroots level, regarding prevention and treatment measures. Most recorded deaths have occurred at home, which means that more effective messaging directed at all communities, particularly the remotest parts of the country, is crucial for the Zimbabwean public to be best prepared to act against the epidemic.
Making available more medicines, particularly oral rehydration salts (ORS) and chlorine tablets, at community level so health care workers, and ordinary people themselves, have the means to quickly treat cases of cholera that emerge. One of the greatest challenges is ensuring people can access health services. As this is not possible for many people, due to limited access to transport or money to pay for the trip to the health facility, stocks of simple yet life-saving supplies, such as ORS and chlorine tablets, must be provided to each community.
Mobilizing resources to pay thousands of Zimbabwean doctors, nurses and other health staff who have been unable to obtain salaries and have not had enough money for basic needs, such as buying a bus ticket to get to work. This vacuum in availability of national health staff is a prime factor in the increasing number of cholera sufferers dying.
Opening access to more nongovernmental organizations (NGOs) to respond to the cholera outbreak in more areas of the country. Currently, NGOs, such as Médecins Sans Frontières, are operating large numbers of cholera treatment centers and units in areas where other support, including government, is not available. Such activities must be promoted so to increase access to health care, particularly at district level.
Strengthening the multisectoral response being provided by all players – United Nations, NGOs, governments and donors – is vital. More effort is needed in multiple areas, including improved case management, water and sanitation, social mobilization, provision of financial resources to health providers operating in Zimbabwe, and increasing health staff in the field.

“We are dealing with an extraordinary public health crisis that requires from us all an extraordinary public health emergency response, and this must happen now before the outbreak causes more needless suffering and death,” Dr Laroche said. “Political differences need to be put aside, economic barriers overcome, health services in the country’s periphery strengthened and community awareness to respond enhanced to save many more people from dying due to a disease that can be readily prevented and treated.”

As of 29 January, 2009, that number had reached 60 401, with 3161 deaths, and showed no signs of abating. All 10 provinces, as well as neighboring countries, have been affected. Although the Case Fatality Rate has decreased slightly, it is still above 5%, with about three times more deaths being recorded at community level rather than within health facilities. The acceptable level should be below 1%. Neighboring South Africa has also reported 3000 cases, but the strength of its health care and water and sanitation systems have seen the case fatality rate remain below 1%.

WHO and its partners have worked efficiently with the MoHCW to date to respond to the outbreak, including by:

Establishing a Cholera Command and Control Centre in the capital, Harare, to coordinate and strengthen alert, response, case management, social mobilization and logistics activities.
Mobilizing an outbreak response team of more than 40 experts, including national and international disease control specialists from across WHO. This team has been working on technical coordination, early warning alerts, social mobilization activities, case management and training, outbreak logistics, laboratory support and critical response activities in the most affected provinces.
Deploying 10 experts from public health institutions and technical partners in the Global Outbreak Alert and Response Network (GOARN) to support technical coordination at the Cholera Command and Control Centre, and provide technical support to the MoHCW for outbreak response. These include the Burnet Institute in Australia; the London School of Hygiene and Tropical Medicine (LSHTM) and Health Protection Agency in the UK; the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B); US Centers for Disease Prevention and Control; and the National Board of Health and Welfare, Sweden.
Delivering medicines and other health equipment to health centers treating cholera patients.
Working with the donor community to raise badly needed resources for cholera response activities, as well as the overall strengthening of Zimbabwe’s health sector.

Dr David Heymann, WHO’s Assistant Director-General for Health Security and Environment Cluster, said despite these measures, the scale of the outbreak should serve as a catalyst for increased support from all parties involved in response efforts.

“The challenge is not just in Harare, but in remote, hard-to-access parts of the country where the effective implementation of control measures to contain Zimbabwe’s cholera epidemic is very difficult,” said Dr Heymann. “In addition to the issue of staff shortages, there is a need for increased awareness about how to treat cholera, filling the gaps in medical supplies, providing reliable logistics support and capacity to deliver supplies, and increasing access to health services and safe water supply in remote areas where nongovernmental organizations are not operating. Combined, these factors present a major challenge to bringing this outbreak quickly under control.”

3 February 2009

Daniel R. Lucey, MD, MPH

Traveler Infected with Marburg Virus in Uganda Hospitalized on Return to USA in 2008 and Survived

Marburg virus, like Ebola virus, is a filovirus that can cause viral hemorrhagic fever (VHF). There is no FDA-licensed antiviral drug treatment or preventive vaccine or drug for Marburg virus. The case-fatality rate is often very high. Marburg virus is usually reported in certain parts of Africa and can be found in some species of fruit bats. The virus is known to infect non-human primates as well as humans. Reports of infections in travelers to the USA are extremely rare. This case emphasizes again the importance of taking a detailed travel history.

In a 12-month retrospective diagnosis, the US Centers for Disease Control and Prevention (CDC) confirmed on January 22, 2009 that a woman who was a returning traveler to the USA in January 2008 had Marburg virus infection.

The patient was hospitalized after becoming ill four days after returning to the USA. Fortunately, she survived the Marburg virus infection and no one else was infected. The CDC report, described on their Special Pathogens Branch website (www.cdc.gov/ncidod/dvrd/spb/outbreaks/index.htm) under “Outbreak Postings”, did not state the location of the US hospital or provide clinical details.

Testing of patient samples in January 2008 was initially negative. The CDC stated that: “Testing of a convalescent sample indicated a possible previous infection, and more detailed testing of both samples at CDC confirmed that the patient’s illness was due to Marburg hemorrhagic fever.

The woman had visited a bat-infested cave popular with tourists in Maramagambo Forest, Queen Elizabeth Park, western Uganda. Later, in July 2008, another tourist, from the Netherlands, visited this cave and also became infected with Marburg virus. The Ugandan Ministry of Health closed this particular cave to visitors in August 2008.

4 February 2009

Daniel R. Lucey, MD, MPH

WHO: Urgent Efforts Needed to Control Cholera Outbreak in Zimbabwe, including Oral Rehydration Salts (ORS) at the Community Level

The World Health Organization (WHO) has posted three additional documents since last Friday, January 30^th, on the serious situation with the cholera outbreak in Zimbabwe that has infected 60,000 people and killed over 3,100 during the past six months.

The WHO”s Dr. Claire-Lise Chaignat stated in the February (2009) issue of the “Bulletin of the World Health Organization”

that: “In early January, 600 new cases of cholera were being reported daily with 5-8% of victims dying. Nearly half of these deaths occurred at home…a possible 80% of those afflicted could have been treated successfully with oral rehydration therapy, which can nearly eliminate deaths. Dehydration can kill a healthy adults in a matter of hours…Severe cases may need intravenous fluids, but most people can be saved by ORS” (oral rehydration salts).

In early December 2008 the WHO advised the Ministry of Health and Child Welfare of Zimbabwe “to endorse the administration of ORS solution by people with no health-care training to treat diarrhea in the home in line with WHO policy…” in conjunction with the Ministry, WHO has now begun operating a Cholera Command and Control Centre to coordinate the response to the epidemic.

The WHO has also posted on its website an updated statement on use of Oral Rehydration Salts (ORS) to decrease cholera deaths . These guidelines include: “ORS is a sodium and glucose solution which is prepared by diluting 1 sachet of ORS in 1 litre of safe water. It is important to administer the solution in small amounts at regular intervals on a continuous basis. In case ORS packets are not available, caregivers at home may use homemade solutions consisting of half a teaspoon of salt and six level teaspoons of sugar dissolved in one litre of safe water. Alternatively, lightly salted rice water or even plain water may be given. To avoid dehydration, increased fluids should be given as soon as possible. All oral fluids, including ORS solution, should be prepared with the best available drinking water and stored safely…”

In a third WHO document on cholera in the past 5 days, a detailed press release entitled Global, national efforts must be urgently intensified to control Zimbabwe cholera outbreak was posted January 30^th: While tis entire document was posted verbatim on this www.BePast.org website that same day, the following excerpt is cited to reemphasize the importance of early therapy with oral rehydration salts (ORS), including at home:

“Urgent measures needed in Zimbabwe include:

Increasing awareness, particularly at grassroots level, regarding prevention and treatment measures. Most recorded deaths have occurred at home, which means that more effective messaging directed at all communities, particularly the remotest parts of the country, is crucial for the Zimbabwean public to be best prepared to act against the epidemic.
Making available more medicines, particularly oral rehydration salts (ORS) and chlorine tablets, at community level so health care workers, and ordinary people themselves, have the means to quickly treat cases of cholera that emerge. One of the greatest challenges is ensuring people can access health services. As this is not possible for many people, due to limited access to transport or money to pay for the trip to the health facility, stocks of simple yet life-saving supplies, such as ORS and chlorine tablets, must be provided to each community.”

5 February 2009

Daniel R. Lucey, MD, MPH

Poultry-to-Human H5N1 Influenza Infections Continue in China and Egypt

This week the World Health Organization (WHO) posted updates on additional patients infected with the H5N1 influenza virus via exposure to infected poultry. On Monday, February 3, China’s Ministry of Health reported a 21 year-old female hospitalized and now in stable condition, from Xupu County in Hunan Province. Initial epidemiological investigation suggests “possible exposure to sick and dead poultry”. In 2009 to date, China has reported 7 new cases, with 4 fatalities. Since 2003, 25 of the 38 cases in China have been fatal.

Today (5 Feb) the Egyptian Ministry of Health and Population (MOHP) reported a 2-year-old male from Suez Governate who became ill February 2^nd and was hospitalized February 3^rd. He also is in stable condition. The WHO Eastern Mediterranean Regional Office (EMRO) website reported that the antiviral drug oseltamivir (Tamiflu) was started on hospital admission February 3^rd. A throat swab and blood tests were obtained and a diagnosis of H5N1 influenza A was made the next day at the Egyptian Central Public Health Laboratory.

Epi-investigation “indicates a recent history of contact with dead poultry”. In 2009 t date, Egypt has had three cases, none of which have been fatal. Since 2006, 23/54 cases in Egypt have been fatal.

Globally, WHO has reported a cumulative number of confirmed human cases of Avian influenza A/ (H5N1) of 405, with 254 fatalities.

Additional human cases linked to poultry should be anticipated in the winter months ahead, as in past years.

5 February 2009

Daniel R. Lucey, MD, MPH

H5N1 Vaccine Update from WHO

Last week the World Health Organization (WHO) posted on their avian influenza website a six-page pdf document with the latest in a series of updates on “Antigenic and genetic characteristics of H5N1 viruses and candidate vaccine viruses developed for potential use in human vaccines”.

In terms of molecular epidemiology of H5N1 an updated nomenclature of the expanding H5N1 clades (families) and their status relative to vaccine development is provided in figure 1. Clades 0, 1, 2, 3, 4, 5, 6, 7, 8, and 9 are now recognized to have caused avian infections, and several have caused human infections. Clade 2 is further subdivided into subclades 2.1, 2.2, 2.3 (including 2.3.1, 2.3.2, 2.3.3, and 2.3.4) and 2.4.

Since September 2008, human infections have been laboratory-confirmed by WHO as follows:

Clade 1:	Cambodia
Clade 2.1:	Indonesia
Clade 2.2:	Egypt
Clade 2.3.2:	China
Clade 2.3.4:	China and Vietnam

The recent clade 2.3.2 infection in China (A/Guangzi/1/2009) is the first reported human infection with this clade.

The recent clade 2.3.4 infection in China (A/Hunan/2/2009) is genetically divergent from other viruses of this clade (Tables 1, 2).

The H5N1 vaccine update in Table 3 is divided into 3 groups:

a. Reassortants with complete regulatory approval (e.g., from isolates of clades 1, 2.1., 2.2, 2.3.4, and 4).

b. Reassortants prepared and awaiting regulatory approval (e.g., 2.2, 2.3.2, 7)

c. Viruses proposed (by WHO) for candidate vaccine preparation (e.g. 2.3.4, and 7)

With regard to clade 2.1-based vaccines it is noted in Table 3 that availability “Requires Indonesian Government permission”.

Although the fortunate absence of a human influenza pandemic due to an H5N1 virus has understandably decreased the media ‘newsworthiness’ of the ongoing animal H5N1 epidemic and non-sustained human H5N1 infections, updates and guidance such as that contained in this WHO document are essential to the long-term global preparedness for a potential H5N1-specific human pandemic.

6 February 2009

Daniel R. Lucey, MD, MPH

40 WHO Websites on Infectious Diseases listed in today’s WHO Weekly Epidemiological Record (WER)

In today’s (Feb 6) issue of the Weekly Epidemiological Record (WER) of the World Health Organization (WHO) a list of 40 specific website addresses for a spectrum of infectious diseases is provided. The complete list is available on page 48 of today’s WER at: www.who.int/wer

A partial list (10) of these WHO websites includes:

Global Atlas of infectious Diseases:	www.globalatlas.who.int
Malaria:	www.who.int/malaria
Tuberculosis:	www.who.int/tb and www.who.stoptb.org
Deliberate use, biological agents:	www.who.int/csr/delibepidemics
Smallpox:	www.who.int/csr/disease/smallpox
Vaccines:	www.who.int/immunization/en
International travel and health:	www.who.int/ith
Cholera:	www.who.int/cholera
International Health Regulations:	www.who.int/csr/inhr/en
Tropical Disease Research:	www.who.int/tdr

Use of these WHO websites for Infectious Diseases affords an excellent resource for reliable updated information on the 40 topics from an international perspective. Other topics covered in today’s Weekly Epidemiologic Record include:

— A report from the Leptospirosis scientific meeting in Manila in November 2008, and

— A summary report on Burulli ulcer from the first program review meeting for West Africa.

7 February 2009

Daniel R. Lucey, MD, MPH

Peanut-Containing Product Recalls Exceeds 1,500 with Updated Identifications on FDA website and “Widget”

On Saturday, February 7, the US Food and Drug Administration (FDA) posted on their website an update on the recall of peanut-containing products due to the risk of Salmonella Typhimurium infection (www.fda.gov/oc/opacom/hottopics/salmonellatyph.html). They confirm that “the sources of the outbreak of illnesses caused by Salmonella Typhimurium are peanut butter and peanut paste produced by the Peanut Corporation of America (PCA) at its Blakely, Georgia processing plant.” On January 30^th the FDA confirmed that a criminal investigation is underway.

In today’s posting, the FDA also emphasized in bold type that: “Major national brands of jarred peanut butter found in grocery stores are not affected by the PCA recall.

On Friday, February 6^th, the top of the homepage of the website (www.hhs.gov) for the US Department of Health and Human Services (HHS) reported that “Peanut-Containing Product Recalls Top 1500”.

On both this HHS website and the above FDA website there is provided, and available to both professionals and to the public, a “New FDA Widget Browse Peanut-Containing Recalls”. This allows one to search rapidly for specific recalled products. Moreover, it is automatically updated. This is a particularly valuable function given the very large number of peanut–containing products that have been recalled. These include, but are not limited to, certain donuts, ice cream, cookies, crackers, cakes, pies, brownies, and candy.

The FDA and partners at the CDC (both organizations are part of the larger HHS) are providing a valuable resource for consumers and professionals on this outbreak, with updates even on weekends.

10 February 2009

Daniel R. Lucey, MD, MPH

U.S. Army temporarily suspends much of their biodefense laboratory research at Ft. Detrick, Maryland

Today’s New York Times (page A16 by Scott Shane) reports “Army Slows Bioresearch at Maryland Laboratory” beginning last Friday, February 6, after “discovering that some pathogens stored there were not listed in a laboratory database”. The research laboratory is the renowned U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), located at Ft. Detrick in Frederick, Maryland.

The Institute’s Commander, Colonel John Skvorak, is cited both in the NY Times article and in yesterday’s online ScienceInsiderblog as expressing concern that some biological select agents and toxins stored in the Institute might not be in their current database inventory. The partial suspension on further research was begun while a complete inventory of biohazardous threat agents is being completed.

The NY Times cited a spokesman for the Institute who noted that some critical experiments involving animals would not be halted.

On another issue related to the national increase in biodefense research labs, the same NY Times article concluded by noting that:

“Before 2001, only a few dozen such facilities worked with anthrax. Today, the Centers for Disease Control and Prevention has registered 219 laboratories to do so, said an agency spokesman, Von Roebuck. He said 10, 474 people had been cleared to work with dangerous pathogens and toxins nationwide after background checks by the Justice Department.”

20 February 2009

Daniel R. Lucey, MD, MPH

Cholera epidemic persists throughout Zimbabwe

Today (20 Feb) the World Health Organization (WHO) posted an update on their website (www.who.int) concerning the ongoing cholera epidemic in Zimbabwe. The facts are sobering. The case fatality rate remains much higher, at 4.7%, than “the expected level of 1%”. Over the past six months, since August 2008, there have been 79, 613 suspected cholera cases, including 3,731 deaths, according to Zimbabwe’s Ministry of Health and Child Welfare.

In addition, all 10 provinces in Zimbabwe have been involved by this cholera epidemic. Nearby nations that have also reported cholera cases include: South Africa, Malawi, Mozambique, and Zambia. In some of these countries cholera is endemic; however, the outbreak in Zimbabwe is certainly linked to the high number of cholera cases across the border in South Africa. Fortunately, the case fatality rate due to the recent outbreak is less than 1% in South Africa.

The WHO update concludes with the following assessment and plan going forward as international efforts to control the outbreak continue:

“Given the outbreak’s dynamic, in the context of a dilapidated water and sanitation infrastructure and a weak health system, the practical implementation of control measures remains a challenge. Priorities now include decentralizing response activities to the periphery, particularly to areas with no active nongovernmental organizations, and strengthening social mobilization in communities to improve access to health services and earlier treatment. Activities will also focus on resource mobilization and greater involvement of partners in the field.”

24 February 2009

Daniel R. Lucey, MD, MPH

Meningococcal Outbreak in Nigeria and “Meningitis Belt” of Africa: CDC advises Vaccination for Travelers

During the past week the World Health Organization (WHO) announced on their website homepage (www.who.int) an outbreak of meningococcal disease, due to the gram-negative bacteria Neisseria meningitides, had begun in Nigeria. Earlier this month the Ministry of Health of Nigeria reported the outbreak involved 19 of 35 states and included Abuja. The initial case-fatality rate was 7.9% (108 deaths/ 1364 suspected cases). Mass vaccination with a polysaccharide meningococcal vaccine is anticipated to help prevent infection and control the outbreak.

Preliminary data showed that serogroup A Neisseria meningitides is likely to be the serogroup responsible for the current outbreak, based on spinal fluid specimen tests. Serogroup A has frequently caused past epidemics across the so-called meningococcal “meningitis belt” of sub-Saharan Africa extending from Mali to Ethiopia. Typically, these meningococcal outbreaks occur during the dry season that occurs between December and June.

The US Centers for Disease Control and Prevention (CDC) reported on February 20 that “official reports indicate that meningitis epidemics have also begun in the western portion of the “meningitis belt”, including parts of Niger, Mali, and Burkina Faso”.

The CDC also recommended that travelers receive the meningococcal vaccine at least 10 days before travel to sub-Saharan Africa between December and June, or to areas currently known to have outbreaks of meningococcal disease.

26 Feb 2009

Daniel R. Lucey, MD, MPH

WHO Announces Agreement on Live, Attenuated Influenza Vaccines

On February 25 the World Health Organization (WHO) posted on the top of their website homepage a synopsis of “Progress in Pandemic Influenza Vaccine Preparedness”. They noted that by early April (within 6 weeks from now) revised and updated (from 2005) guidelines will be issued by WHO on their entire global influenza preparedness plan.

In a major announcement the WHO reported that it has recently signed an agreement with the vaccines division (called “Nobilon”)of the company Schering-Plough “in which WHO has been granted a non-exclusive license to develop, register, manufacture, use and sell seasonal and pandemic live, attenutated (or weakened) influenza (LAIV) vaccines produced on chicken eggs. WHO will thus be able to grant sub-licenses to vaccine manufacturers in developing countries who are working within the framework of the WHO Global Influenza Action Plan to Increase Vaccine Supply”.

The WHO emphasized that the above nations will then be able to provide such vaccines royalty-free to their public sectors.

Live attenuated influenza vaccines were noted by WHO to have the following three advantages over the current inactivated flu vaccines:

“The number of doses of LAIV which can be produced per egg are much higher than with inactivated vaccines, Especially in a pandemic situation, this is considered to be a major advantage since more vaccine doses can be made available in a shorter time.
LAIVs are administered in the nose through a very simple device, which can be much easier to put into practice on a large-scale by non-medically trained staff in case of a pandemic.
Since a LAIV mimics natural infection more than injectable vaccines, it is expected that LAIV induces a more rapid and broader immune response. This may be of particular interest in pandemic situations.”

27 February 2009

Daniel R. Lucey, MD, MPH

Artemisinin-resistant malaria parasites emerge along the Thai-Cambodia border: Control Efforts Announced

Over the past several decades malaria parasite resistance to anti-malaria drugs has emerged at the Thai-Cambodia border beginning with chloroquine, then sulfadoxine-pyrimethamine, and mefloquine. Unfortunately, artemisinin-resistant malaria parasites have recently been found as well here as well. Thus, the progress against malaria made in part by implementation of the World Health Organization (WHO)’s policy of using Artemisinin-Combination Therapy (ACT) for all patients with uncomplicated falciparum malaria is now in jeopardy. Moreover, it reinforces the WHO’s position that all monotherapies of artemisinin and its derivatives should be removed from the market, and thus not available for use in place of combination antimalarial drug therapy.

On 25 February the WHO announced how they will work with partners in Thailand and Cambodia, as well as Oxford, to use a grant ($22.5 million USD) from the Gates Foundation to contain these artemisinin-resistant malaria parasites before they spread to other parts of the world, as occurred in the past with chloroquine, sulfadoxine-pyrimethamine, and mefloquine.

“We know that malaria can be treated and prevented,” said Dr Regina Rabinovich, Director of Infectious Diseases Development at the Bill & Melinda Gates Foundation, “and if we lose the key treatment available at this time, it’s like living in a house with a half a roof.”

“The grant will be used to meet the following key objectives:

Eliminate artemisinin-tolerant parasites by detecting all malaria cases in target areas and ensuring effective treatment;
Reduce exposure of the parasites to artemisinin to limit emergence of resistance;
Prevent transmission of artemisinin-tolerant malaria parasites through mosquito control and personal protection;
Limit the spread of artemisinin-tolerant malaria parasites by mobile populations;
Support the containment and elimination of artemisinin-tolerant parasites through comprehensive behavior change, communication, community mobilization and advocacy;
Undertake basic and operational research to fill knowledge gaps and ensure that strategies applied are evidence-based; and
Provide effective management, surveillance and coordination to enable a rapid and high-quality implementation of the strategy.”

Much is at stake in this collaborative international effort to control these emerging artemisinin-resistant malaria parasites. Particularly in the current absence of a vaccine against falciparum malaria, widespread loss of Artemisinin Combination Therapy (ACT) could impair global efforts to control this disease, even with the expanding use of long-lasting insecticide bed nets and indoor residual spraying of specific insecticides.

2 March 2009

Daniel R. Lucey, MD, MPH

Delivery Begins of Human Moncolonal Anthrax Antitoxin to the U.S. Strategic National Stockpile (SNS)

Last month (February) the Maryland-based company Human Genome Sciences, Inc. announced that “it has begun delivery of 20,000 doses of its human monocolonal antibody drug ABthrax (raxibacumab) to the U.S. Strategic National Stockpile for use in the treatment of inhalation anthrax”.

The company reports that “ABthrax is being developed under a contract entered into in 2006 with the Biomedical Advanced Research and Development Authority (BARDA) of the Office of the Assistant Secretary for Preparedness and Response (ASPR), U.S. Department of Health and Human Services.“ They also state that human safety studies of this human monocolonal antibody have been performed in over 400 volunteers. Some of these volunteers participated in a study that also gave the antibiotic ciprofloxacin at the same time as the anthrax antitoxin in order to assess pharmacokinetic interactions.

As described previously on this website in 2006 (see the 29 July Newsletter) the U.S. Department of Health and Human Services (HHS) had announced funding of two anthrax antitoxin products for the Strategic National Stockpile (SNS). One was for 20,000 treatment courses of this ABthrax monoclonal antitoxin from Human Genome Sciences, Inc., while the other was for 10,000 treatment courses of a human hyperimmune plasma called anthrax immune globulin (AIG) produced by a Canadian company called Cangene corporation.

This monocolonal anthrax antitoxin is not licensed by the Food and Drug Administration (FDA) at this time. The company reported, however, that it “plans to file a Biologics License Application (BLA) with the FDA in the second quarter of 2009.”

3 March 2009

Daniel R. Lucey, MD, MPH

Poliovirus: Very High Risk of Further International Spread from Sudan

On March 2^nd the World Health Organization (WHO) posted on their website (www.who.int) the following notice: “The recent expansion of a prolonged outbreak of wild poliovirus type 1 (WPV1) in Sudan poses a very high risk of further international spread, requiring urgent and immediate outbreak response activities in the affected areas and heightened surveillance in countries at risk.”

Of specific concern to WHO is the presence of poliovirus in Port Sudan because from this area poliovirus type 1 spread to cause over 1,200 cases of polio from 2004-2006, and re-infected four nations:

Saudi Arabia, Yemen, Somalia and Indonesia. Emergency outbreak response costs in these nations totaled over $150 million USD.

WHO reports that the current poliovirus type 1 outbreak is no longer confined to southern Sudan and western Ethiopia. Instead, polio infections have been documented in Uganda, Kenya, and northern Sudan (Khartoum and Port Sudan).

In response, “large-scale supplementary immunization activity (SIA)” has begun in northern and southern Sudan, and is planned for later this month in Uganda and Kenya.

While WHO advises increased surveillance for acute flaccid paralysis (AFP) cases “across central Africa, the Horn of Africa and the Gulf”, travelers to areas with polio outbreaks who then arrive in the USA and are diagnosed clinically with acute flaccid paralysis should also be evaluated for poliovirus infection.

4 March 2009

Daniel R. Lucey, MD, MPH

Patient Safety Awareness Week March 8-14

Today the Association of Professionals in Infection Control and Epidemiology (APIC) released a one page summary of 7 straightforward steps for visitors to health care facilities to decrease the risk of patients acquiring infections in healthcare facilities. These steps include “sanitize hands before and after visiting”, “staying home if you are sick”, and “check first before you bring food, send flowers, or take the kids”.

APIC has 12,000 members. Many are directly involved with infection prevention programs in hospitals and other health care facilities worldwide. Their website iswww.apic.org

In the press release from Washington, D.C. today, APIC notes that Patient Safety Awareness Week, March 8-14, is approaching. They refer readers to the website www.preventinfection.org where the statement is made that “Currently, 271 people a day die on average from healthcare-associated infections (“HAI’s”). They go on to say that many of these infections have the skin as the source of the infection. A link to a DVD on Hand Hygiene, and other infection prevention information from the CDC, is provided on this website. In addition, a link is provided to information such as ‘How to be a Good Visitor to a Health Care Facility’ as part of the March 8-14 Patient Safety Awareness Week.

Such readily feasible, and critically important, information is very valuable in the multidisciplinary effort to decrease the above-mentioned extremely high number of average daily healthcare-associated infections and deaths.

9 March 2009

Daniel R. Lucey, MD, MPH

GAO reports on sustaining pandemic flu preparedness: 10 of 23 recommendations remain

On Friday, March 6 the U.S. Government Pandemic Influenza website (www.pandemicflu.gov) posted a Government Accounting Office (GAO) 58-page pdf. document titled: “Influenza Pandemic: Sustaining Focus on the Nation’s Planning and Preparedness Efforts”. This report did not contain any new recommendations. The GAO did note, however, that in its previous reports on pandemic flu preparedness a total of 23 recommendations had been made. Of these, 10 “remain outstanding” (summarized in Appendix I, page 42-25), while the other 13 recommendations have been implemented (Appendix II).

Examples (3) of the prior GAO recommendations that remain outstanding include:

Finalizing guidance on how to prioritize target groups for pre-pandemic vaccine.
“The Homeland Security Council should establish a specific process and time frame for updating the National Pandemic Implementation Plan…” (This GAO report states that “HSC did not comment on the recommendation and has not indicated if it plans to implement it”.
The US Department of Agriculture (USDA) Secretary should determine the amount of antiviral USDA would need to protect animal health responders…and determine how to obtain and provide supplies within 24 hours of an outbreak. (This GAO report stated that USDA now has an antiviral stockpile to “protect 30,000 animal health responders for 40 days. However, USDA has yet to determine the number of individuals that would need medicine based on a calculation of those exposed to the virus under a specific scenario. Further, USDA officials told us that a contract for additional medication for the stockpile has not yet been secured…”

Examples of the 13 prior GAO recommendations that have been implemented include:

The Secretary of the Department of Defense (DOD) should specify via the chain-of-command that U.S. Northern Command has the role and responsibilities as “global synchronizer” for pandemic influenza planning within the DOD.
“The Chairman, Federal Reserve, the Comptroller of the Currency, and the Chairman, Securities and Exchange Commission, should consider taking additional actions to ensure that market participants adequately prepare for an outbreak, including issuing formal expectations that business continuity plans for a pandemic should include measures likely to be effective even during severe outbreaks…”

Clearly, progress has been made over the past 5 or more years in the USA on pandemic influenza preparedness.

As this report discusses, however, sustaining this trajectory of progress is essential given that, as the GAO one-page summary states, “an influenza pandemic remains a real threat to our nation and the world”.

10 March 2009

Daniel R. Lucey, MD, MPH

New Facility in Mexico to make Seasonal and Pandemic Flu Vaccine

On 9 March this week the vaccine manufacturer sanofi-pasteur announced at a ceremony attended by the Presidents of Mexico and France that a new vaccine production facility will be built, starting in the next few weeks, that will eventually produce up to 25 million doses each year of seasonal influenza vaccine.

This new vaccine facility will have the capability to convert to producing pandemic flu vaccine once it is completed in 2013.

Sanofi-pasteur will collaborate with Birmex, a federal vaccine manufacturer in Mexico. The Minister of Health of Mexico, Dr. Jose Angel Cordova Villalobos also attended the signing of this agreement.

The new vaccine facility will be constructed in Ocoyoacac, Mexico, where sanofi-pasteur already operates a facility.

Sanofi-pasteur is well-known to be actively involved in pandemic influenza vaccine development.

The capacity to produce pandemic flu vaccine in nations other than those in Europe, Japan, Australia, the USA, and Canada will be critical once the next pandemic begins.

12 March 2009

Daniel R. Lucey, MD, MPH

WHO Focuses on Three Key Health Arguments on Climate Change

In a March 11 document posted on its Media Centre website the World Health Organization (WHO) listed three (3) “key health arguments for stronger climate change measures” advocating for them to be “at the center of the forthcoming Conference of the Parties (COP-15) in Copenhagen later this year… (To) ensure that in the new post-Kyoto agreement we will all share in the health and economic benefits that can accrue from countering climate change”.

The three health arguments are:

1). Climate change has adverse consequences for health: as carbon goes up health goes down. WHO estimates approximately 150,000 deaths (85% in young children) occur each year due to climate change from “four climate-sensitive health outcomes”:

a. Crop failure and malnutrition

b. Diarrheal disease

c. Malaria

d. Flooding

2). reducing green house gases emissions can be beneficial to health: as carbon goes down health goes up. A significant portion of the global disease burden is linked to energy consumption and transport systems. Changing these two systems to mitigate climate change could help address four major public health problems:

a. Outdoor air pollution (800,000 annual global deaths)

b. Indoor air pollution (1.5 million annual deaths)

c. Traffic accidents (1.2 million annual deaths)

d. Physical inactivity (1.9 million deaths).

3). the health impacts of climate change are felt unequally: effective response requires global action. Persons most at risk:

a. The poor

b. The very young and the elderly

c. Women

d. The “geographically vulnerable” (e.g., megacities and coastal

Areas in developing countries such as delta regions of

Asia; small island developing nations, mountain regions, and

“Water-stressed areas”).

The complete WHO statement on this critically important, evolving issue regarding health effects of climate change can be found at: www.who.int/mediacentre/news/notes/2009/climate_change_20090311/en/index.html

13 March 2009

Daniel R. Lucey, MD, MPH

US Guidance on Cleaning EMS and Other Transit Vehicles during a Flu Pandemic

On 11 March the U.S. government posted on their one website (www.pandemicflu.gov) for all pandemic influenza (flu) official information a seven-part document titled “Interim Guidance on Cleaning Transit Vehicles and Facilities during a Pandemic”. Such vehicles range from aircraft to railcars to cargo trucks to passenger vessels.

One of these seven guidelines focused specifically on Emergency Medical Service (EMS) vehicles (with the exception of helicopters and airplanes). This 2-page guidance can be found at: www.pandemicflu.gov/plan/healthcare/cleaning_ems.html. Detailed guidance is provided, including 11 points that address “routine cleaning methods…with special attention in certain areas as specified”.

Regarding use of facemasks for patients the following is advised:

“If the patient to be transported can tolerate a facemask (e.g., a surgical mask), its use can help minimize the spread of infectious droplets in the patient care compartment. After the patient has been removed and prior to cleaning, the air within the vehicle may be exhausted by opening the doors and windows of the vehicle while the ventilation system is running. This should be done outdoors and away from pedestrian traffic.”

Regarding gloves and eye protection the following is advised:

“Never wash or reuse disposable gloves. Avoid activities that may generate aerosols. Eye protection, such as a face shield or goggles, may be required if splashing is expected”.

Such detailed interim guidance for many different types of transit vehicles, as well as specific individuals, is welcomed. It may need to be updated as more information and feedback from recipients of this guidance is obtained.

16 March 2009

Daniel R. Lucey, MD, MPH

New Clade 2.1 and Clade 4 recombinant H5N1 Vaccine Viruses Announced by WHO

On March 10 the World Health Organization (WHO) posted on their avian flu website under the “General guidelines” section an important update titled “Availability of new recombinant H5N1 vaccine viruses”. These viruses have been developed at St. Jude’s Research Hospital in Memphis, Tennessee (USA) and are available under a Material Transfer Agreement (MTA).

The two new recombinant viruses are:

Clade 2.1 A/duck/Hunan/795/2002. The HA and NA sequences are provided on the public website of GenBank and are referenced in the following paper: Wang J. et al. Identification of the progenitors of Indonesian and Vietnamese avian influenza A (H5N1) viruses from southern China. J Virol 2008; 82 (7): 3405-3414.

Clade 4 A/goose/Guiyang/337/2006. The HA and Na sequences are provided on the GenBank website and are referenced in the following paper: Smith GJ. Et al. Emergence and predominance of an H5N1 influenza variant in China. Proc Natl Acad Sci 2006; 103 (45): 16936-16941.

This laboratory at St. Jude’s is a WHO Collaborating Centre for Studies on the Ecology of Influenza in Animals.

The complete WHO announcement from March 10 can be found at:

www.who.int/csr/disease/avian_influenza/guidelinestopics/en/index.html

Of note, although the Clade 2.1 virus appears to be derived early on from China (“duck/Hunan/795/2002” above), today it is recognized to be the primary clade of Influenza A (H5N1) that infects humans (and avians) in Indonesia. On the other hand, Clade 4 Influenza A (H5N1) viruses have not (yet) been reported to infect humans frequently anywhere.

March 17, 2009

Daniel R. Lucey, MD, MPH

Smallpox Vaccine Guidance Updated by CDC

On Friday, March 13, the U.S. Centers for Disease Control and Prevention (CDC) posted (www.cdc.gov) on their Emergency Preparedness and Response website updated information on smallpox vaccination.

Practical information, mostly in the format of nearly 100 “Questions and Answers”, was provided on topics including:

—Pre-event and Post-event vaccination

—Vaccine storage and distribution

—Contraindications and screening

—Vaccination while pregnant or breastfeeding

—“About smallpox vaccine”

Key examples (bold type added by this author, not CDC) include:

Q.—What is the ACIP recommendation about the # of needle sticks?

A. …’The Dryvax vaccine…is no longer available and has been replaced by ACAM2000. ACAM 2000 uses 15 insertions for both primary and revaccination and has no provision for additional insertions if no trace of blood is visible after vaccination…’

Q.—Can diluted vaccine (1:5 or 1:10) be used for mass vaccination?

A.—…there are no protocols for using diluted ACAM2000.’

Q.—Is there any need for people who have been vaccinated for

smallpox as children to be vaccinated?

A.—‘Yes. Smallpox vaccination provides high immunity for 3 to 5 years and decreasing immunity thereafter…Now, the CDC is recommending that members of smallpox health care response teams who have not been vaccinated for smallpox in the past 3 years get the vaccine…’

Q.—If someone is exposed to smallpox, is it too late to get a

vaccination?

A.— ‘Vaccination within 3 days of exposure will completely prevent or significantly modify smallpox in the vast majority of people. Vaccination 4 to 7 days after exposure likely offers some protection from disease or may modify the severity of disease.’

Q.—‘If an outbreak of smallpox occurs, will the Strategic National

Stockpile (SNS) be able to quickly ship smallpox vaccine?’

A.— “The SNS plans to distribute smallpox vaccine on the first day of a bioterrorism event to anyone who has been exposed. After that initial shipment, CDC will ship smallpox vaccine over the next 5-6 days to the rest of the country as needed.”

On the other hand, a rare example appears that could be more clearly answered in this updated CDC guidance, such as the question “Why is aspirin not to be used to treat robust reactions (takes) from smallpox vaccine?” (see the “Questions and Answers About Smallpox Contraindications and Screening” section. The CDC answer focuses on varicella vaccine and natural varicella infection, but does not explicitly mention the virologically-unrelated smallpox vaccine, or other live virus vaccines such as MMR).

Overall, this is a very practical and helpful update from the CDC.

23 March 2009

Daniel R. Lucey, MD, MPH

March 24 is World Tuberculosis (TB) Day

The World Health organization (WHO) and Stop TB Partnership recognizes every March 24^th as World TB Day. This date is 1882 is when Dr. Robert Koch found the bacteria that causes the airborne disease tuberculosis. Extensive information on most aspects of tuberculosis can be located via the WHO link at: www.who.int/mediacentre/events/annual/world_tb_day/en/index.html

Specific information on the timely topics of multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (“M/XDR-TB”) can be found at: www.who.int/tb/challenges/mdr/en/index.html

As of 2008, one or more XDR-TB cases had been confirmed in 45 nations. Each year an estimated 40,000 new cases of XDR-TB occur. An estimated 490,000 new cases of MDR-TB cases occur each year, with over 130,000 deaths.

The dual pandemics of HIV and TB are most common in Africa. South Africa is reported by the WHO and Stop TB partnership as having 28% of the global number of HIV-positive TB cases. Persons living with HIV and infected with the TB bacteria are up to 50 times more likely to develop active TB in their lifetime than persons who are not infected with HIV.

This week international TB conferences include the “Stop TB Partners Forum” in Brazil (Rio De Janeiro) from March 23-25. In Beijing, from April 1-3, a high level meeting with Health Ministers from many nations, particularly those with the highest M/XDR TB burdens, will be held.

Stop TB Partnership is a network of 700 stakeholders and its secretariat is based at the WHO. Stop TB has seven working groups that include: Advocacy, Communication and Social Mobilization; DOTS Expansion, MDR-TB, TB/HIV, New Drugs, New Diagnostics, and New Vaccines.

The Stop TB and WHO has as one target goal to decrease by half tuberculosis prevalence and deaths by the year 2015 compared with 1990. Currently, they report that progress toward this goal is behind schedule in Africa and Europe.

26 March 2009

Daniel R. Lucey, MD, MPH

A Pandemic Flu Vaccine granted marketing authorization in Australia but not in Europe

In Lyon, France, a press release today from the vaccines division of sanofi-aventis Group reported that its pandemic flu vaccine known as “Emerflu” “has “been granted marketing authorization from the Australian Therapeutic Goods Administration (TGA). Emerflu vaccine is now approved for the prevention of pandemic influenza in Australiaupon official declaration of a pandemic. Emerflu vaccine is intended to be manufactured and distributed with the identified pandemic strain and used in Australia in accordance with official Australian government guidance.”

One week ago, however, on March 19^th, the European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (CHMP) made the recommendation for the refusal of the marketing authorization for Emerflu in Europe, and provided an explanatory 2-page question and answer document on their website at: www.emea.europa.eu/pdfs/human/opinion/Emerflu_Q&A_15441009en.pdf

In response to the question “What is Emerflu?” the EMEA noted that it is a vaccine “suspension for injection that contains parts of influenza (flu) viruses that have been inactivated (killed). Emerflu contains a flu strain called ‘A/Vietnam/1194/2004 NIBRG_14’ (H5N1)”.

Human volunteers received two injections of Emerflu containing one of two different doses of haemaglutinin, spaced 21 days apart. The higher dose vaccine also contained a vaccine adjuvant containing aluminum called “alum”, in an effort to increase antibody production against the influenza virus (“antigen”) component in the vaccine.

The European Medicines Agency goes on to explain that Emerflu is a ‘mock-up’ vaccine. While this vaccine contains haemagglutinins from the H5N1 virus currently, “if a pandemic were to start, the virus strain in Emerflu would have been replaced by the strain causing the pandemic before the vaccine could have been used.”

In response to the question as to why a recommendation was made to refuse marketing authorization of Emerflu, the EMEA stated that the Committee (CHMP) “was concerned over the ability of Emerflu to trigger the production of enough antibodies against the flu virus. According to criteria laid down by the CHMP, a mock-up vaccine needs to bring about protective levels of antibodies in at least 70% of people for it to be considered suitable. Because antibody production following Emerflu administration was below this level in the main studies (less than 40% in participants aged below 60 years), the CHMP was concerned that Emerflu was not suitable for use as a mock-up vaccine.”

27 March 2009

Daniel R. Lucey, MD, MPH

Meningococcal Meningitis Cases Increase in the Meningitis Belt in Africa

On March 25 the World Health Organization (WHO) posted on their homepage (www.who.int) the information that since January 1st this year a total of 24,868 suspected cases of meningococcal disease have been reported from the “Meningitis Belt” of Africa. The bacteria that causes meningococcal disease is Neisseria meningitides, of which there are four main serogroups. Testing of cerebrospinal fluid (CSF) has established that most confirmed cases are serogroup A in the ongoing outbreak in Africa.

Approximately 85% of these meningococcal cases have been reported from northern Nigeria and Niger. Fewer cases have been reported from Burkina Faso, and other nations extending across the continent in the “Meningitis Belt”.

In Nigeria 17, 462 suspected cases, including 960 deaths (case fatality rate ~5.5%) have been reported to the WHO by the Ministry of Health. Mass immunization efforts with polysaccharide vaccine, known to be effective against serogroup A, have begun in order to counter the epidemic. In Niger 4, 513 suspected cases of meningococcal disease, including 169 deaths (case fatality rate 3.7%) have been reported by the Ministry of Health.

Meningococcal polysaccharide vaccine has been released to both Nigeria and Niger by the International Coordinating Group on Vaccine Provision for Epidemic Meningitis Control (ICG). Partners of the ICG include WHO, the International Federation of Red Cross and Red Crescent Societies, the UN Children’s Fund, and Medecins sans Frontieres (MSF). The emergency stockpile of vaccine was created with support from the Global Alliance for Vaccines and Immunization (GAVI) and the European Union (EU) Humanitarian Aid Office (ECHO).

30 March 2009

Daniel R. Lucey, MD, MPH

No Deaths in Nine Patients with Avian Influenza A (H5N1) Reported from Egypt in 2009

On 30 March the World Health Organization (WHO) posted on their avian flu website that the Egyptian Ministry of Health and Population reported to WHO their 9^th patient with H5N1 avian influenza since January 1, 2009. Notably, none of these 9 patients have died, in contrast to 23/51 patients (45%) from 2006-2008 in Egypt. ((www.who.int/csr/disease/avian_influenza/en/index.html).

There are likely multiple reasons for this admirable achievement of zero fatalities among these nine patients infected with a virus that typically has a very high case fatality rate of 62% worldwide (256 fatalities / 413 patients since 2003 in 15 nations). As an Infectious Disease physician reviewing the brief reports for each of these nine patients posted on the WHO website, this writer was impressed by the consistently short time interval (see table created below) given between the onset of illness symptoms and the time to hospitalization. In some cases, a short time interval to time of laboratory diagnosis of H5N1 virus infection was provided or implied. Also of note, in the final two patients a time interval of 0-1 days was stated until antiviral treatment with oseltamivir was started.

Illness Onset Hospitalization on WHO website Lab Diagnosis

9 January 10 January 14 January (by 14 Jan)

23 January 23 January 26 January (Mon) (by 26 Jan)

2 February 3 February 5 February (by 5 Feb)

6 February 7 February 9 February (Mon) (by 9 Feb)

25 February 28 February 2 March (Mon) 1 March

3 March 3-4 March 10 March 4 March

6 March 9 March 11 March 10 March

14 March 14 March 23 March (Mon) 18 March

23 March 24 March 30 March (Mon) 26 March

For the most recent two patients the very important information was included on the WHO website as to what day antiviral medical therapy was started (e.g., with oseltamivir) for the presumed or laboratory-confirmed H5N1 avian flu virus. Specifically, the patient with onset of illness symptoms (fever and headache) was started on oseltamivir the same day (March 14) at Assiut Fever Hospital. Similarly, the patient who became ill on 23 March was started on oseltamivir treatment the next day (24 March) when she was admitted to Qena Fever Hospital.

The time interval from illness onset until the start of oseltamivir treatment was not listed in these brief WHO clinical summaries for the other seven patients.

It would be useful to know the date of antiviral treatment initiation, and the date of laboratory diagnosis of H5N1 avian flu infection, for every patient. This information could provide better understanding of how to decrease the very high mortality rate of this disease.

Given the careful medical coordination of care throughout Egypt for patients with H5N1 avian flu infection since the disease was first reported there in March 2006, a detailed clinical publication from Egyptian clinicians and public health officials can be anticipated.

Clinically, one could argue that the single most important variable in predicting whether an H5N1 avian flu virus infection was going to be fatal is the time interval between onset of symptoms and therapeutic levels of anti-influenza medication(s) (e.g., oseltamivir).

Arguing against a chance occurrence to explain the case fatality rate being so low in Egypt in 2009 one can look at the WHO’s cumulative number of lab-confirmed cases and deaths, for Egypt and for the world. In contrast to the remarkable 2009 experience in Egypt, in 2008 Egypt reported that 4/8 patients (50%) with H5N1 avian flu infection died, in 2007 9/25 patients died (36%), and in 2006 10/18 (55.5%) of patients died. Overall, from 2006-2008 23/51 (45%) patients died in Egypt due to H5N1 avian flu virus infection.

The only other two nations reporting H5N1 avian flu human infections to the WHO to date in 2009 are China and Vietnam. China has reported 4/7 (57%) patients having fatal H5N1 infection, while Vietnam has reported 2/2 patient fatalities during the initial three months of this year. (According to the current WHO avian flu website Indonesia has not reported to WHO any patients diagnosed with H5N1 virus infection since January 1st this year, although an article online from the Associated Press in The Jakarta Post on 3 March 2009 by Irwan Firdaus reported 4/4 patients died of H5N1 avian flu virus on the island of Java in January-February 2009).

Lessons learned from Egypt in 2009 that have been associated with reducing the case fatality rate of H5N1 avian flu virus infection may be offered to other nations. There are multiple such lessons. These include, but are not limited to, strong political leadership and interministerial collaborations, early and sustained educational initiatives by the Ministry of Health and Population since the start of 2006, and clinical care protocols with emphasis on rapid diagnosis and treatment.

31 March 2009

Daniel R. Lucey, MD, MPH

FDA Licenses New Japanese B Encephalitis Vaccine

On 30 March 2009 the U.S. Food and Drug Administration (FDA) licensed a new vaccine against Japanese B Encephalitis (named IXIARO and made by the U.K. companyIntercell Biomedical). This will be the only available vaccine in the USA because the former vaccine (“JE-VAX”) is no longer being manufactured.

Compared with the older JE-VAX vaccine, IXIARO is made using tissue culture techniques, requires one less dose, and overall “was more tolerable and had fewer side effects” according to the FDA licensure summary yesterday.

Japanese B encephalitis virus is a flavivirus that is transmitted by mosquitoes, specifically Culex species. It is not spread from person to person. It is not endemic to the USA. According to the CDC “Japanese Encephalitis Fact Sheet’ this virus occurs not only in parts of Asia but also northern Australia, has a case-fatality ratio of 30%, and is the leading cause of viral encephalitis in Asia where 30,000-50,000 cases are reported each year.

Most infections with this virus are subclinical. It can, however, cause seizures, encephalitis, coma, as well as a very high case fatality rate.

According to the acting director of the Center for Biologics Evaluation and Research (CBER) at the FDA, Karen Midthun, M.D. “This vaccine offers protection for individuals who travel or live in areas where outbreaks are known to occur”.

This IXIARO vaccine is an important addition to the list of available FDA-licensed vaccines, particularly for military deployed to endemic parts of the world, expatriates and other residents living in certain (rural) endemic areas, and some travelers depending on the time of year and duration of exposure in endemic areas.

April 4, 2009

Daniel R. Lucey, MD, MPH

Levofloxacin Boxed Warning on Risk of Tendinitis and Tendon Rupture.

In a letter dated March 27, 2009 to Healthcare Professionals who had attended the October 26-28, 2008 Infectious Disease national meeting (ICAAC/IDSA) the Vice-President, Medical Affairs for the makers of the antibiotic LEVAQUIN (Levofloxacin) emphasized the ”Boxed Warning” that reads as follows:

“Fluoroquinolones, including LEVAQUIN, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants [See Warnings and Precautions]”.

Levofloxacin is a commonly used antibiotic that is approved for multiple clinical indications. In addition, a rare indication for which levofloxacin is approved is inhalational anthrax (post-exposure).The antibiotic’s package insert addresses this indication as follows:

“To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. The effectiveness of LEVAQUIN is based on plasma concentrations achieved in humans, a surrogate endpoint reasonably likely to predict clinical benefit. LEVAQUIN has not been tested in humans for the post-exposure prevention of inhalation anthrax. The safety of LEVAQUIN in adults for durations of therapy beyond 28 days or in pediatric patients for durations of therapy beyond 14 days has not been studied. Prolonged LEVAQUIN therapy should only be used when the benefit outweighs the risk.”

8 April 2009

Daniel R. Lucey, MD, MPH

No Deaths in 12 Patients with Avian Influenza A (H5N1) Reported from Egypt since January 1, 2009

Today the World Health Organization (WHO) posted on their avian flu website that the Egyptian Ministry of Health and Population reported their 10th, 11th, and 12th patients with H5N1 avian influenza since January 1, 2009. Notably, none of these 12 patients have died, in contrast to 23/51 patients (45%) from 2006-2008. (www.who.int/csr/disease/avian_influenza/en/index.html).

A short time interval of < 3 days was reported between the onset of illness and the time to hospitalization for 11 of the 12 patients. In some cases, a relatively short interval between hospitalization and time of laboratory diagnosis of H5N1 virus infection was provided, or implied based on the date of the WHO posting of the case (e.g., “by 14 Jan, by 26 Jan, by 5 Feb” in the table below created by this author based on the WHO case reports for the 12 patients).

Importantly, in four of the last five patients (in the table below) a time interval of 0-3 days was noted between illness onset and starting antiviral treatment with oseltamivir. The 12^th patient had a 12-day interval between illness onset 22 March and starting therapy with oseltamivir on 3 April. That patient was reported today to be in critical condition.

Illness Onset	Hospitalization	Lab Diagnosis	Antiviral started
9 January	10 January	(by 14 Jan)	Not stated
23 January	23 January	(by 26 Jan)	Not stated
2 February	3 February	3 February)	Not stated
6 February	7 February	(by 9 Feb)	Not stated
25-February	26 February	1 March	Not started
3 March	3-4 March	4 March	Not stated
6 March	9 March	18 March	14 March
23 March	24 March	26 March	24 March
27 March	30 March	(by 7 April )	30 March
31 March	1 April	(by 7 April)	1 April
22 March	28 March	(by 7 April	3 April

It would be informative to tabulate for each H5N1 patient the date of:

(1) Illness onset

(2) “Hospitalization” * (see below)

(3) Laboratory diagnosis of H5N1 avian flu infection

(4) Antiviral treatment initiation (with dose/frequency of drug(s))

This information could provide better understanding of how to decrease the very high mortality rate of H5N1 avian flu infection.

“Hospitalization” could be further detailed as the date(s) of entering the health care system initially, at either an outpatient clinic or inpatient facility, AND (whenever applicable) the date of transfer to an avian flu referral hospital or other health care facility.

9 April 2009

Daniel R. Lucey, MD, MPH

First Artemesinin Combination Therapy (ACT) to Treat Malaria in the USA approved by the FDA

The US Food and Drug Administration (FDA) on April 8^th approved for the first time in the USA an artemesinin class drug (“artemether”) in combination as a tablet with another antimalarial drug (“lumefantrine”) that acts via an independent mechanism. Together these two drugs are marketed as an oral tablet called “Coartem”. The manufacturer of Coartem is Novartis Pharmaceuticals in Basel, Switzerland.

Coartem is approved for:

Uncomplicated malaria
Patients who can take oral therapy (tablets).
Adults and children weighing at least 11 pounds (5 kilograms).
Malaria resistant to other treatments.

Coartem is not approved for:

Complicated malaria, or when intravenous therapy is needed.
Prophylaxis against malaria
Small children weighing less than 11 pounds (5 kilos).

In their news release posted on their website yesterday, the FDA reported that the “most common adverse reactions to Coartem shown in clinical trials in adults are headache, anorexia, dizziness, physical weakness (asthenia), joint pain (arthralgia) and muscle pain (myalgia).”

Of note, the FDA states that Coartem tablets are best taken with food that contains fat, in order to maximize absorption of the drug.

On the website of Novartis, the April 8^th press release on Coartem approval by the FDA stated that: “Coartem is a fixed-dose combination of two novel antimalarials. It is a highly effective three-day malaria treatment with cure rates of over 96%…even in areas of multi-drug resistance”.

On the World Health Organization (WHO) malaria website four Artemesinin Combination Therapies (ACTs) are recommended for treatment of uncomplicated P. falciparum malaria, of which Coartem (artemether-lumefantrine) is one. The other three are:

Artesunate + amodiaquine

Artesunate + mefloquine

Artesunate + sulfadoxine-pyrimethamine

Overall, approval of this ACT “Coartem” in the USA for treatment of uncomplicated malaria should be an important addition for clinicians treating patients, particularly those returning from parts of the world with Multi-Drug Resistant (MDR) malaria.

14 April 2009

Daniel R. Lucey, MD, MPH

Lack of fatal H5N1 Avian Flu infections in 31 patients under 10 years of age, compared with 23 deaths in 32 patients > 10 years of age, in Egypt since 2006.

Egypt has reported a total of 63 patients with laboratory-confirmed H5N1 avian influenza infection (23 fatal, 40 non-fatal cases) to the World Health Organization (WHO) between March 2006 and 8 April, 2009. A review by this author of each of the 63 case reports posted on the WHO avian flu website is summarized below, with a table and figure created to illustrate case fatality rates at different age groups. Of note, there were zero deaths in the 23 patients less than 5 years of age, and zero deaths in the 8 children who were 5-9 years of age. In contrast, all 23 deaths in Egypt were in the 32 remaining patients, ages 10-75 years.

By comparison, using worldwide data, the WHO reported that between 25 November 2003 and 24 November 2006 there were 12 deaths in 27 patients less than 5 years of age (44%), and 19 deaths in 29 patients (49%) ages 5-9 years with laboratory-confirmed H5N1 infections (WHO Weekly Epidemiologic Record No. 6, 9 Feb 2007 p. 46; table 6). Reasons for this apparent difference in mortality rates in the under 5 years and in the 5-9 year-old groups are uncertain at this point, and likely multifactorial if real (e.g., virologic, epidemiologic, therapeutic, and/or for other reasons).

Also of note, 10 of the 12 patients with H5N1 virus infection reported to date in 2009 have been less than 5 years of age, while one is 6 years old, and only one is an adult (38 years old). To date, none of these 12 patients have died, although two have been in critical condition. This age-distribution of non-fatal cases to date in 2009 would be consistent with a continuing pattern in Egypt since 2006 of zero fatalities in persons 0-9 years of age due to H5N1 virus infection.

A WHO avian flu expert and epidemiologist, John Jabbour, has been actively involved with the Egyptian Ministry of Health and Population (MOHP) since the first patient in Egypt was diagnosed with the H5N1 virus in March 2006. In a Reuters News article online 8 April 2009, written by Cynthia Johnston, he was quoted as stating: “There is something strange happening in Egypt. Why in children now and not in adults? We need to see if there are sub-clinical cases in the community”. Such a study is anticipated to begin soon in Egypt. Of note, Jabbour was also quoted stating: “There is no change in the virus at all in the virus strain in Egypt. It is the same since the beginning of the outbreak. There is no mutation, nothing.”

To this author, Jabbour’s comments sound balanced and helpful given current observations. Further studies to address the question of sub-clinical infections, and ongoing genetic analysis for significant mutations will be important.

24 April 2009

Friday

Novel Influenza Virus A (H1N1) with Genes of Swine, Avian, and Human origin causing infection in parts of California, Texas, and Mexico, with some person-to-person spread

In a rapidly evolving situation as of this evening (Friday, 24 April) information from the US CDC, the WHO, the Minister of Health of Mexico, and other sources can be highlighted as followed:

I. The US CDC has laboratory confirmation of eight (8) non-fatal human infections with a novel influenza virus, with 6 in southern California (San Diego County and ImperialCounty) and two (2) near San Antonio, Texas. The identification of more cases is anticipated in the USA.

II. The CDC media conference call yesterday, Thursday, 23 April at 3pm included data from Dr. Nancy Cox, Chief influenza virologist at the CDC, that this novel virus has genetic components from three different species: swine, avian and human. The written transcript of this teleconference yesterday quotes Dr.Cox as follows:

“So we have some gene segments that are North American swine influenza viruses. Some gene segments North American avian influenza viruses. One gene segment from a human influenza virus and two gene segments that are normally found from swine influenza viruses in Asia and in Europe.”

In the CDC’s MMWR Dispatch from April 21 reporting the initial two cases from the USA infected with this novel virus, it was stated that the neuraminidase and matrix genes are of swine influenza origin, but from viruses in swine in Europe/Asia and not North America. Which of the gene segments is of human origin was not stated in yesterday’s conference. Nor was the origin stated of the haemagglutinin gene, the influenza gene responsible for the dominant immune response against an influenza virus.

III. There is at least limited person-to-person spread according to the CDC, citing the father and daughter infected in California, and possibly the two teenagers near San Diego who attend the same school. Dr. Cox of the CDC stated yesterday in the same teleconference:

“So, we’re seeing basically a virus that appears to be spreading from person to person in humans and viruses have very similar genetic characteristics to each other”.

IV. The CDC has provided (April 20) interim guidance for clinical evaluation of persons with suspected swine flu on their website titled: Interim Guidance on Infection Control and Antiviral Recommendations for Patients with Confirmed or Suspected Swine Influenza A Virus Infection www.cdc.gov/flu/swine/recommendations.htm

V. CDC also advised: Clinicians should consider the possibility of swine influenza virus infections in patients presenting with febrile respiratory illness who:

Live in San Diego County or Imperial County, California or San Antonio, Texas or
Have traveled to San Diego and/or Imperial County, California or San Antonio, Texas or
Have been in contact with ill persons from these areas in the 7 days prior to their illness onset.

If swine flu is suspected, clinicians should obtain a respiratory swab for swine influenza testing and place it in a refrigerator (not a freezer). Once collected, the clinician should contact their state or local health department to facilitate transport and timely diagnosis at a state public health laboratory.

VI. Today the CDC published on their website (www.cdc.gov) another Morbidity and Mortality Weekly Report (MMWR) “Dispatch” that gives more detailed clinical and epidemiological information on the US patients with this “swine flu” virus infection.

VII. Today, the CDC held another media teleconference starting at 2:30pm. The acting Director of the CDC, Dr. Richard Besser, participated. It was reported that of the initial 14 samples tested at CDC-Atlanta from patients in Mexico with an influenza-like illness, seven (7) were positive for this swine flu virus. No clinical details were reported on these seven patients from Mexico. However, it was reported in this conference that the Minister of Health of Mexico had stated that at least some deaths were due to swine flu. (In the USA none of the 8 lab-confirmed patients have died. Only one, who was immunocompromised, required hospitalization).

VII. Early today the World Health organization (WHO) held a conference in Geneva regarding this situation. It was reported that the WHO had activated their emergency response command center. Later today the WHO posted on their website a summary update. Regarding Mexico they reported the following:

“The Government of Mexico has reported three separate events. In the Federal District of Mexico, surveillance began picking up cases of ILI starting 18 March. The number of cases has risen steadily through April and as of 23 April there are now more than 854 cases of pneumonia from the capital. Of those, 59 have died. In San Luis Potosi, in central Mexico, 24 cases of ILI, with three deaths, have been reported. And from Mexicali, near the border with the United States, four cases of ILI, with no deaths, have been reported.

Of the Mexican cases, 18 have been laboratory confirmed in Canada as Swine Influenza A/H1N1, while 12 of those are genetically identical to the Swine Influenza A/H1N1 viruses from California.

The majority of these cases have occurred in otherwise healthy young adults. Influenza normally affects the very young and the very old, but these age groups have not been heavily affected in Mexico.

Because there are human cases associated with an animal influenza virus, and because of the geographical spread of multiple community outbreaks, plus the somewhat unusual age groups affected, these events are of high concern”.

Certainly a number of critical questions remain, and some answers are likely to appear this weekend and over the coming days and week(s). A central issue is whether there is sustained and efficient human transmission of this novel influenza virus. If so, then the WHO would likely consider whether or not to raise their pandemic alert level and what that would mean if a large urban area is already involved with the outbreak in terms of potential interventions.

The WHO, Pan American Health Organization (PAHO), the US CDC, and the governments of Mexico and the USA are involved, among others. One can anticipate evolving interim guidance updates as more data becomes available day-by-day.

25 April 2009

Daniel R. Lucey, MD, MPH

CDC Confirms Two Swine Flu H1N1 cases in Kansas and WHO Chief Dr. Chan Declares Swine Flu Outbreak in Mexicoand USA a “Public Health Emergency of International Concern” per the International Health Regulations (IHR)

Updates on the ongoing rapidly evolving outbreak of swine influenza A (H1N1) infecting humans in at least three US states and parts of Mexico include:

Today the US CDC reported on their website late today that there are now 11 lab-confirmed cases in the USA: 2 in Kansas, 2 in Texas, and 7 in California. None of these 11 persons have died, and only 2 have required hospitalization. The 7^th patient confirmed in California was reported today.
Today the Director of the New York City Health Department, Dr. Thomas Freiden, gave a televised press conference at approximately 4:15pm (seen on CNN) that reported 8 students at a high school in the Queens borough of NY City had positive lab tests for an Influenza A virus that he suspected could be the same swine flu virus reported from California, Texas, and Mexico; however, lab-confirmation is pending the results of definitive tests at CDC. None of these 8 persons suspected to have swine flu have required hospitalization.
Today the World Health Organization (WHO) Director-General, Dr. Margaret Chan, officially declared this swine influenza A (H1N1) a “Public Health Emergency of International Concern” (PHEIC). This specific term is described in the recent International Health Regulations (IHR 2005), a legally binding document signed by 194 nations that went into effect 15 June 2007. The IHR (2005) document is posted on the WHO website. Annex 2 on page 42 of this document addresses the decision process as to when an event must be reported to the WHO as a potential PHEIC, under Article 6 of the IHR. As of today, this declaration specifically means that nations are to increase their surveillance for this novel swine influenza, according to the WHO.
Today the WHO’s Expert Advisory Committee met and decided not to change the pandemic alert level (currently at level 3), although this decision could change in the near future as more data becomes available day-by-day on the situation with this novel influenza virus.
The gene sequences of this novel virus were made public and can be found, along with multiple other useful documents and updates, on the WHO swine influenza website.
Photos appeared online today and on the front page of the New York Times showing persons of the general population in Mexico City wearing masks. (To this author such photos were similar to those in Hong Kong during SARS in 2003 and were quite understandable in both situations). Very important “lessons learned” are and will continue to be offered by the response to this outbreak in Mexico and the several US states already involved with case investigations.
Neither the WHO nor US CDC issued any travel restrictions today.
An increasing number of persons were reported to have been hospitalized in Mexico today for possible swine influenza. Ongoing lab tests and epidemiologic assessments are being carried out. A more accurate case fatality rate (CFR) can be determined through these assessments. Efforts to limit spread of the virus continue to be taken by the Mexican Government. These include, but are not limited to keeping schools, offices, and museums closed. Public gatherings are being minimized.

Additional data are expected tomorrow, such as the results of the CDC lab tests on the 8 high school students in New York City with an as-yet unidentified Influenza A virus infection, as well as updates from Mexico, Kansas, Texas, and California.

Follow-up to the WHO’s Director General Dr. Margaret Chan’s declaration of this swine influenza A (H1H1) outbreak as a “Public Health Event of International Concern (PHEIC) under the International Health Regulations (IHR) is also anticipated.

26 April 2009

Daniel R. Lucey, MD, MPH

Sunday 10:30pm

Canada confirms 6 cases of swine flu, NYC 8 cases and Ohio 1 case as US Declares Public Health Emergency during televised White House Press Briefing Sunday

The World Health Organization (WHO) held another (daily) swine flu press conference on Sunday and in the transcript was noted to maintain its pandemic alert phase at 3. The next meeting was scheduled for this Tuesday, in part again to consider the rapidly evolving situation in Mexico, as well as the USA (20 confirmed cases), and Canada (6 cases). Dr. Fukuda was quoted speaking for the WHO in Geneva. He noted that of 51 specimens from 51 patients in Mexico, 16 had tested positive in the national reference lab in Winnipeg. The clinical condition of these 16 patients was not discussed, nor how many of these 16, if any, overlapped with the 7 swine influenza A (H1N1)-positive tests from patients in Mexico tested at the US CDC Atlanta.

The WHO also posted on their website a diagram and updated text definitions for each of the WHO pandemic phases 1-6, with 6 being a global epidemic or “pandemic”, a condition not yet documented to exist. There appears to be quite reasonable grounds, however, for the WHO Expert Advisory Committee to continue to meet often to address whether to elevate the pandemic phase to 4, if community-level outbreaks due to SUSTAINED person-to-person spread are proven to exist in Mexico already. IF a second nation (e.g., the USA or Canada) in the same WHO region (e.g., of the Americas) were also to have proven community-level outbreaks with this novel flu virus then the criteria would appear to have been met for Phase 5.

Canada reported late in the day 6 lab-confirmed cases of the same “swine flu”. Nova Scotia had 4 cases, at least some of whom had an epidemiological link (“epi-link”) to recent travel in Mexico. British Columbia had two lab-confirmed cases.

At 12:30pm the White House held a special televised press conference to address the evolving swine flu situation and responses. A total of 20 cases were confirmed in the USA: 8 in NY City, 7 in California, 2 in Texas, 2 in Kansas, and 1 in Ohio. The Director of the Department of Homeland Security (DHS), Ms. Janet Napolitano, was introduced as a speaker and identified as the person in charge of the overall federal response to this outbreak. The Acting Director of the CDC, Richard Besser, MD, was also introduced as a speaker at the press conference and addressed the medical and public health issues.

This swine flu outbreak was designated as a Public Health Emergency by the US Government. Thus, specific results can follow, from a legal and government perspective. For example, it was announced that the US would release 25% of the 50 million treatment courses of oseltamivir (Tamiflu) held in the Strategic National Stockpile (SNS). A potential result of this US declaration is the ability to invoke the legal framework for Emergency Use Authorization (EUA) for public health countermeasures against this novel influenza outbreak.

One can anticipate that the important data from Mexico will be available soon regarding laboratory diagnostic results of persons who have died, as well as persons who are ill and/or have recovered, as well as persons with asymptomatic infection with this novel virus. This data will allow a more accurate initial determination of the critically important case-fatality rate (CFR), and modeling of the severity of this epidemic and resultant scale of public health responses.

27 April

Daniel R. Lucey, MD, MPH

WHO Raises Pandemic Alert to Phase 4 due to swine influenza A (H1N1); Infections and some Deaths Continue in Mexico, US Cases Increase to 40 (none fatal), and Confirmed Case(s) Occur in Spain and Scotland. Will this Virus Become Established in the Southern Hemisphere by their Upcoming Flu Season (June-August, 2009)?

The Director-General of the World Health Organization, Dr. Margaret Chan, declared in a one-page statement posted April 27^th on the WHO website (www.who.int/mediacentre/news/statements/2009/h1n1_20090427/en/index.html

that on the advice of the WHO Emergency Committee advising her on the epidemic of swine influenza A (H1N1), she raised the level of influenza pandemic alert from the current Phase 3 to Phase 4.

Phase 4 is characterized by verified human-to-human transmission of an animal or human influenza reassortant virus able to cause “community-level outbreaks” …Phase 4 indicates a significant risk of a pandemic but does not necessarily mean that a pandemic is a foregone conclusion.”

An excellent one-page color diagram with the latest (this week) definitions of WHO phases of pandemic alert are posted on their website at: www.who.int/csr/disease/avian_influenza/phase/en/index.html

In the USA a total of 40 cases of lab-confirmed swine influenza A (H1N1) were posted on the daily CDC updated website. None of these cases have been fatal, and nearly all have recovered without hospitalization. The 20 new cases reported since Sunday were in the NY City (Queens) high school cluster that included persons who had traveled to Mexico.

In my opinion, there will be deaths in the USA due to this novel virus, as has occurred in Mexico.

We known the virus is reported to be genetically identical in both countries. The most likely explanation at this point for the absence of deaths in the USA, in contrast to Mexico, is that many more infections have occurred in Mexico. If the US had as many infections with this new virus as Mexico has had, then there would already be some deaths in the USA.

To illustrate by a purely hypothetical example: If a novel virus infects 1,000 people in country A, and kills 10 of these 1,000 persons, then it has a case-fatality rate (CFR) of 10/1000 = 1% (or 1 in 100). Thus, if there are only 40 persons infected with this same virus in country B, it is not surprising that none of these 40 persons have died.

In Europe, one lab-confirmed case was reported from Spain (non-fatal), and two confirmed cases were reported in Scotland (where both were reported to be recovering well in hospital).

The Food and Drug Administration (FDA) posted a 2-page document of far-reaching importance on their website (www.fda.gov) April 27 titled “FDA Authorizes Emergency Use of Influenza Medicines, Diagnostic Test(s) in Response to Swine Flu Outbreak in Humans”. In response to requests from the CDC the FDA reported issuing “EMERGENCY USE AUTHORIZATIONS (EUAs) to expand the availability of anti-influenza drugs and new lab diagnostic tests for this swine flu virus: http://www.fda.gov/bbs/topics/NEWS/2009/NEWO2002.html

For example, “The EUAs allow for Tamiflu also to be used to treat and prevent influenza in children under 1.” Tamiflu (oseltamivir, an oral anti-influenza drug) is not FDA-licensed for use in children under one year. But now it can be used for children < 1 year of age with this FDA Emergency Use Authorization (EUA).

In addition, this FDA EUA allows for both the oral Tamiflu (oseltamivir) and the inhaled anti-flu drug zanamivir (Relenza) to be “distributed to large segments of the population without complying with the label requirements otherwise applicable to dispensed drugs, and accompanied by written information pertaining to the emergency use. They may also be distributed by a broader range of health care workers, including some public health officials and volunteers, in accordance with applicable states and local laws and/or public health emergency responses.”

Moreover this FDA EUA “allows the CDC to distribute the swine flu test to public health and other qualified laboratories that have the needed equipment and the personnel who are trained to perform and interpret the results.”

Will this Novel Swine Flu Virus Become Established in the Southern Hemisphere by their Upcoming Flu Season (June-August, 2009)?

One can hope that this novel influenza virus will sharply decrease its transmission during the upcoming warmer (summer) months June-August in the northern hemisphere, by analogy to seasonal human influenza, and the SARS coronavirus in 2003.

At the same time, however, it is critically important to recall that, generally speaking, the SOUTHERN Hemisphere will be having their upcoming winter influenza season during these same June-August months (while recognizing that some nations have two seasonal peaks of influenza (e.g., Hong Kong) and others close to the equator may have some cases year-round).

Thus, if the current novel swine flu virus spreads between now and the upcoming influenza season in the Southern Hemisphere (June-August 2009), then conceivably widespread “community-level outbreaks” due to sustained human-to-human transmission could occur in two or more nations in one WHO region (i.e., the defining characteristic of WHO Phase 5) in the SOUTHERN Hemisphere.

If this does occur in the SOUTHERN Hemisphere, then in the Northern Hemisphere’s next autumn-winter (September 2009-March 2010), this swine flu virus H1N1, or an evolved/mutated version, could be transmitted back with subsequent WHO Phase 5 spread, or even true pandemic spread i.e., WHO Pandemic Phase 6.

Thus, it is in everyone’s interest to maximize efforts immediately to diagnose and treat each patient anywhere in the world with this novel swine flu virus infection, and prevent (or mitigate) the transmission of this virus anywhere it occurs as soon as possible.

29 April 2009

Daniel R. Lucey, MD, MPH

WHO Raises Pandemic Alert to Phase 5 (Pandemic is “Imminent”) as US Cases Increase to 91 in 10 States, and Nine Nations Confirm Cases including New Zealand in the SOUTHERN Hemisphere. WHO Hosts Meeting on Evolving Clinical and Epidemiological Facts.

The Director-General of the WHO, Dr. Margaret Chan, held a live press conference from Geneva at ~ 4:15pm (ET) to announce the increase to Pandemic Phase 5 based on community-level outbreaks in Mexico and the USA of the novel influenza A (H1N1) virus (until yesterday referred to as “swine flu”). According to the updated WHO Pandemic Phase definitions, Phase 5 means that an influenza pandemic (Phase 6) is “imminent”.

Globally, WHO reported nine (9) nations with lab-confirmed infections with this new virus. Only Mexico and the USA have confirmed deaths due to this virus so far. The first death in the USA occurred yesterday in a 23 month-old child from Mexico City who was visiting Texas with family, became ill, and was hospitalized.

Overall, the WHO data are: USA (91 cases with 1 death), Mexico (26 cases with 7 deaths),Canada (13 cases), UK (5 cases), Spain (4 cases), Germany (3 cases), New Zealand (3 cases), Israel (2 cases), and Austria (1 case).

The WHO today held a special meeting to discuss the specific clinical, epidemiological, and virological data from nations, including the USA and Mexico, that have patients infected with this novel virus. The results are expected to be posted on the WHO website soon, hopefully within 24 hours. This information will be very helpful to clinicians and public health officials as well as other emergency responders and planners around the world.

In the USA the CDC reported an increase from 64 to 91 lab-confirmed cases yesterday, in ten states: New York (51 cases), Texas (16), California (14), Michigan (2), Kansas(2), Massachusetts (2), Ohio (1), Indiana (1), Arizona (1), Nevada (1).

In a live televised press conference at 3pm (ET) the Secretary of the Department of Homeland Security (DHS), the overall lead federal official for this outbreak, and the newly-confirmed Secretary of Health and Human Services (HHS) stated that anti-influenza medications and other emergency supplies from the US Strategic National Stockpile (SNS) were being distributed across the entire nation.

The US Federal Response Pandemic Stage remained at zero (0) on the official government website www.pandemicflu.gov in the morning. It can be anticipated that the question of the applicability of this US staging system for this specific pandemic influenza threat will be reviewed and news of the outcome of the review disseminated soon.

As noted in this newsletter two days ago (Monday, April 28) the Southern Hemisphere will begin their seasonal influenza season in their winter months of June, July, and August. Thus, if this novel influenza A (H1N1) virus becomes established in the Southern Hemisphere now, then it may spread extensively during June-August. To date, this has not occurred. New Zealand is the only nation with lab-confirmed cases so far in the Southern Hemisphere.

The threat exists that this novel virus could mutate or recombine with other human influenza, or avian influenza viruses if it spreads widely in the human population globally. Such a recombination event could include the acquisition of an oseltamivir (Tamiflu)-resistant neuraminidase from another human influenza H1N1 virus.

If the current novel virus becomes dominant in the Southern Hemisphere from June to August, then it may well become the dominant influenza virus in the Northern Hemisphere as well.

Hopefully, this novel influenza A (H1N1) virus will not become resistant to the antiviral drug oseltamivir (Tamilfu), as recently occurred, over the past two years, in both the northern and southern hemisphere with seasonal human influenza A (H1N1).

May 1, 2009

Daniel R. Lucey MD, MPH

Key differences between the new influenza A (H1N1) virus from this 2009 outbreak and the usual yearly (seasonal) human influenza A (H1N1) virus

	New Influenza A H1N1 (2009)	Yearly Influenza A H1N1

Oseltamivir (Tamiflu) *sensitive*?	*YES*	No
Vaccine Exists?	No	Yes
Human Immunity?	No	Yes
Human Infections known prior to 2009	No	Yes
Hemagglutinin (H1) origin	Swine influenza virus	Human Influenza virus

4 May 2009

Daniel R. Lucey MD, MPH

Will Survivors of the New Influenza A (H1N1) 2009 Virus be Immune to Re-infection, Protected from Severe Disease if Infected with a Related Flu Virus, and/or Able to Donate Immune Plasma? Lab-Confirmed Cases reach 1,085 with 26 Deaths, in 21 Nations and 36 US States.

Looking ahead as the new Influenza A (H1N1) 2009 virus continues to be confirmed in more persons in North America, Europe, Asia, South America, the Middle East, and New Zealand a crucial set of related questions will surely be asked soon, namely: Will Survivors of the New Influenza A (H1N1) 2009 Virus be Immune to Re-infection, Protected from Severe Disease if Infected with a Related Flu Virus, and/or Able to Donate Immune Plasma?

These questions, while difficult to answer today, will need to be answered as the coming winter influenza months in the Southern Hemisphere approach, and the Fall-Winter months approach in the Northern Hemisphere. Already, some potential analogies are being drawn between the current Spring 2009 new Influenza A (H1N1) virus outbreak (WHO Phase 5 of 6) and the relatively mild new Influenza A (H1N1) virus in the Spring (Northern Hemisphere) of 1918 that was followed in the Fall of 1918 by a much more fatal Influenza A (H1N1) pandemic.

These questions have been raised in a number of publications, and in slide presentations at the International Emerging Infectious Disease conference (IMED 2007) and US FDA, as well in discussions with the WHO, US NIH, in a letter to the Washington Post April 29, 2006, and in a Newsletter in this space May 2, 2006 (1-4).

For example, Barry and colleagues concluded in a paper in the 15 Nov 2008 Journal of Infectious Diseases that “Exposure to influenza in the spring and summer of 1918 provided mortality and morbidity protection during the fall pandemic wave. The intensity of the first wave may have differed across US cities and countries and may partly explain geographic variation in pandemic mortality rates in the fall. Pandemic preparedness plans should consider that immune protection could be naturally acquired during the first wave of mild influenza illness.”

Depending on the extent of spread of the new Influenza A (H1N1) this year and whether it reappears in the Fall, the same hypothesis from 1918 may be tested in the Spring and Fall of 2009.

12 May 2009

Daniel R. Lucey MD, MPH

WHO assesses the severity of an influenza pandemic, as Phase 5 is maintained for this novel Influenza A (H1N1) with 5,251 confirmed cases (61 fatal) in 30 nations

The issue of disease severity in assessing an influenza pandemic was discussed in the May 11 WHO daily press conference, and also in a 2-page document posted on the WHO homepage for the current novel Influenza A (H1N1) epidemic at: www.who.int/csr/disease/swineflu/assess/disease_swineflu_assess_20090511/en/index.html

In this document WHO addresses “properties of the virus”, “population vulnerabilities”, “subsequent waves of spread” and “capacity to respond” as key considerations in assessing the severity of an influenza pandemic. They concluded by providing an interim assessment of the current situation with the novel Influenza A (H1N1) epidemic, still at WHO Phase 5, meaning it is not a pandemic at this time, but one is considered to be “imminent” (see today’s WHO revised “Levels of pandemic alert” document at: www.who.int/csr/disease/swineflu/frequently_asked_questions/levels_pandemic_alert/en/index.html)

WHO noted that all three influenza pandemics of the 20^th century were “mild” when they began in 1918, 1957, and 1968. As is often cited, the 1918 pandemic had a much more lethal second wave during the Fall in the Northern Hemisphere. The 1957 pandemic “started mild, and returned in a somewhat more severe form, though significantly less devastating than seen in 1918.” The 1968 pandemic remained mild in most nations.

In addition to the intrinsic virulence of the virus, WHO stated that multiple other factors impact the overall severity of a pandemic. Such factors include morbidity and mortality due to the virus that focuses on one or more specific age groups (e.g., young adults, children, or the elderly), contagiousness of the virus, speed of national and international spread, and the health care infrastructure remaining functional or to being overwhelmed.

Several key points made by the WHO regarding the current situation with the novel Influenza A (H1N1) epidemic included:

“H1N1 appears to be more contagious than seasonal influenza. The secondary attack rate of seasonal influenza ranges from 5% to 15%. Current estimates of the secondary attack rate of H1N1 range from 22% to 33%.”
In the outbreaks in the USA and Mexico so far, “the youth of patients with severe or lethal infections is a striking feature…”
“In terms of population vulnerability, the tendency of the H1N1 virus to cause more severe and lethal infections in people with underlying conditions is of particular concern…the prevalence of chronic diseases has risen dramatically since 1968, when the last pandemic …occurred…WHO estimates that 85% of the burden of chronic diseases is now concentrated in low-and middle-income countries.”
Scientists are concerned about possible changes in the virus in the upcoming southern hemisphere’s flu season.
Any impact of the novel H1N1 virus on the avian H5N1 influenza virus is unpredictable at this time.

18 May 2009

Daniel R. Lucey MD, MPH

Will the new Influenza A (H1N1) virus continue to spread this summer in the Northern Hemisphere? Cases total 8,829 with 74 deaths in 40 nations, cases in Japan jump from 7 to 125, and still no confirmed cases in Africa.

The Canadian Press carried an article online from Sunday, May 17, titled “Swine Flu spread in North America may extend into summer, experts say” and the same possibility was acknowledged today (May 18) during the US CDC press conference.

Dr. Allison McGeer, a respiratory disease expert renowned for helping to coordinate Toronto’s response to SARS in 2003 was cited in The Canadian Press article as follows: “McGeer says abnormal flu activity levels for this time of year are making her question “the delusion that this was actually going to quiet down and we weren’t going to have a first wave” over the late spring and summer.”

McGeer was also quoted as stating that the amount of infection with the novel H1N1 virus is “very clearly starting to increase. I suppose it could shut itself off at any given time. But the last couple of days look like we’re going to see a (flu) season…In Toronto, at least, I think we’re gone”.

Similarly, Dr. Arnold Monto from the University of Michigan was quoted in the same article as commenting he also is concerned about transmission continuing into the summer: “We are seeing a fair amount of circulation of the swine flu virus. And I’m not yet convinced that it’s going to go away completely. It may dampen down a bit as schools close. But I think we’re still seeing increasing transmission in the U.S.”

Dr. Anne Schuchat, from the U.S. CDC, responded to a question from Richard Knox at today’s press conference by stating: “We wonder whether this strain will continue during the summer, and give us more of a summer influenza pattern. This is certainly a possibility. It is not something I can predict. Most years, the seasonal influenza strains have very reduced amounts here in the northern hemisphere. Unfortunately, we don’t know whether we’ll get a break this summer with this virus. We’ll be looking there and also in the southern hemisphere where we expect there may be an important increase of this virus.”

Over the weekend there were 118 new lab-confirmed cases in Japan, mostly in young people, including non-travelers. Thus, many schools were closed in the areas of Osakaand Kobe. The WHO was continuing to monitor for community-level transmission in Japan as well as Spain (103 cases) and the UK (101 confirmed cases). Such transmission in either the western Pacific or European WHO regions, in conjunction with the proven community-level spread in North America, would meet current criteria for changing from WHO Phase 5 (“imminent pandemic”) to Phase 6 (actual pandemic).

Today marked the opening of the annual World Health Assembly. The threat of pandemic influenza, sharing of viral isolates and future novel influenza vaccine(s) are topics likely to be discussed at length.

27 May 2009

Daniel R. Lucey MD, MPH

Still no confirmed case in Africa of the novel H1N1 flu virus as WHO reports 13,398 cases in 48 nations, and WHO recommends virus for novel H1N1 vaccines

As of this morning the World Health Organization (WHO) has posted on a global map showing the 48 nations with a total of 13,398 cases of lab-confirmed novel H1N1 infections: http://www.who.int/csr/don/h1n1_20090527_0800.jpg

Strikingly absent are any confirmed cases from the continent of Africa. Cases have been reported from the Americas, Europe, Oceania, and Asia. Information on this novel virus and preparedness measures such as distribution of the anti-influenza drug “oseltamivir” (“Tamiflu”) and personal protective equipment (“PPE”) across Africa have been noted by WHO officials. Both WHO regional offices for Africa have updated Information on their websites, including in several languages:

Eastern Mediterranean Regional Office (EMRO): http://www.emro.who.int/csr/h1n1/

WHO Regional Office for Africa: http://www.afro.who.int/

Given the high level of alertness that nations in Africa have for human cases of avian flu H5N1 (e.g., with documented cases in Egypt, Nigeria, and Djibouti), as well as yearly monitoring for seasonal influenza (e.g., in 2008 South Africa documented oseltamivir-resistant seasonal influenza A (H1N1)), one could anticipate detection of this novel H1N1 virus soon in Africa. As with other parts of the world, these initial infections will occur most likely via travelers from H1N1-infected areas.

Thorough surveillance testing as well as interventions against this novel H1N1 virus in Africa, from the beginning of the highly predictable outbreaks, will be essential to minimize the morbidity and mortality of this virus in Africa.

In addition, such surveillance and tracking of the new virus in Africa, once it appears anywhere on the continent, will help the global effort to monitor for changes in the virus that could impact vaccine development and antiviral efficacy.

International partnerships should be strengthened now in anticipation of these novel H1N1 influenza virus outbreaks occurring in Africa very soon.

On another topic, on May 26 the WHO posted at the following URL (http://www.who.int/csr/resources/publications/swineflu/vaccine_recommendations/en/index.html) a recommendation on selection of a specific novel H1N1 virus related to an isolate from California be used for potential vaccine development:

“The majority of the novel influenza A (H1N1) isolates are antigenically and genetically related to the A/California/7/2009 (H1N1) v virus. Should vaccines be prepared against the

novel influenza A (H1N1) virus, it is therefore recommended that vaccines contain the following:

An A/California/7/2009 (H1N1)v ‐like virus

WHO Collaborating Centres (WHO CCs), Essential Regulatory Laboratories (ERLs) and other partners are developing high‐growth reassortant A/California/7/2009 (H1N1)v‐like viruses. WHO will announce on its website the availability of these reassortants as soon as they are available.”

28 May 2009

Daniel R. Lucey MD, MPH

Egypt Provides H5N1 Avian Flu Vaccine Virus Clade 2.2.1

The World Health Organization (WHO) posted on its avian flu (H5N1) website today two updates from Egypt. The first involved two new cases of H5N1 avian flu infection. Both were 4 year-old children. They had onset of symptoms May 23-24. The diagnosis was confirmed May 26 by the Egyptian Central Public Health Laboratories. Both were admitted to the same Fever hospital, treated with the anti-influenza oral neuraminidase medication “oseltamivir” (Tamiflu), and were reported in stable condition.

The relatively short time from onset of symptoms until the institution of effective anti-influenza therapy is typical for many of the children with H5N1 infection in Egypt, and is likely to contribute to their relatively low case-fatality rate.

Also, the WHO announced today that a new recombinant H5N1 vaccine virus was now available “thanks to the Ministry of Health and Population of Egypt for providing the virus specimens”. This virus is from clade 2, and is specifically subclade 2.2.1. It is referred to as A/Egypt/2321-NAMRU3/2007, and is “available for distribution, under a Material Transfer Agreement (MTA)”.

This candidate vaccine virus was developed in collaboration with the WHO Influenza Center at the US CDC in Atlanta.

Such H5N1 virus isolates are extremely important for potential vaccine development, particularly from parts of the world where the virus is known to be still quite active in causing human infections.

The only US FDA-licensed H5N1 vaccine is based on a clade of the virus that circulated mostly in parts of SE Asia (Clade 1, Vietnam 2004). Clade 1 did not spread across SW Asia and into Africa as did clade 2.2. The US has stated as a goal the development of H5N1 vaccines against different clade 2 viruses in addition to clade 1 H5N1 viruses, given that cross-clade protection is considered partial at best.

4 June 2009

Daniel R. Lucey MD, MPH

Australia reports jump to 876 cases of novel H1N1 flu infection, mostly in Victoria, while Egypt and Saudi Arabia report first cases in travelers

Today the Australian Department of Health and Ageing posted a 5pm update that reports a total of 876 cases of the novel H1N1 influenza virus across the country. The majority of these patients are in Victoria, where a total of 752 cases have been diagnosed. New South Wales (NSW) has the next largest number of cases with 74. The response level in Victoria has been elevated from “Contain” to “modified Sustain Phase”. In the other states and territories of Australia the level has been maintained at “Contain”. A degree of community-level spread of the virus in Victoria is evident given that not all these cases are in travelers, and the total number of cases has been rising sharply this week.

The H1N1 homepage for the Australian Department of Health and Ageing, with several daily updates, can be found at: www.healthemergency.gov.au/internet/healthemergency/publishing.nsf/Content/home-1

Precisely how the World Health Organization (WHO) will respond officially via public announcement regarding these evolving transmission events in Australia, as well as those in some parts of South America (e.g., Chile) and Europe (e.g., UK) is uncertain. During the WHO weekly (each Tuesday) press conference on June 2^nd, Dr. Fukuda discussed that they were getting closer to declaring Phase 6 (an actual flu pandemic).

Importantly, however, Dr. Fukuda also emphasized that WHO, with advice from its expert consultants constituted from over 20 nations, plan to provide more specific guidance to countries on what to do if differently if Phase 6 is declared by the Director-General of the WHO, Dr. Margaret Chan. This additional guidance would be calibrated to the current degree of “severity” as assessed most likely in terms not only of individual clinical outcomes, but also in terms of international public health and economic impact.

Dr. Fukuda noted that such assessments of severity may differ between nations now, as well as in the future as the virus evolves over time. Dr. Fukuda’s complete June 2^ndtranscript can be read at: www.who.int/mediacentre/influenzaAH1N1_presstranscript_20090602.pdf

The total number of novel H1N1 cases reported to the WHO is 19,273, in 66 nations, with 117 deaths as of the latest update June 3. The Eastern Mediterranean Regional Office (EMRO) of the WHO has on its novel H1N1 website today a brief description of the first lab-confirmed patients in Egypt and Saudi Arabia. The patients are travelers from the USA (to Egypt), and from the Philippines (to Saudi Arabia). The H1N1 website for EMRO is: www.emro.who.int/csr/h1n1

As discussed in this forum on several occasions, previously there was not a single lab-confirmed case diagnosed anywhere in Africa. This first patient was identified as having a fever at entry to the Cairo airport by use of a thermal scanner that is explicitly used for each individual arriving passenger. She was admitted to the renowned Abbassia Fever Hospital in Cairo for care. One can anticipate that other travelers will be identified with this novel H1N1 virus in Africa just as in the Americas, Europe, Asia, and Australia.

6 June 2009

Daniel R. Lucey MD, MPH

Morocco Reports its 2^nd case of Novel Influenza A (H1N1), and Egypt its 23^rd Case, totaling 25 lab-confirmed cases in Africa

Today the World Health Organization (WHO) Eastern Mediterranean Regional Office (EMRO) reported on their daily update of novel Influenza A (H1N1) cases that Moroccohas now reported its second lab-confirmed case. Morocco joins Egypt as the only two nations in Africa to date that have reported lab-confirmed cases of infection with this novel virus.

According to this same update, Egypt now has 23 lab-confirmed cases. The complete daily updates from EMRO can be found at: http://www.emro.who.int/index.asp

EMRO reports a total of 74 lab-confirmed cases. None have been fatal. These 74 cases are distributed across the following 8 nations: Kuwait (18 cases), United Arab Emirates (1), Bahrain (8), Lebanon (9), Egypt (23), Saudi Arabia (11), Palestine (2), and Morocco (2).

Of note, EMRO’s assessment states that all 74 cases are travel-related. None are the result of local transmission. Thus, there are no known cases of secondary transmission or community-level spread of this new virus in any of the EMRO nations.

EMRO also noted that a four-day training course for Regional Outbreak Alert and Response Network began on 15 June at EMRO.

Outside of EMRO, other nations in Africa, such as Gambia and Namibia, have confirmed earlier this month receiving from WHO anti-influenza medications (e.g., oseltamivir (Tamiflu)) and personal protective equipment (PPE) including masks, gowns, gloves, and other related material.

Such preparedness measures, virus surveillance, and rapid clinical management of patients with this novel Influenza A (H1N1) should help mitigate the initial impact of this virus both in Africa and in the Middle East. Enhanced surveillance and support from WHO will hopefully continue during this critically important time. Eventual community-level spread of this pandemic influenza virus is likely to occur on all continents.

The clinical and economic impact of the pandemic virus may be more severe in some nations and populations than others, as noted by, among others, the WHO Director-General Dr. Margaret Chan.

11 June 2009

Daniel R. Lucey MD, MPH

Phase 6 Declared by WHO for Novel Influenza A (H1N1) Based on International Spread at the Community Level

This afternoon, Dr. Margaret Chan, the Director-General of the World Health Organization (WHO) declared the novel influenza A (H1N1) to have triggered a pandemic (“Phase 6” in the 6 phase WHO classification system) based solely on community-level person-to-person transmission in at least two WHO regions.

WHO reported that as of today 74 nations have reported a total of 28, 774 cases, and 144 deaths. In addition to the well-known outbreaks in North America, Chile has reported 1,694 cases (2 deaths), Australia 1,307 cases (0 deaths), the UK 822 cases (0 deaths), and Japan 518 cases (0 deaths). Notably, on the continent of Africa only Egypt has reported confirmed cases (10, with 0 deaths), most of whom are American students in Cairo.

Dr. Chan emphasized that we are witnessing and monitoring in real-time the longitudinal unfolding of an influenza pandemic, and noted that its “moderate” severity could change over time, including in less-developed nations:

“Globally, we have good reason to believe that this pandemic, at least in its early days, will be of moderate severity. As we know from experience, severity can vary, depending on many factors, from one country to another”…Finally, and perhaps of greatest concern, we do not know how this virus will behave under conditions typically found in the developing world. To date, the vast majority of cases have been detected and investigated in comparatively well-off countries”.

Dr. Chan also already advised anticipation and preparation for a second pandemic wave:

“Countries should prepare to see cases, or the further spread of cases, in the near future. Countries where outbreaks appear to have peaked should prepare for a second wave of infection”.

In addition, the WHO posted on their H1N1 influenza website http://www.who.int/csr/disease/swineflu/frequently_asked_questions/levels_pandemic_alert/en/index.html a document that was titled “What is Phase 6?”

This document explicitly addressed the recurring issue of the “severity” assessment of this virus and the pandemic it has started:

“What about severity?

At this time, WHO considers the overall severity of the influenza pandemic to be moderate. This assessment is based on scientific evidence available to WHO, as well as input from its Member States on the pandemic’s impact on their health systems, and their social and economic functioning.

The moderate assessment reflects that:

Most people recover from infection without the need for hospitalization or medical care.

Overall, national levels of severe illness from influenza A (H1N1) appear similar to levels seen during local seasonal influenza periods, although high levels of disease have occurred in some local areas and institutions.

Overall, hospitals and health care systems in most countries have been able to cope with the numbers of people seeking care, although some facilities and systems have been stressed in some localities.

WHO is concerned about current patterns of serious cases and deaths that are occurring primarily among young persons, including the previously healthy and those with pre-existing medical conditions or pregnancy.

Large outbreaks of disease have not yet been reported in many countries, and the full clinical spectrum of disease is not yet known”.

No mention was made by WHO today, however, of whether persons who recovered from infection with this virus were immune to re-infection with this same virus, a concept discussed in this space several times since 2006.

15 June 2009

Daniel R. Lucey MD, MPH

Egypt Reports 20^th Case of Novel Influenza A (H1N1), and Remains the Only Nation in Africa with Lab-Confirmed Cases

As of this morning the World Health Organization (WHO) Eastern Mediterranean Region has reported an ongoing increase to 20 lab-confirmed cases in Egypt of the novel Influenza A (H1N1) virus. Daily updates can be found at: http://www.emro.who.int/csr/h1n1/

No other African nations have reported any lab-confirmed cases, according to the websites for the two WHO regions in Africa: this Eastern Mediterranean Region Office (EMRO) and the 46-nation African Regional Office (AFRO): http://www.afro.who.int/ddc/influenzaa/index.html

On Sunday, June 14, the WHO EMRO Influenza A (H1N1) website “highlights” section summarized three cases reported by the Ministry of Health of Egypt on June 13^th. These three patients were travelers to Egypt. The first was a 45 year-old Columbian woman who flew from Columbia to Frankfurt, Germany and then to Cairo on June 10^th. Her symptoms did not start until June 12 while visiting the Egyptian Museum. Fortunately, a physician at this Museum suggested she go to a hospital for evaluation.

A second case was a 7 year-old boy who flew with his mother from Minnesota (USA) to London and then to Egypt on June 7. He was diagnosed in the governorate of Alexandria. His brother was diagnosed with the same novel virus (case 12 in Egypt). Of note, the mother reported that the child was evaluated by a physician in the USA on June 5 for influenza-like illness, told he had the novel Influenza A (H1N1) virus, and treated with the inhaled neuraminidase inhibitor “Relenza” (zanamivir).

The third case was an 8 year-old Egyptian-Canadian boy who flew from Canada to Egypt on June 12 and was “detected by the quarantine staff at the airport”.

All three of these patients were reported to be in stable condition while receiving the oral neuraminidase drug “Tamiflu” (oseltamivir), in a referral hospital.

Today, the American University of Cairo (AUC) dormitory in the Zamalek area of Cairo, where several American students had been diagnosed with this novel influenza virus, is scheduled to reopen.

The latest update from the WHO African Regional Office reports that there are still zero lab-confirmed cases in the 46 nations in this part of the continent. The following information is posted on their website summarizing key actions at the Regional office in Brazzaviulle, as well as in Zimbabwe, Gabon, and Burkina Faso. http://www.afro.who.int/ddc/influenzaa/index.html

“All countries in the region have activated their national emergency preparedness and contingency response plans

A crisis management team has been put in place by the Regional Director at the regional office (Brazzaville) and the sub regional levels (Intercountry Support teams in Harare, Zimbabwe, Gabon and Burkina Faso)) to work closely with countries to boost their disease surveillance to ensure that any suspected case of Influenza A H1N1 is detected early.

Stockpiles of relevant medicines have been dispatched to all countries in the region as well as mapping laboratory and human resources capability at country and regional levels to enable WHO to support Member States to respond rapidly to any suspected outbreaks.”

In sum, currently there is no reported community-level transmission of this novel Influenza A (H1N1) virus anywhere in Africa. Increased surveillance and vigilance is warranted now across all of Africa, not only in Egypt, for cases of this new virus. There is no biologically plausible reason to assume that this virus will not spread in Africa as it has in the Americas, Europe, and Asia.

In addition, increased surveillance for avian flu H5N1, and other avian flu viruses (e.g., H7, H9, and H10) should be considered. Continued animal-to-human cases of Influenza A (H5N1) have been reported in Egypt during the first six months of this year. Such increased surveillance would help to monitor for, and guide responses to, any reassortment between an avian flu virus and the novel “swine flu” Influenza A (H1N1) virus.

19 June 2009

Daniel R. Lucey MD, MPH

South Africa is the third African Nation to confirm the Novel Influenza A (H1N1), as cases in Morocco rise to 8 and in Egypt to 29

The World Health Organization (WHO) update on global Influenza A (H1N1) today included the first case in South Africa. According to an official statement in Pretoria today by the Minister of Health and posted on their website at http://www.doh.gov.za/docs/sp/sp0619-f.html the patient was a 12-year old boy on a plane from Atlanta (USA) that arrived Sunday, June 14. The boy was hospitalized on Monday, June 15, treated successfully, and discharged later in the week.

The South African Health Minister stated “We are in the process of tracing the contacts who have been with him on the flight from Atlanta” and went on to list the following measures now in place:

“We have a Preparedness Plan in place and remain confident that we will continue to respond positively to any further cases that may be confirmed. Among the measures that we have in place one can just highlight the following:

A Multi-sectoral Committee meets weekly to monitor and assess the situation and guide our response;
Guidelines on National Pandemic Influenza Preparedness Plan and Influenza Case Management were distributed;
Outbreak response teams that are operational in all provinces;
Training of Provincial Rapid Response Teams on Influenza pandemic preparedness;
Heightened clinical and laboratory surveillance that we have in place to identify any suspected human case of H1N1 Influenza; and
Assessment of capacity for Epidemic Preparedness and Response including Port Health services within the context of International Health Regulations.

In terms of operations at the country’s major Airport (OR Tambo Airport), two rooms have been designated for Port Health Services, with one being used as a clinic and the other for isolation purposes. The clinic caters for both arrivals and departures. There are four (4) registered nurses and one (1) supporting Doctor”.

Meanwhile, elsewhere in Africa the number of confirmed cases with this novel influenza virus rose to 8 in Morocco and 29 in Egypt. None of these cases have been fatal.

In a front-page story written by Safaa Abdoun in the print-version of the Egyptian “Daily News” on Thursday, June 18, it was noted that of the three most recently identified cases in Egypt, “The most alarming case among those three is of an unidentified 21-year-old hotel staffer, according to Health Ministry Spokesperson Abdel Rahman Shahin. This man has not traveled recently and has not come in contact with any of the previously reported cases.”

This person is the first in Egypt confirmed to have this novel virus who does not have an epidemiological link to travel or known contact with a traveler. This pattern has been seen in many other nations in which initial confirmed cases have been in travelers, or contacts of travelers, followed by infections in persons lacking such epidemiological links.

More infections in African nations should be anticipated. Increasing support from WHO and elsewhere should hopefully also be anticipated before transmission of the virus is at the community-level as has already occurred in parts of the Americas, Oceania, Europe, and Asia.

24 June 2009

Daniel R. Lucey MD, MPH

Six African Nations now confirm Novel Influenza A/H1N1: Ethiopia, Tunisia, Cote d’Ivoire, S. Africa, Morocco and Egypt

Today’s update from the World Health Organization (WHO) added initial confirmed cases of the novel Influenza A/H1N1 from three more African nations: Ethiopia (2 cases), Tunisia (2 cases), and Cote d’Ivoire (2 cases). Three additional African nations previously reporting cases were: Egypt (40 cases), Morocco (9 cases), and South Africa (1 case). There is no reason to expect that the spread of this novel virus in Africa will not eventually be as widespread as in the Americas, Europe, and Asia.

The Ethiopian Federal Ministry of Health (FMoH) press release June 19 from Addis Ababa stated that the two patients confirmed as positive for this novel virus were a 16 year-old and a 17 year-old who returned home to Addis from a cultural exchange program in the USA. Confirmation was performed at the US CDC Atlanta. Both young women have recovered from their illness. The full press release can be found at: www.moh.gov.et/images/stories/h1n1_press_release.pdf

Ethiopia reports having stockpiled enough anti-influenza oral therapy with oseltamivir (Tamiflu) in coordination with the WHO, and is in the process of distributing the antivirals across the nation. A specific hospital, St. Paulos, has been designated to admit passengers suspected of having this novel influenza upon arrival at the Bole International airport in Addis. Ethiopian Airlines crew have also been reported by the Federal MoH to have had training in the detection and reporting of symptomatic cases of influenza-like illness.

Overall, today’s WHO global update on confirmed counts of infections due to this virus included 55,867 cases including 238 fatalities. The largest number of cases and deaths have been reported to WHO from the USA (21,449 cases with 87 deaths) and Mexico (7,847 cases with 115 deaths).

Predictably, the number of cases in Africa will only increase along with the initial fatalities and the challenges to the public health and economic infrastructures.

16 July 2009

Daniel R. Lucey, MD, MPH

WHO changes reporting for pandemic (H1N1) 2009 virus today; 15 Nations in Africa now with known cases

Today the World Health Organization (WHO) posted on their website changes in reporting requirements for what they now term “pandemic (H1N1) 2009 virus infection”. As a result, WHO “will no longer issue the global tables showing the numbers of confirmed cases for all countries” in the world. Regular updates, including descriptive epidemiology of cases, will still be provided by WHO with regard to newly affected nations. Today’s WHO posting is at: www.who.int/csr/disease/swineflu/notes/h1n1_surveillance_20090710/en/index.html

The reporting focus will shift from laboratory testing of both mild and severe cases to monitoring “unusual events, such as clusters of cases of severe or fatal pandemic (H1N1) 2009 virus infection, clusters of respiratory illness requiring hospitalization, or unexplained or unusual clinical patterns associated with serious or fatal cases.”

Of note, WHO stated that this flu pandemic has spread more widely in ”less than six weeks” than pandemic influenza viruses in the past have spread “in six months”.

In continuing to focus on cases in Africa in this series of Newsletters on www.BePast.org, two WHO regions in Africa (“AFRO” and “EMRO”) have posted on their respective websites the following 15 nations on the continent with their respective number of lab-confirmed pandemic (H1N1) 2009 cases:

Algeria (8), Botswana (2), Cape Verde (3), Cote d’Ivoire (2), Egypt (108), Ethiopia (3), Kenya (22), Libyan Arab Jamahiriya (4), Mauritius (1), Morocco (20), Seychelles (1), South Africa (103), Tanzania (1), Tunisia (5), and Uganda (6).

Of these 289 lab-confirmed cases in Africa that have been reported officially to the WHO, none have been fatal.

In theory, the new WHO guidelines for laboratory testing should still identify rapidly any increased virulence of this pandemic (H1N1) 2009 virus as manifest by clusters of clinically more severe disease.

27 July 2009

Daniel R. Lucey, MD, MPH

WHO Regional Office Addresses Pandemic (H1N1) 2009 virus with Regard to the Hajj and Umrah Pilgrimages

The World Health Organization (WHO) Eastern Mediterranean Regional Office (EMRO) posted on its pandemic (H1N1) influenza website Sunday, July 26, a situation report that provides important interim updates. They note that one person has died and there have been 1,028 lab-confirmed H1N1 virus infections. The single lab-confirmed fatality was a 28 year-old woman from Egypt who died on July 19. She was reported previously in the media to have become ill while traveling to Saudi Arabia.

The section of this July 26 EMRO/WHO update that pertain specifically to the discussions recently in the media regarding public health measures for persons making the Hajj and the minor pilgrimage, or Umrah, to Saudi Arabia is quoted below. The full update is available at: www.emro.who.int/csr/h1n1

“A special session of the Regional Committee of the WHO Eastern Mediterranean Region on

pandemic (H1N1) 2009 was held on 22 July 2009 at WHO-EMRO Office, Cairo, Egypt. Twenty

one countries participated in this special session represented by 15 Ministers, 4 Deputy Ministers

and 2 Directors. Following the technical discussions the Regional Committee approved a draft

resolution directed to the Member States and the Regional Director in the form of

recommendations. Key recommendations included a call to Member States to adopt and

implement the public health measures recommended for Hajj and Umrah by the international

consultative workshop held in Jeddah from 27 to 30 June 2009, and request Saudi Arabia to

translate the recommendations of the workshop into clear requirements for the Hajj and Umrah

this year; and other requests the Regional Director to “Form a regional technical committee

comprising experts from the countries of the Region and the WHO Secretariat to study and

update all information regarding the development of the pandemic and viral change, and

establish appropriate criteria for measuring the severity of the infection.”

“The workshop on “Influenza A (H1N1) Pandemic Communication Strategies: Principles, Lessons Learnt and the Way Forward” is scheduled to be held in Cairo from 29 to 30 July 2009. This workshop is being organized by the WHO’s Regional Office for the Eastern Mediterranean and will be participated by the communication focal points of Ministries of Health of Member States of WHO Eastern Mediterranean Region, WHO Country Offices and UNRWA.

Updated behavioural interventions, communication strategies for public with regards to

Pandemic (H1N1) 2009 as well as risk communication strategies for religious mass gatherings

will be discussed and presented in the workshop”.

Additional further communications from the WHO and its Regional Office (EMRO) following this July 29-30 conference this week are awaited and will be posted here.

29 July 2009

Daniel R. Lucey, MD, MPH

South Africa to Host a WHO Regional Conference on Pandemic Influenza August 11-13

The World Health Organization (WHO) African Regional Office (AFRO) has posted on their website homepage the news that a 3-day “Regional Conference on Pandemic Influenza” will be held in Johannesburg, South Africa August 11-13.

South Africa has the largest number of lab-confirmed cases of pandemic (H1N1) /2009 influenza cases in the WHO/AFRO area, with 151 cases out of the total 221 cases in 13 nations that have at least one case in the WHO/AFRO area. Kenya has 22 cases, Algeria 14 cases and the other ten nations fewer lab-confirmed cases as of the 28 July update.

The full report on the August 11-13 conference in Joburg and lab-confirmed pandemic H1N1 cases in the WHO/AFRO area can be found at: www.afro.who.int

The 3-day conference is planned to be comprehensive in its presentations and discussions on pandemic H1N1 influenza issues. For example, specific areas that will be included are: lab testing and surveillance, clinical management and infection control, risk communication strategies, vaccines, global perspectives and lessons learned from Mexico and other areas harder hit (i.e., many more lab-confirmed cases) by the pandemic to date than the WHO/AFRO area.

This should be a very timely and important conference, the results of which will hopefully be well-publicized internationally.

2 August 2009

Daniel R. Lucey, MD, MPH

Avoid Aspirin in Persons with possible Influenza Infection to Avoid “Reye’s Syndrome” with Brain and Liver Damage

Given the ongoing influenza pandemic with the H1N1/2009 virus in the southern and northern hemispheres it is timely to emphasize to the general public the critical importance of avoiding all aspirin-containing substances (e.g., aspirin or Pepto Bismol (bismuth subsalicylate) in persons less than 19 years of age who could possibly have influenza infection in order to avoid severe and sometimes fatal “Reye’s syndrome.”

This advice has appeared on the US CDC and World Health Organization (WHO) H1N1 pandemic flu websites, as cited below, but warrants a much higher level of visibility for the general public worldwide in order to prevent Reye’s Syndrome during the ongoing influenza pandemic.

The US National Institutes of Health (NIH) defines Reye’s Syndrome, and briefly discusses the lack of a cure and the often serious prognosis, on its website for the National Institute of Neurological Disorders and Stroke (NINDS) as follows below at: www.ninds.nih.gov/disorders/reyes_syndrome/reyes_syndrome.htm

“What is Reye’s Syndrome?

Reye’s syndrome (RS) is primarily a children’s disease, although it can occur at any age. It affects all organs of the body but is most harmful to the brain and the liver–causing an acute increase of pressure within the brain and, often, massive accumulations of fat in the liver and other organs. RS is defined as a two-phase illness because it generally occurs in conjunction with a previous viral infection, such as the flu or chicken pox. The disorder commonly occurs during recovery from a viral infection, although it can also develop 3 to 5 days after the onset of the viral illness. RS is often misdiagnosed as encephalitis, meningitis, diabetes, drug overdose, poisoning, sudden infant death syndrome, or psychiatric illness. Symptoms of RS include persistent or recurrent vomiting, listlessness, personality changes such as irritability or combativeness, disorientation or confusion, delirium, convulsions, and loss of consciousness. If these symptoms are present during or soon after a viral illness, medical attention should be sought immediately. The symptoms of RS in infants do not follow a typical pattern; for example, vomiting does not always occur. The cause of RS remains a mystery. However studies have shown that using aspirin or salicylate-containing medications to treat viral illnesses increases the risk of developing RS. A physician should be consulted before giving a child any aspirin or anti-nausea medicines during a viral illness, which can mask the symptoms of RS.

Is there any treatment?

There is no cure for RS. Successful management, which depends on early diagnosis, is primarily aimed at protecting the brain against irreversible damage by reducing brain swelling, reversing the metabolic injury, preventing complications in the lungs, and anticipating cardiac arrest. It has been learned that several inborn errors of metabolism mimic RS in that the first manifestation of these errors may be an encephalopathy with liver dysfunction. These disorders must be considered in all suspected cases of RS. Some evidence suggests that treatment in the end stages of RS with hypertonic IV glucose solutions may prevent progression of the syndrome.

What is the prognosis?

Recovery from RS is directly related to the severity of the swelling of the brain. Some people recover completely, while others may sustain varying degrees of brain damage. Those cases in which the disorder progresses rapidly and the patient lapses into a coma have a poorer prognosis than those with a less severe course. Statistics indicate that when RS is diagnosed and treated in its early stages, chances of recovery are excellent. When diagnosis and treatment are delayed, the chances for successful recovery and survival are severely reduced. Unless RS is diagnosed and treated successfully, death is common, often within a few days.” (NINDS/NIH).

The US Centers for Disease Control and Prevention (CDC) included the following advice on May 13, 2009 in its guidance for clinicians for the treatment of the novel (now pandemic) influenza A (H1N1) under a section titled “Special considerations for children” as follows:

“Aspirin or aspirin-containing products (e.g. bismuth subsalicylate – Pepto Bismol) should not be administered to any confirmed or suspected ill case of novel influenza H1N1 virus infection aged 18 years old and younger due to the risk of Reye syndrome. For relief of fever, other anti-pyretic medications such as acetaminophen or non- steroidal anti-inflammatory drugs are recommended”.

The CDC has also included the following advice in its July 16, 2009 “Home Care Guidance: Physician Directions to Patient/Parent”

Take medications for symptom relief as needed for fever and pain such as acetaminophen (Tylenol®) and ibuprofen (Advil®, Motrin®, Nuprin ®), and cough medicine. These medicines do not need to be taken regularly if your symptoms improve.
Do not give aspirin (acetylsalicylic acid) or products that contain aspirin (e.g. bismuth subsalicylate – Pepto Bismol) to children or teenagers 18 years old or younger.

Similarly, the WHO included in its updated 11 June 2009 on the new influenza A (H1N1) virus the following advice regarding treatment: “Supportive care at home – resting, drinking plenty of fluids and using a pain reliever for aches – is adequate for recovery in most cases. (A non-aspirin pain reliever should be used by children and young adults because of the risk of Reye’s syndrome.)”Given the global spread of this pandemic influenza (H1N1) 2009 it is important to make this information available and familiar on a world-wide scale, to the general public, in addition to the health care community. This risk communication can be facilitated by National public health organizations around the world as well as the World Health Organization and its regional offices.

10 August 2009

Daniel R. Lucey, MD, MPH

WHO addresses Pandemic Flu Vaccine Safety: Studies begin in China, Australia, the UK, Germany, and the USA

An 11-page transcript was posted on the World Health Organization (WHO) pandemic flu website after their August 6 press conference lead by Dr. Marie-Paule Kieny, Director of the Initiative for Vaccine Research at WHO. Vaccine safety issues were the primary focus, although three points were covered:

(1) State of Vaccine Development;

(2) Vaccine safety;

(3) When pandemic H1N1 flu vaccines will likely become available.

The complete transcript can be accessed at: www.who.int/mediacentre/pandemic_h1n1_presstranscript_2009_08_06.pdf

Excerpts from this 11-page transcript are emphasized below:

(1) In terms of pandemic H1N1 vaccine development, Dr. Kieny stated that “In terms of clinical trials, we now have seven manufacturers who have started clinical trials and these…are going on in at least five countries…China, Australia, the United Kingdom, Germany, and the U.S.A.”

(2) These initial clinical trials that began in July should yield data “by the first half of September”. They will tell whether one dose or two doses are needed in order to induce what is considered to be immunologic protection against the pandemic virus.

(3) In terms of vaccine safety, multiple statements were notable, e.g., “There is no vaccine that induces zero safety concerns…there will be people who will have an adverse event. The large majority of these events will not be associated at all with the vaccine which is given. It will be temporally associated which means this is something that would have happened anyway but which just by chance is happening after a person has had a vaccination.”

(4) “For those vaccines where the technology remains exactly the same as for seasonal vaccines, what happens or the way it is treated, is called a “strain change”…In the USA, for example, the FDA approves a strain change by looking at the quality control dossier that the manufacturer submits and does not require a clinical trial. Therefore, for those pandemic vaccines that will be like a strain change, only it will be H1N1 instead of another seasonal strain, the FDA has decided that they will treat this as a normal strain change and, therefore, the vaccine will be registered without clinical trials.”

(5) “All manufacturers, of course, will conduct a clinical trial if only to confirm whether one or two doses are needed as I said a few minutes ago.”

(6) “In Europe the procedure for registration of seasonal influenza vaccine is slightly different. In the sense that the regulatory authority requests every year a small clinical trial of the new seasonal vaccine…”

(7) “Now for pandemic use, there are a number of vaccines which are not the classical seasonal vaccines. These are the vaccines which have an addition of an adjuvant. These adjuvant vaccines have been tested extensively at the time when all manufacturers were preparing vaccines for a potential H5N1 pandemic. In view of the potential gravity of an H5N1 vaccine, the European Regulatory Agency had designed a special process by which manufacturers would test extensively in clinical trials, prototypes of H5N1 vaccines, including with adjuvants, which submit all the safety data of clinical trials. Immunogenicity to the regulatory agency and obtain what is called a “mock-up registration”. So this is a registration for a prototype.”

(8) “So those manufacturers who do have a mock-up dossier can go and present to the EMEA all their documentation for the H1N1 vaccine and as previously agreed already in 2007 with the regulatory authority, obtain registration without clinical trials. But again as I said for the USA, all manufacturers will conduct clinical trials and the earliest results of these clinical trials will be available in September.”

(9) Regarding when pandemic flu vaccine might first become available, Dr. Kieney stated: “Now the manufacturers have started to submit these dossiers to the regulators and to expect that the regulators will make decisions on these vaccines that will allow use in populations during September when the first authorization may be in September, and then going into October, when the dossiers are ready and are submitted by the manufacturers.”

(10) In response to questions from the media at this press conference, Dr. Kieney addressed in more detail adjuvanted influenza vaccines, based on “more than 40 million doses of adjuvanted flu vaccines have been used in Europe” (i.e., prior to the current pandemic H1N1 virus).

(11) In contrast, in the USA, no adjuvanted influenza vaccines have ever been licensed.

(12) Similarly, Dr. Kieney later stated that “As you rightly point out there is no experience with using adjuvanted vaccines on pregnant women…”

(13) Regarding concern about Guillan-Barre Syndrome (GBS) due to a “swine flu vaccine” as was reported with the 1976 USA vaccine, Dr. Kieney stated: “In addition what we will really look with great scrutiny by all involved in post-marketing surveillance will be what is called Guillanin Barre Syndrome, which is a very rare side effect which happens sometimes after vaccination. It is not something which has been described for seasonal influenza vaccination. It has been described in one situation which was in the 1976 vaccination against Swine flu in the USA but even there it was a very rare event-30 people died out of 40 million people immunized. Because of this event, the causes of which are only starting to be understood and not completely, all the post marketing surveillance will certainly be very wary of this possibility of this Guillan Barre Syndrome and will follow this very closely and a procedure put in place in countries to be sure that even in low income countries it will be possible to detect this side effect very early.”

(14) Later in the conference in response to a question, Dr. Kieney noted that in 1976 flu vaccines “there were very many more impurities” compared with flu vaccines today.

In my opinion, this press conference is a good start to addressing the concerns many people in the general public and medical professions, in addition to the media, have regarding the safety of pandemic H1N1 influenza vaccines. For example, Dr. Kieney made an excellent point by emphasizing from the beginning that adverse events after vaccination will occur, but that they might be the result of a temporal association, and not actually caused by the pandemic H1N1influenza vaccine.

There are, however, multiple areas that would be helpful for WHO to address in further detail. For example, detailed safety data should be tabulated and summarized by WHO on the specific adjuvanted influenza vaccines that Dr. Kieney mentioned have been used in Europe. In addition, the adjuvants that have been most often mentioned as candidate adjuvants for influenza vaccines (e.g., MF-59, and others) should be discussed in detail with regard to their safety profile, both for influenza and non-influenza vaccines.

If there are specific past concerns regarding these adjuvants (e.g., MF-59 and others), including with non-influenza vaccines, whether in Europe, the USA, or anywhere else in the world then it is best if WHO address these concerns soon, before pandemic H1N1 vaccines using adjuvants become available, whether in the less-developed or developed world, in the southern or northern hemisphere.

In addition, more specific information regarding the surveillance that will be put into place, apparently worldwide, for Guillain Barre Syndrome, should be provided as soon as possible. Doing so will hopefully increase trust, and allay fear, on the part of everyone including the general population that may receive the vaccine, the media, and global health care communities.

21 August 2009

Daniel R. Lucey, MD, MPH

Chile reports turkeys infected with human pandemic influenza virus H1N1/2009

Today the World Organization for Animal Health (Organization International Epizootic (OIE)) reported an “immediate notification” on their website (www.oie.int/eng/en_index.htm) that Chile has reported the first known infection of an avian species (turkeys) with the human pandemic H1N1/2009 influenza virus (formerly referred to as “swine flu” in April 2009). The source of the infection is listed currently on the OIE website as “Unknown or inconclusive”, although they also report that “prior to the appearance of clinical signs, some birds were exposed to people showing respiratory symptoms”.

The specific laboratory tests reported to the OIE as positive included: real-time PCR on August 20^th (with virus sequencing pending today), performed at the Chilean Public Health Institute (National laboratory); as well as the neuraminidase inhibition assay (on 19 August), haemagglutination inhibition test (HT) (also on 19 August), agar-gel immunodiffusion (AGID) (on 15 August), and antibody detection by ELISA (on 14 August). These latter four tests were performed at the Lo Aguirre Laboratory and quarantine station (National Laboratory), according to the OIE posting. In addition, “Samples will be sent to the OIE Reference Laboratory”.

There were two outbreaks reported in Chile. One began 23 July 2009 at Las Palmas, Quilpue, Valparaiso, VALPARAISO and involved breeding turkeys which “presented a drop from 70% to an average of 31% and a reduction in the quality of the shell”. Neither respiratory signs nor increased mortality were observed. Necropsy showed salpingitis, peritonitis, and an interruption of the follicular development. No other lesions were observed.”

The 2^nd outbreak began 29 July in Pucalan, Quillota, Nogales, VALPARAISO. Again, the “birds are breeding turkeys showing an abnormal decrease in the laying rate. Neither respiratory signs nor increased mortality were observed.”

Taken together, these two outbreaks posted by the OIE were notable for no (i.e., zero) “apparent mortality rate”, “apparent case fatality” rate, and zero animals lost to death, destruction and/or slaughter”.

Follow-up epidemiological and virological investigations of this novel infection of an avian species are anticipated soon.

So far, there is no evidence of any individual humans, swine, or avians (e.g., turkeys) having dual infection with the pandemic H1N1/2009 virus and any H5 or H7 virus; however, one could expect increased surveillance for this pandemic virus in other turkey and avian populations worldwide.

Reports appeared today in the media (e.g., Reuters) and on the ProMed-mail website. The Reuters article reported that the location of the two outbreaks is 120km west of Santiago, the capital.

The virologic sequencing and antiviral susceptibility test results can also be anticipated soon, as well as test results for humans who had been present on these turkey farms recently.

The absence of any respiratory symptoms, or any lung involvement at the initial necropsies, is also noteworthy as this story unfolds.

31 August 2009

Daniel R. Lucey, MD, MPH

WHO offers lessons for the upcoming second wave of pandemic H1N1 Influenza virus

On Friday, August 28, the World Health Organization (WHO) posted online a succinct discussion regarding the pandemic influenza H1N1/2009 situation titled “Preparing for the second wave: lessons from current outbreaks”. The full document appears at: www.who.int/csr/disease/swineflu/notes/h1n1_second_wave_20090828/en/index.html. The three-page WHO document is divided into nine (9) subheadings:

H1N1 now the dominant strain
Large populations susceptible to infection
Monitoring for drug resistance
Not the same as seasonal influenza
Severe respiratory failure
Vulnerable groups
Higher risk of hospitalization and death
Implications for the developing world
Co-infection with HIV

Several points of emphasis include:

a. Globally, the new pandemic virus has become the predominant strain of influenza in the southern hemisphere’s now concluding winter season, as well as the northern hemisphere’s concluding summer. Unlike seasonal flu, this virus has continued to be transmitted in the temperate regions of the northern hemisphere during the summer (including the USA, Mexico, and Canada). Fortunately, so far, no significant mutations or recombination events have occurred that increased the virulence of this new virus.

b. “Large numbers of severely ill patients requiring intensive care are likely to be the most urgent burden on health services, creating pressures that could overwhelm intensive care units and possibly disrupt the provision of care for other diseases.” (bold type added).

c. “To date, most severe cases and deaths have occurred in adults under the age of 50 years, with deaths in the elderly comparatively rare.”

d. “Perhaps most significantly, clinicians from around the world are reporting a very severe form of disease, also in young and otherwise healthy people, which is rarely seen during seasonal influenza infections. In these patients, the virus directly infects the lungs, causing severe respiratory failure…During the winter season in the southern hemisphere, several countries have viewed the need for intensive care as the greatest burden on health services. Some cities in these countries report that nearly 15 percent of hospitalized cases have required intensive care. Preparedness measures need to anticipate this increased demand on intensive care units, which could be overwhelmed by a sudden surge in the number of severe cases”.

e. Asthma and diabetes are risk factors for more severe pandemic H1N1 flu disease. “WHO estimates that, worldwide, more than 230 million people suffer from asthma, and more than 220 million have diabetes”.

f. Referring to these and other risk factors for severe pandemic H1N1 flu virus disease, WHO emphasized that “such findings are likely to have growing relevance as the pandemic gains ground in the developing world, where many millions of people live under deprived conditions and have multiple health problems, with little access to basic health care. As much current data about the pandemic comes from wealthy and middle-income countries, the situation in developing countries will need to be very closely watched. The same virus that causes manageable disruption in affluent countries could have a devastating impact in many parts of the developing world.” (bold type added).

g. “Early data from two countries suggest that people co-infected with H1N1 and HIV are not at increased risk of severe or fatal illness, provided these patients are receiving antiretroviral therapy.”

Soon the pandemic H1N1/2009 influenza virus will return for its second wave in the northern hemisphere. At the same time it quite possibly will continue to be transmitted in the tropical regions and in the southern hemisphere, albeit at a slower rate than during the past three months of winter there. Thus, these WHO “lessons” and observations are timely.

A crucial point is the limited data from developing nations, and that “much current data about the pandemic comes from wealthy and middle income countries”. At this point, therefore, we do not really have a robust or sufficient understanding of what this virus has done, and is likely to do, in the coming six months in many of the developing nations where so much of the global population lives.

This is the same large part of the global population that will have the least, if any, access to pandemic H1N1 influenza vaccine and effective antiviral drugs and intensive care.

For these reasons, along with being more vulnerable to severe pandemic flu disease due to underlying respiratory diseases, diabetes, and other such risk factors, actual mortality figures will highest in such nations. Clearly, it bears remembering that insufficient measurement of such mortality does not mean that it does not occur and might not be at least partially mitigated.

1 September 2009

Daniel R. Lucey, MD, MPH

An Excellent Idea: The American Academy of Neurology asks Neurologists to Report any Cases of Guillain-Barre Syndrome after Pandemic H1N1 Flu Vaccination

In a very positive development the American Academy of Neurology (AAN) announced in a press release August 31 that they will partner with the Centers for Disease Control and Prevention (CDC) to ask neurologists to report “any possible new cases” of Guillain-Barre syndrome (GBS) that occur after a person receives a pandemic H1N1 influenza vaccine. This vaccine is anticipated to first be available in mid-October. Neurologists are physicians who specialize in the care of patients with diseases involving the nervous system. The full story can be found on the website of the American Academy of Neurology at: www.AAN.com

Guillain-Barre syndrome (GBS) is an autoimmune disease in which a person’s immune system attacks and damages nerves. It can result in weakness, difficulty breathing, numbness or tingling, and is fatal in 4-15% of patients. GBS “affects between 1 and 4 per 100,000 of the population annually throughout the world…” (Hughes R. et al. NEUROLOGY 2003; 61:736-740).

According to the AAN press release “It is not anticipated that the 2009 H1N1 vaccine will have an increased risk of GBS. However, out of an abundance of caution, and given that GBS may be of greater concern with any pandemic vaccine because of the association with the 1976 swine flu vaccine, the CDC and AAN are asking neurologists to report any potential new cases of GBS after-vaccination as part of the CDC’s national vaccine safety monitoring campaign…All neurologists nationwide who encounter patients with adverse events post-vaccination should use the CDC and FDA Vaccine Adverse Event Reporting System (VAERS) to report their observations” (see www.vaers.hhs.gov and the www.AAN.com websites for standardized online reporting forms).

This appeal to neurologists across the USA to report even “any potential new cases of GBS” after a person receives the soon-to-be available pandemic H1N1 flu vaccine is a very positive development for multiple reasons, including those below, because it should:

Maximize the chance for early diagnosis of this sometimes very serious disease, so that therapy can be started quickly for that individual, whether or not the GBS was causally related to the flu vaccine.
Increase substantially the probability that any true causal link between the pandemic H1N1 flu vaccine and GBS will be recognized as soon as possible, and appropriate responses can be made by persons and organizations involved in the US and global pandemic H1N1 flu vaccine program.
Demonstrate an awareness of, and a positive response to, this potential safety concern that some persons understandably have with respect to the 2009 pandemic H1N1 vaccine, due to the above-mentioned association of GBS with the 1976 swine flu H1N1 vaccine.

3 Sept 2009

Daniel R. Lucey, MD, MPH

Institute of Medicine Report Recommends Fit-Tested N-95 Respirators for Healthcare Workers as Respiratory Protection against Pandemic H1N1 Influenza

Today the Institute of Medicine (IOM) posted online (www.nap.edu) a 68-page report titled: “Respiratory Protection for Healthcare Workers in the Workplace against Novel H1N1 Influenza A: a Letter Report”. Their first recommendation was that:

“Healthcare workers (including those in non-hospital settings) who are in close contact with individuals with H1N1 influenza or influenza-like illnesses should use fit-tested N95 respirators or respirators that are demonstrably more effective as one measure in the continuum of safety and infection control efforts to reduce the risk of infection.

–The committee endorses the current CDC guidelines and recommends that these guidelines should be continued until or unless further evidence can be provided to the effect that other forms of protection or other guidelines are equally or more effective.

–Employees should ensure that the use and fit-testing of N-95 respirators be conducted in accordance with OSHA regulations, and healthcare workers should use the equipment as required by regulations and employer policies”.

This recommendation to use fit-tested N-95 respirators, rather than surgical masks, will prove controversial among some healthcare workers and administrators, in part for the following reasons cited by the IOM committee:

“It is important to note that controversy exists regarding clinical guideline decision making as many factors besides efficacy may affect policy decisions for PPE guidance including economics, equipment supplies, vaccine availability, immunization status, extent of worker compliance, and logistical considerations in the implementation of such guidance. The committee was not charged to address these issues.”

For hospitals and clinics that decide to follow, as best as possible, the IOM/CDC/OSHA guidance and perform fit-testing for N-95 respirators for healthcare workers during this time of pandemic H1N1 influenza, the following information from our hospital should be useful. This abstract was presented in 2007 at the “International Meeting on Emerging Diseases and Surveillance (IMED 2007)” in Vienna, Austria by Ella Dade (first author).

As reproduced below, it provides five (5) practical “lessons learned” from the experience of fit-testing over 5,200 persons working in the largest hospital (907 beds) in Washington, DC, the Washington Hospital Center. The study and the abstract presentation were strongly supported by Dr. Mark Smith, Director of the Department of Emergency Medicine and EROne Institutes at Washington Hospital Center, and his colleagues.

N-95 Respirator Fit-Testing of 5,200 Persons in One Hospital over 6 months: Lessons Learned

E.S. Dade, M.S. Smith, D.R. Lucey, C.F. Feied, C.K. Wuerker, K. Myerson

Washington Hospital Center, Washington, DC, USA

Background: Our 907-bed tertiary hospital, the largest in the District of Columbia (DC), decided to offer N-95 respirator fit-testing to all full-time and part-time workers in order to enhance preparedness for SARS, tuberculosis, avian influenza, smallpox, measles, viral hemorrhagic fevers and any other natural or bioterrorist airborne-transmitted disease.  Methods: From November 1, 2003 until May 1, 2004 we partnered with a private occupational health company to offer N-95 fit-testing following the standard two-step process. First, via an optical-mark recognition questionnaire we determined if each participant could be medically cleared. Second, if this clearance was obtained then qualitative N-95 fit-testing was performed. One fit-test technician, testing four persons at a time, could test a maximum 84 persons/8-hour day. Fit-testing was offered on both day and night shifts, in large central areas and in individual smaller parts of the medical campus. Results: 5,377 persons were medically cleared for fit-testing. 5,097 (95%) were able to be successfully fit-tested with the initial N-95 respirator. An additional 200 failed using the initial respirator but passed the fit-testing using one of two alternative N-95 respirators. Only the remaining 80 (1.5%) persons could not be fit-tested.  Conclusions: Lessons learned included: (1) by the third month of the program a directive from the hospital President was needed to increase participation in the fit-testing program; (2) Detailed information system support was essential to track what became a multi-step process from the distribution of questionnaires to the final documentation of compliance reports to department managers. (3) confidentiality concerns regarding the medical clearance questionnaires were resolved in some cases only by face-to-face interviews with an occupational health nurse; (4) time requirements ranged from 10-30 minutes for the questionnaire, and 18-35 minutes for fit-testing, including the ‘fit-check’ demonstration on how to self-monitor the respirator seal; (5) easy access to handwashing and drinking water were important to remove the testing solution and decrease the test-failure rate.

17 September 2009

Daniel R. Lucey, MD, MPH

President Obama announces US will donate 10% of its 2009 H1N1 pandemic flu vaccine (non-adjuvanted) to WHO for other nations, as WHO Director Dr. Margaret Chan sees devastating impact of the pandemic virus in some countries

Today the White House posted a press release on their website stating that the US will donate 10% of its 2009 H1N1 pandemic flu vaccine, on a rolling basis as the vaccine becomes available, to the World Health Organization (WHO) for distribution to nations “that will not otherwise have direct access to the vaccine”. The US is joining at least eight (8) other nations in donating vaccine to the WHO. These nations (in alphabetical order) are: Australia, Brazil, France, Italy, New Zealand, Norway, Switzerland, and the UK. Additional nations were invited to join these nine countries as vaccine becomes available more widely in the months ahead.

None of the four US pandemic vaccines licensed by the Food and Drug Administration (FDA) on September 15 contain any vaccine adjuvant. Specifically, none of the USpandemic vaccines containing any MF-59, squalene, or any other adjuvant. The four vaccines licensed this week by the FDA are made by: Sanofi, MedImmune, CSL, and Novartis. (Some confusion may have arisen among some health care workers and some members of the general population regarding pandemic vaccine adjuvant because Novartis also has an MF-59 adjuvanted pandemic 2009 H1N1 vaccine about which they reported a clinical study online September 10^th in the New England Journal of Medicine). The FDA-licensed Novartis pandemic flu vaccine, however, is a NON-adjuvanted vaccine.

President Obama’s announcement today is particularly timely. Two days ago (September 15), the Director-General of the World Health Organization (WHO) Dr. Margaret Chan made the following poignant statement on her view of the likely impact of the influenza pandemic in some developing nations, during her address in Denmark to the Regional Committee for Europe:

“To date, we have been fortunate in the way the pandemic has evolved. The overwhelming majority of cases continue to experience mild symptoms and recover fully within a week, even without any medical treatment.

But clinically, this is a virus of extremes. It does not seem to have a middle ground. At one extreme are the mild cases. At the other extreme is a small subset of patients who quickly develop very severe disease.

Though the numbers are small, the demands on health services are disproportionately high. Saving these lives depends on highly specialized intensive care, with highly specialized equipment and highly skilled staff. In countries that lack such capacities, these lives will be at great danger.

Of course, this is true for a multitude of other diseases and health problems. Weak capacities cost lives. But this pandemic, I believe, will make the same old point in an especially visible and tragic manner.

I believe that this pandemic will be a watershed event. It is taking place at a time when differences, within and between countries, in income levels, in health status, and in levels of care, are greater than at any time in recent history. The pandemic will test the world on the issue of fairness in a substantial way.

The same virus that causes manageable disruption in affluent countries will almost certainly have a devastating impact in countries with too few health facilities and staff, no regular supplies of essential medicines, little diagnostic and laboratory capacity, and vast populations with no access to safe water and sanitation. For these populations, advice such as wash your hands, call your doctor, or rush to the emergency ward will mean very little.

Let me give just one precise example. We know, from all outbreak sites, that pregnant women are at increased risk of severe or fatal infections. Increased deaths of these women, because of the pandemic, will be tragic everywhere, but most especially so in the developing world, as the numbers will be so much greater.”

Taken together, the above statement by Dr. Margaret Chan of the WHO and the announcement by President Obama will hopefully serve as a precedent not only for protection against pandemic influenza by vaccines now, but for enhanced international protection against other vaccine-preventable infectious diseases in the near-term future.

27 September 2009

Daniel R. Lucey, MD, MPH

In the Time of Pandemic Flu: Remember Reye’s Syndrome (Vomiting, Liver and Brain Damage) Warnings on Pepto-Bismol, Alka-Seltzer Plus, Excedrin Extra Strength, and Aspirin.

As the pandemic influenza A virus 2009 H1N1 continues to spread in the Northern Hemisphere and tropics following its spread in the Southern Hemisphere over the past four months, it is worthwhile to reemphasize the important public health prevention message:

In persons younger than 19 years of age who have flu-like symptoms (e.g., cough, muscle pains, fever, fatigue), AVOID ASPIRIN or any aspiring-containing medications because of the risk of Reye’s syndrome (that can include liver and brain damage as well as death).

In addition to aspirin, over-the-counter medications that contain aspirin, such as Alka-Seltzer Plus (includes 325 mg aspirin) and Excedrin Extra Strength (includes 250mg aspirin) should be avoided. Pepto-Bismol also carries a risk of Reye’s syndrome due to the aspirin-like chemical, or “salicylate”, contained in the “bismuth subsalicylate” (262mg) that is the active ingredient in Pepto-Bismol.

Given that the pandemic influenza A 2009 H1N1 virus is:

1) more common and serious in young people than in persons over 65, and

2) it can cause intestinal problems including diarrhea, then

a non-prescription medication such as Pepto-Bismol might be taken by persons under the age of 19 years because this medicine is described on the box as “5 symptom relief” for “Nausea, Heartburn, Indigestion, Upset Stomach, Diarrhea”.

Of note, all four of these over-the-counter (OTC) medications contain the identical warning on the outside of the box that reads:

Reye’s syndrome: children and teenagers who have or are recovering from chicken pox or flu-like symptoms should not use this product. When using this product, if changes in behavior with nausea and vomiting occur, consult a doctor because these symptoms could be an early sign of Reye’s syndrome, a rare but serious illness.

In 1980 some of the initial reports linking Reye’s syndrome were published from Ohio and Michigan in the November 7^th issue of the CDC’s MMWR (Morbidity and Mortality Weekly Report) and reprinted due to their importance by the CDC in the August 15, 1997 issue of the MMWR still available online.

In 1982 the U.S. Surgeon General issued an “Advisory on the Use of Salicylates and Reye syndrome” (MMWR (CDC) 1982/31(22):289-90.

In 1999 CDC co-authors Belay, Bresee, Holman, Khan, Shahriari, and Schonberger published a paper describing “Reye’s syndrome in the United States from 1981 through 1997” (NEJM 1999; May 2; 340 (18): 1377-1382). They noted that a peak of 555 cases of Reye’s syndrome were reported in 1980, but that with increased awareness and avoidance of aspirin in children with flu or chickenpox no more than 36 cases per year occurred between 1987 and 1997. The authors reported that “The overall case fatality rate was 31 percent.”

This advice to avoid aspirin (salicylate)-containing substances in young people with flu-like illness has appeared on the US CDC and World Health Organization (WHO) H1N1 pandemic flu websites, as cited below; however, this important advice warrants a much higher level of visibility for the general public worldwide in order to prevent Reye’s Syndrome during the ongoing influenza pandemic.

“What is Reye’s Syndrome?

Is there any treatment?

What is the prognosis?

The CDC has also included the following advice in its July 16, 2009 “Home Care Guidance: Physician Directions to Patient/Parent”

Take medications for symptom relief as needed for fever and pain such as acetaminophen (Tylenol®) and ibuprofen (Advil®, Motrin®, Nuprin ®), and cough medicine. These medicines do not need to be taken regularly if your symptoms improve.

Do not give aspirin (acetylsalicylic acid) or products that contain aspirin (e.g. bismuth subsalicylate – Pepto Bismol) to children or teenagers 18 years old or younger.

More recently, on August 5 and September 24, the CDC again included warnings regarding Reye’s syndrome and avoiding aspirin-containing medications in their updated pandemic influenza A H1N1 document titled: “Interim Guidance for Novel H1N1 Flu (Swine Flu): taking Care of a Sick Person in Your Home” posted online at: www.cdc.gov/h1n1/guidance_homecare.htm

Similarly, the World health Organization (WHO) included in its updated 11 June 2009 on the new influenza A (H1N1) virus the following advice regarding treatment: “Supportive care at home – resting, drinking plenty of fluids and using a pain reliever for aches – is adequate for recovery in most cases. (A non-aspirin pain reliever should be used by children and young adults because of the risk of Reye’s syndrome.)”

Given the global spread of this pandemic influenza (H1N1) 2009 it is important to make this information available and familiar on a world-wide scale, to the general public, in addition to the health care community. This request was made previously in a Newsletter on this website (www.BePast.org) August 2nd.

This risk communication message would be greatly facilitated by stand-alone documents that include “Reye’s syndrome” and “Avoid Aspirin” in the title on influenza websites ranging from the WHO, to CDC, to state, county, and city public health departments as well as widespread and multi-modality coverage by the media.

8 October 2009

Daniel R. Lucey, MD, MPH

Does Infection with the Pandemic H1N1 Influenza A Virus/2009 Confer Protection Against Re-Infection?

In an extensive interview with USA Today’s Editorial Board, Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) was asked “If you suspect that you’ve been exposed to swine flu, should you still get vaccinated?”(See “Swine Flu: What You Need to Know”, October 7, page 9A).

Dr. Fauci’s was: “Yes, because you just don’t know. There are a lot of viruses out there that aren’t necessarily influenza. If I had a laboratory test that definitively said, yes, you did get infected with H1N1, I would tell you no, don’t get vaccinated because natural vaccination is the best vaccine you can give for yourself. But unless you’re sure, I would go ahead and take it.”

Today’s (Oct 8) NY Times front page contains a detailed article titled “Areas Hard Hit by Flu in Spring See Little Now” by Anemona Hartocollis and Donald G. McNeil, Jr. (p.A1 and A4). The pandemic H1N1/2009 influenza A experience in New York City is cited:

“…New York City health officials now believe that while 10 percent to 20 percent of New Yorkers were reportedly ill with flu last spring, as many as 20 percent to 40 percent may have been exposed to the disease and developed immunity that has prevented it from spreading”.

“Although it is too early to be sure, they said, the high level of immunity may mean that the second wave of swine flu infection ends up being far less extensive than expected.”

“The immunity theory has gained enough credence that Dr. Thomas A. Farley, New York City’s health commissioner, put it forward at a conference on the national preparations for H1N1 last Friday in New York, led by Kathleen Sebelius, the health and human services secretary, and Dr. Thomas R. Frieden, director of the disease control centers…”

Unfortunately, routine laboratory tests with a rapid turn-around time are not available to prove whether or not protective immunity is certain in persons who were already infected and recovered from this pandemic influenza A H1N1/2009 virus. If such protection could be proven, then indeed such “immune survivors” might not need to receive the pandemic flu vaccine, take anti-influenza drugs, or perhaps require the same personal protective equipment (PPE) as non-immune persons.

This writer, along with many others such as John Barry, has raised this concept previously. For example, in a letter to the Washington Post three years ago, on April 29, 2006 and in this www.BePast.org Newsletter space on May 2, 2006, and again three years later on May 4, 2009, as well as in a slide presentation Feb 24, 2007 at the first International Meeting on Emerging Diseases (IMED 2007) in Austria and in a similar presentation to the FDA (CDER) on April 30, 2007.

The influenza historian John Barry, and colleagues, concluded in a paper in the 15 Nov 2008 Journal of Infectious Diseases that “Exposure to influenza in the spring and summer of 1918 provided mortality and morbidity protection during the fall pandemic wave. The intensity of the first wave may have differed across US cities and countries and may partly explain geographic variation in pandemic mortality rates in the fall. Pandemic preparedness plans should consider that immune protection could be naturally acquired during the first wave of mild influenza illness.”

In my opinion, we can hope that both epidemiological data and immunological data will be forthcoming this fall 2009 and in the winter 2010 that will either prove or disprove this immunity hypothesis regarding pandemic influenza. If so, such evidence should help national and international preparedness efforts for future waves of this pandemic flu virus, and future influenza pandemics.

15 October 2009

Daniel R. Lucey, MD, MPH

WARNING following Fatality : Relenza (zanamivir) is NOT recommended for use in a nebulizer or mechanical ventilator

In a “Dear Healthcare Professional Letter” dated October 8, 2009 GlaxoSmithKline (GSK) strongly emphasized that its anti-influenza drug Relenza (zanamivir) inhalation powder “is not intended to be reconstituted in any liquid formulation and is not recommended for use in any nebulizer or mechanical ventilator”.

The company reported that they received a report of the death of a “pregnant woman on mechanical ventilation who received zanamivir solution made from dry powder product from RELENZA Rotadisks via nebulizer for three days. Death was attributed to obstruction of the ventilator. The reporting physician believed that the obstruction in the ventilator was due to stickiness caused by lactose (from RLENZA Inhalation Powder) in the nebulizing solution.”

GSK stated furthermore that “RELENZA Inhalation Powder is a mixture of zanamivir active drug substance (5mg) and lactose drug carrier (20mg). This formula is not designed or intended to be administered by nebulization. There is a risk that the lactose sugar in this formulation can obstruct proper functioning of mechanical ventilator equipment.”

20 October 2009

Daniel R. Lucey, MD, MPH

Today the CDC posted the following important information regarding the anti-influenza medication Tamiflu (oseltamivir) for children.

QUESTIONS & ANSWERS

Opening and Mixing Tamiflu® Capsules with Liquids if Child Cannot Swallow Capsules

October 20, 2009 5:30 PM ET

Is there a shortage of oral suspension (liquid) Tamiflu®?

The Food and Drug Administration (FDA) and the maker of Tamiflu® (Roche ) have said that available supplies of liquid Tamiflu® for children are limited.

What is being done about this?

There are child doses of Tamiflu® in capsules (30 mg and 45 mg). It also is possible for a pharmacist to create a liquid children’s dose using adult doses of Tamiflu®. CDC is alerting pharmacists, doctors, and parents about these options. (Note: Children weighing more than 88 pounds would receive a 75 mg dose Tamiflu®, which is the adult dose.)

What can I do if my child cannot swallow capsules?

If your doctor prescribes Tamiflu® capsules for your child and your child cannot swallow capsules, the prescribed capsules may be opened and mixed with a sweetened liquid, which may be sugar-free, that the child will consume completely.

What liquids can I use?

A thickened and sweet liquid that masks the flavor of the medicine can be mixed with the contents of the Tamiflu® capsule. Sugar-free sweetened liquids are available. The child should consume the liquid mixture entirely. Examples are: applesauce, corn syrup, pudding, or chocolate/caramel/butterscotch syrup. Honey may be used if the child is older than 1 year.

If my child can’t swallow capsules, how do I open Tamiflu capsules and mix the medicine?

Carefully open the Tamiflu® capsule and mix the powder inside the capsule with regular or sugar-free chocolate syrup. Use only the prescribed dose.

What will I need to do this?

You will need

The prescribed Tamiflu® capsule

A small bowl or cup and a spoon

1-2 Teaspoons of sweetened liquid

How do I mix the ingredients?

Holding one capsule over a small bowl, carefully pull the capsule open and pour the complete contents of the capsule into the bowl.

Add 1-2 teaspoons of the sweetened liquid that the child will consume completely.

Stir the mixture and give the entire dose to the child.

Should my child take all of the mixture?

Yes, make sure your child takes all of the medicine mixture.

October 24, 2009

Daniel R. Lucey, MD, MPH

President Obama Signs Emergency Declaration for H1N1 Flu

Authority

Section 1135 of the Social Security Act [42 USC §1320b–5] permits the Secretary of Health and Human Services to waive certain regulatory requirements for healthcare facilities in response to emergencies. Two conditions must be met for the Secretary to be able to issue such “1135 waivers”: first, the Secretary must have declared a Public Health Emergency; second, the President must have declared a National Emergency either through a Stafford Act Declaration or National Emergencies act Declaration. If these conditions are met, then healthcare facilities may petition for 1135 waivers in response to particular needs, and only within the geographic and temporal limits of the emergency declarations.

Under Section 1135:

The Secretary may tailor authorities granted under Section 1135 waivers to match the specific situational needs, but the requirements that may be waived include those related to Medicare, Medicaid or the Children’s Health Insurance Program (CHIP), the Emergency Medical Treatment and Active Labor Act (EMTALA), and the Health Insurance Portability and Accountability Act (HIPAA). These requirements provide important protections for patients during normal day-to-day operations, but they may impede the ability of healthcare facilities to fully implement disaster operations plans that enable appropriate care during emergencies. For example, requirements under the Emergency Medical Treatment and Active Labor Act (EMTALA) would prohibit hospitals from certain rapid triage or sorting activities and prevent the establishment of off-site, alternate care facilities that could off-load emergency department demand.

Waivers are permitted only to the extent they ensure that sufficient health care items and services are available to meet the needs of Medicare, Medicaid, and CHIP beneficiaries in the emergency area during the emergency period. The “emergency area” and the “emergency period” are the geographic area, in which, and the time period, during which, the dual declarations exist.

Permitted actions include the waiver or modification of conditions of participation, other certification requirements, program participation requirements, pre-approval requirements for health care providers; waiver of sanctions for certain directions or relocations and transfers that otherwise would violate the Emergency Medical Treatment and Labor Act (EMTALA); waiver of sanctions related to Stark self-referral prohibitions; modifications to deadlines and timetables for the performance of required activities; and waiver of sanctions and penalties arising from noncompliance with certain Health Insurance Portability and Accountability Act (HIPAA) privacy regulations.

Examples of use of waivers:

Hospitals request to set up an alternative screening location for patients away from the hospital’s main campus (requiring waiver of the Emergency Medical Treatment and Labor Act-EMTALA)
Hospitals request to facilitate transfer of patients between ERs and inpatient wards between hospitals (requiring waiver of both EMTALA and HIPAA regulations)
Critical Access Hospitals requesting waiver of 42 CFR 485.620, which requires a 25-bed limit and average patient stays less than 96 hours
Skilled Nursing Facilities requesting a waiver of 42 CFR 483.5, which requires CMS approval prior to increasing the number of certified beds in a distinct part

Past instances where authority to grant Section 1135 waivers was enabled for recent disaster events include

Hurricane Katrina (2005)
56th Presidential Inauguration (2009)
Hurricanes Ike and Gustav (2008)
North Dakota flooding (2009)

Q: Why do this now; why can’t we wait until a hospital or region needs these 1135 Waivers?

A: The H1N1 epidemic is moving rapidly. By the time regions or healthcare systems recognize they are becoming overburdened, they need to implement disaster plans quickly. 1135 Waivers still require specific requests be submitted to HHS and processed, and some State laws may need to be addressed as well. Adding a potential delay while waiting for a National Emergency Declaration is not in the best interest of the public, particularly if this step can be done proactively as the President has done today.

Q: Has the authority to grant 1135 waivers been granted before?

A: Yes, there are several instances where 1135 Waiver authority has been granted under the Stafford Disaster Relief and Emergency Assistance Act (vice National Emergencies Act) to help healthcare facilities cope with large patient burdens. Recent examples include Hurricane Katrina (2005), Hurricanes Ike and Gustav (2008), and the North Dakota flooding (2009). In addition, 1135 waiver authority has been granted previously as a precautionary measure, as in the case of the recent 56th Presidential Inauguration (2009).

Q: Specifically, what will this NEA Declaration enable and what will this allow hospitals to do, if a waiver is requested and granted?

A: An NEA Declaration fulfills the second of the two conditions required for the Secretary of HHS to be able to grant 1135 waivers. If requested, and HHS grants an 1135 waiver, healthcare facilities will be able to utilize alternate care sites, modified patient triage protocols, patient transfer procedures, and other actions that occur when they fully implement disaster operations plans.

Q: Is the HIPAA Privacy Rule suspended during a national or public health emergency?

A (from the HHS Office of Civil Rights website): No; however, the Secretary of HHS may waive certain provisions of the Rule under the Project Bioshield Act of 2004 (PL 108-276) and section 1135(b)(7) of the Social Security Act.

What provisions may be waived

If the President declares an emergency or disaster and the Secretary declares a public health emergency, the Secretary may waive sanctions and penalties against a covered hospital that does not comply with certain provisions of the HIPAA Privacy Rule:

The requirements to obtain a patient’s agreement to speak with family members or friends involved in the patient’s care (45 CFR 164.510(b))
The requirement to honor a request to opt out of the facility directory (45 CFR 164.510(a))
The requirement to distribute a notice of privacy practices (45 CFR 164.520)
The patient’s right to request privacy restrictions (45 CFR 164.522(a))
The patient’s right to request confidential communications (45 CFR 164.522(b))

When and to what entities does the waiver apply

If the Secretary issues such a waiver, it only applies:

1. In the emergency area and for the emergency period identified in the public health emergency declaration.

2. To hospitals that have instituted a disaster protocol. The waiver would apply to all patients at such hospitals.

3. For up to 72 hours from the time the hospital implements its disaster protocol.

When the Presidential or Secretarial declaration terminates, a hospital must then comply with all the requirements of the Privacy Rule for any patient still under its care, even if 72 hours has not elapsed since implementation of its disaster protocol.

Regardless of the activation of an emergency waiver, the HIPAA Privacy Rule permits disclosures for treatment purposes and certain disclosures to disaster relief organizations. For instance, the Privacy Rule allows covered entities to share patient information with the American Red Cross so it can notify family members of the patient’s location. See 45 CFR 164.510(b)(4).

Learn More: * See http://www.hhs.gov/ocr/privacy/hipaa/understanding/special/emergency/katrinanhipaa.pdf for information on sharing information in emergency situations

2 November 2009

Daniel R. Lucey, MD, MPH

NIH announces successful results of first study in pregnant women of a non-adjuvanted, thimerosol-free, pandemic flu H1N1 vaccine

Today the US National Institutes of Health, NIAID, posted on their website the following press release at: http://www3.niaid.nih.gov/news/newsreleases/2009/H1N1pregnantresults.htm

“Healthy pregnant women mount a robust immune response following just one dose of 2009 H1N1 influenza vaccine, according to initial results from an ongoing clinical trial sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health.

“For pregnant women, who are among the most vulnerable to serious health problems from 2009 H1N1 infection, these initial results are very reassuring,” says NIAID Director Anthony S. Fauci, M.D. “The immune responses seen in these healthy pregnant women are comparable to those seen in healthy adults at the same time point after a single vaccination, and the vaccine has been well tolerated.”

According to the Centers for Disease Control and Prevention, since the outbreak began last spring, at least 100 pregnant women have been hospitalized in intensive care units in the United States and at the last official count, 28 pregnant women have died.

A preliminary analysis of blood samples taken 21 days post-vaccination from a subgroup of 50 pregnant women participating in the trial shows the following:

In 25 women who received a single 15-microgram dose of the vaccine, theH1N1 flu vaccine elicited an immune response likely to be protective in 92 percent, or 23 of 25, of these women.

In 25 women who received a single 30-microgram dose of the vaccine, the H1N1 flu vaccine elicited an immune response likely to be protective in 96 percent, or 24 of 25, of these women.

The trial began on Sept. 9 and reached its target enrollment of 120 volunteers in mid-October. All participants are between 18 to 39 years old and began the study in their second or third trimester (14 to 34 weeks) of pregnancy.

At entry into the study, the participants were divided at random into two groups: half are receiving two doses of a 15-microgram vaccine and the other half are receiving two doses of a 30-microgram vaccine. The two injections of vaccine are spaced three weeks apart.

Safety is being monitored closely in the trial, by the study investigators and by an independent panel of experts known as a safety monitoring committee. To date, the vaccine appears to be well-tolerated, and no safety concerns related to the vaccine have arisen.

The vaccine used in this clinical trial was manufactured by Sanofi Pasteur in its plant in Swiftwater, Pa., in the same manner as the company’s injectable seasonal influenza vaccine. Like the seasonal flu vaccine, the 2009 H1N1 flu vaccine contains a purified portion of the killed virus and therefore cannot cause infection. The vaccine does not contain the preservative thimerosal or an immune boosting substance known as an adjuvant.

NIAID is conducting this trial through five clinical sites affiliated with its longstanding clinical trials network known as the Vaccine and Treatment Evaluation Units. For additional information about the NIAID trial in healthy pregnant women, see the Sept. 9 NIAID news release and related Q&A. For more information on influenza, including pandemic influenza and avian influenza, visit www.flu.gov. Also see NIAID’s influenza Web portal at http://www3.niaid.nih.gov/topics/Flu/”

6 November 2009

Daniel R. Lucey, MD, MPH

Ukraine MOH reports one week (Oct 29-Nov 5) increase from 951 to 28,836 Hospitalized Patients due to “Acute Respiratory Illness (ARI)”

Today (Nov 6, Friday) the European Center for Disease Prevention and Control (ECDC) posted their Daily Update on Pandemic (H1N1) 2009 website striking data provided by the Ministry of Health (MOH) of the Ukraine in the form of the following table, graph, and map. The full document can be found on the ECDC website as a pdf at: http://ecdc.europa.eu/en/healthtopics/Documents/091106_Influenza_AH1N1_Situation_Report_0900hrs.pdf

The data report a daily rapid rise in the number of patients with ARI from 37, 923 on Thursday, October 29th to 633,877 on Thursday, November 5. The number of deaths during this week rose from 30 to 95. The number of hospitalizations increased dramatically, an immense strain on any nations’ healthcare infrastructure, from 951 to 28, 836 (See the table and color graph below.)

The majority of these respiratory illnesses are reported from western Ukraine (oblasts). Bordering nations include Poland, Slovakia, Hungary, and Romania. To date, these nations have not reported large numbers of respiratory infections on their borders with the Ukraine.

The European Union Community Civil Protection Mechanism and the European Commission’s Monitoring and Information Centre have been requested to assist and have already deployed to Ukraine.

The WHO on Sunday, Nov 1^st, and Tuesday, November 3^rd has posted updates on the situation in Ukraine. The MOH of Ukraine has also requested and received a team of experts from WHO to assist with the assessment of the illness.

Yesterday (Nov 5^th) the WHO “virtual press conference” included comments by Dr. Keiji Fukuda of WHO regarding the situation ion the Ukraine. He provided a balanced update, noting that some of the cases are due to lab-confirmed H1N1 virus infection. He noted that sequencing of these H1N1 isolates is ongoing in a WHO-linked laboratory. So far, preliminary analyses have not shown any significant mutations. More information is anticipated in this regard as the data becomes available.

Rumors of a plague (yersinia pestis) outbreak have been denied by the Ukrainian government as reported in the media. In my opinion, pneumonic plague is not consistent at all with the relatively low number of fatalities from October 29-November 5, given the high case fatality rate of pneumonic plague unless treated rapidly and with appropriate antibiotics and medical care.

This is a rapidly evolving situation that warrants close monitoring. More information is expected over this weekend and the days to come.

16 November 2009

Daniel R. Lucey, MD, MPH

WHO Update on Ukraine Pandemic Influenza A H1N1 Virus: No Evidence of Increased Severity

During the most recent (Nov 12) weekly World Health Organization (WHO) “virtual press conference” held every Thursday (at 1pm Geneva time) a question was asked regarding the pandemic influenza A (H1N1) situation in the Ukraine. A question was posed to the WHO’s Dr. Nikki Shindo, by David Brown of the Washington Post, to talk about countries that the Dr. Shindo had said were “being overwhelmed” by the virus.

According to the transcript posted at: www.who.int/mediacentre/vpc_transcript_12_november_2009_nikki_shindo.pdf Dr. Shindo replied: “I can answer based on the information we received from the Ukraine. The relatively severe cases proportion wise is less than what we had heard from the southern hemisphere. It seems like a load of patients being admitted with rather mild symptoms than people requiring ICU care. And mostly admitted people (are) young adults and middle age adults and we have not seen so much of pediatric patients overwhelming pediatric wards.”

Another relevant document was also posted (see below) November 12 on the WHO European Region website: www.euro.who.int/influenza/AH1N1/20091112_1

“Health facilities in Ukraine well prepared for pandemic (H1N1) 2009 influenza

On Wednesday, 11 November, the last WHO regional investigation team returned to Kyiv. While the teams have yet to finish drawing conclusions, they found health facilities in Ukraine well prepared and highly motivated to deal with the influx of cases.

In separate meetings with the Prime Minister and the President of Ukraine on Monday, 9 November (also attended by the ministers of Foreign Affairs and Health), the WHO mission thanked the Government for its openness and providing unrestricted access to facilities and data. The discussion focused on further action needed to combat the disease, particularly vaccinating the main risk groups in the population. WHO once more offered its full support in all necessary activities.

On 11 November, the Ministry of Health arranged and led a teleconference in Kyiv, connecting 486 hospitals and nearly 10 000 doctors in all 27 regions of Ukraine to facilitate sharing of clinical experience and lessons learned in fighting the pandemic (H1N1) 2009 virus. Clinicians in the worst affected areas had detailed discussions on what therapies they had used and how these could be adapted for the future. The participants discussed a wide range of issues and developments, including primary, obstetrical and intensive care and the essential supplies and equipment that were currently available and being mobilized.”

Further updates from the Ukraine are anticipated.

2 December 2009

Daniel R. Lucey, MD, MPH

WHO Recommends Increased Oseltamivir for Severely Immunocompromised Hospitalized Patients with Pandemic H1N1 Virus Infection

Today the World Health Organization (WHO) posted on their pandemic influenza webpage modified treatment recommendations for patients who are severely immunocompromised. Key points included:

“In these patients, standard treatment doses and duration for treatment with oseltamivir are unlikely to be sufficient. Though clinical judgement is important, doses may need to be increased and continued, without interruption, for the duration of acute illness…”
“Zanamivir should be considered as the treatment of choice for patients who develop prolonged influenza illness despite treatment with oseltamivir.”
“Once oseltamivir resistant virus has been detected in a ward treating severely immunocompromised patients, doctors should consider switching to zanamivir as the antiviral drug of choice for treatment and when considering post exposure prophylactic treatment of other patients on the ward.”

The complete two-page WHO document, “Pandemic (H1N1) 2009 briefing note 18” can be accessed at: www.who.int/csr/disease/swineflu/notes/briefing_20091202/en/index.html

These new WHO recommendations were formulated after WHO organized a telephone conference with “experts in clinical medicine, epidemiology, and virology” as well as “officials and staff from the hospitals” with the two hospital wards (one each in Wales, UK and North Carolina, USA) where clusters of immunocompromised patients with oseltamivir-resistant pandemic H1N1 viruses were recently reported.

All 12 immunocompromised patients (8 in Wales, 4 in the US) in these two clusters had the same H275Y mutation that confers resistance to the oral drug oseltamivir (Tamiflu).

All of these virus isolates, however, continue to be susceptible to the inhaled neuraminidase inhibitor drug zanamvir (Relenza).

This rapid response by WHO to the two reported clusters of oseltamivir-resistant pandemic H1N1 virus is admirable. It would be useful to have additional information included on these 12 virus isolates regarding their susceptibility or resistance to the newly available intravenous neuraminidase inhibitor drug peramivir.

18 December 2009

Daniel R. Lucey, MD, MPH

Two anthrax infections, one fatal, reported in injection drug users in Scotland

Two persons with laboratory-confirmed Bacillus anthracis (anthrax) infection were reported yesterday in Scotland by the BBC(<http://news.bbc.co.uk/2/hi/uk_news/scotland/glasgow_and_west/8419113.stm), and then by ProMED on their website www.promedmail.org.

One of the patients died on 16 December. Both were hospitalized in Glasgow’s Victory Infirmary. A 3^rd patient is being tested at Glasgow Royal Infirmary, and other heroin injection drug users are being investigated. According to the BBC online article and linked video, Public Health officials have sent out multiple alerts to enhance surveillance for any further cases of anthrax in injection drug users.

No direct epidemiological link (“epi-link”) has been made so far, for example to the heroin itself or to material with which it is cut, either overseas or in the UK. Investigations are ongoing.

No public information is available regarding the antibiotic susceptibility or resistance pattern of the Bacillus anthracis isolates. Resistance to any of the usual classes of antibiotics used to prevent or treat B. anthracis would be cause for increased concern as to the origin of the isolates.

Follow-up information is anticipated.

As noted in a Newsletter on this website (www.BePast.org) 7 September 2007, reports of cutaneous anthrax can reinforce the importance for clinicians of having useful references readily available, for example:

—The American College of Physicians (ACP) has posted on their website a PowerPoint presentation with 60 slides titled “Cutaneous Anthrax and its Mimics”. Most of the 20 diseases in the differential diagnosis of cutaneous anthrax also have photos provided. Discussion of all 20 diseases ends with a final slide that helps differentiate the disease from cutaneous anthrax. For example, the bite of the brown recluse spider (Loxosceles reclusa) causes a painful lesion, whereas the lesion of cutanous anthrax is PAINLESS. Also of note, the brown recluse spider bite occurs mainly in the Midwest and Southeast of the US and not in the northeast (e.g., Connecticut). These slides by the ACP and American Society of Internal Medicine are posted at: www.acponline.org/bioterro/#pflu

—The American Society of Dermatology (AAD) posted on their website in November 2001 a detailed “Cutaneous Anthrax Management Algorithm”. This document includes clinical pearls describing the typical appearance and progression of cutaneous anthrax. For example, they note that “pustules are rarely present in anthrax lesions”. Also, although the skin lesion is usually PAINLESS the associated regional lymphadenopathy is usually “tender”. This document also provides specific detailed advice on how best to obtain swab exudates and punch biopsies from the lesion(s), including the type of swab to use, and where exactly to biopsy. This algorithm is posted at: www.aad.org/professionals/educationcme/bioterrorism/CutaneousAnthrax.htm

— The CDC anthrax webpage (at: www.bt.cdc.gov/agent/anthrax) has a specific section on the diagnosis and management of cutaneous anthrax, as well as images of cutaneous anthrax (at: www.bt.cdc.gov/agent/anthrax/anthrax-images/cutaneous.asp). Additional images, cutaneous and microscopic, are also posted on the CDC’s “Public Health Images Library (PHIL), with the largest number of skin photos on page 5 of 8.

—The Infectious Diseases Society of America (IDSA) website contains comprehensive information on all forms of anthrax (at: www.cidrap.umn.edu/idsa/bt/anthrax/biofacts/anthraxfactsheet.html)

This document includes images of cutaneous anthrax, diagnostic steps, therapy and literature references.

—Additional images of cutaneous anthrax can be found on the homepage of this website (www.BePast.org), as well as on the website of the E-Medicine chapter on dermatologic aspects of anthrax (at: www.emedicine.com/derm/topic913.htm).

Without appropriate antibiotics the case-fatality rate has been approximately 20%. Increased risk of death is linked with airway compression due to a cutaneous lesion on the neck (with characteristic extensive edema), or with the development of bacteremia, especially if complicated by meningitis.

A discussion of all aspects of clinical anthrax is also provided by this author in the 6^th edition (2005) of the textbook “Principles and Practice of Infectious Diseases” edited by Mandell, Bennett, and Dolin (pages 2485-2491 and 3618-3624)

31 December 2009

Daniel R. Lucey, MD, MPH

Indonesia Ministry of Health announces 20 H5N1 Avian Flu cases, with 19 deaths, in the year 2009 (in contrast to Egyptwith 4/39 fatal cases in 2009).

As of several months ago, the new Health Minister of the Republic of Indonesia is Dr. Endang Rahayu Sedyaningsih, Ph.D., MPH.

On 28 December the website of the Ministry of Health (MOH) of Indonesia announced the number of new cases of H5N1 Avian flu virus for the year 2009. A total of 20 new cases, with 19 deaths, were reported for this year. No clinical or demographic information was provided either by the MOH or by the World Health Organization (WHO) in their update 30 December of worldwide H5N1 cases, totaling 467 with 262 deaths, posted at: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2009_12_30/en/index.html

The Indonesian MOH also announced that since the first H5N1 virus patient was reported in 2005 there have been 161 lab-confirmed cases and 134 deaths. The following complete statement from the MOH can be read at:

http://www.depkes.go.id/index.php?option=news&task=viewarticle&sid=3663. The full MOH statement from 28 December reads:

Situasi Flu Burung Tahun 2009
28 Dec 2009
Sejak 1 Januari hingga 28 Desember 2009, terdapat 20 kasus H5N1 di Indonesia, 19 diantaranya meninggal dunia. Kasus H5N1 pertama terjadi pada tanggal 9 Januari di Bogor, sementara kasus terakhir ditemukan tanggal 23 September 2009 di Jakarta Selatan. Dengan demikian secara kumulatif, total kasus H5N1 sejak tahun 2005 – 2009 berjumlah 161 kasus 134 diantaranya meninggal dunia.   Berita ini disiarkan oleh Pusat Komunikasi Publik, Sekretariat Jenderal Departemen Kesehatan. Untuk informasi lebih lanjut dapat menghubungi melalui nomor telepon: 021-52907416-9, faks: 52921669, Call Center: 021-30413700, atau alamat e-mail puskom.publik@yahoo.co.id, info@puskom.depkes.go.id, kontak@puskom.depkes.go.id.

It is hoped that further international collaboration will occur in 2010 with regard to the ongoing sporadic human avian influenza H5N1 virus infections, particularly with regard to possible explanations for the much higher case fatality rates reported in 2009 from Indonesia (95% = 19/20 cases) compared with, for example, Egypt (10% =4/39 cases).