4 January 2007
Daniel R. Lucey, MD, MPH
US Funds Clinical Development of Peramivir, a Parenteral Neuraminidase Inhibitor Influenza Antiviral Drug
On January 4 the US Department of Health and Human Services announced on their pandemic influenza website (www.pandemicflu.gov) that they had awarded a four-year contract for $102.6 million for further clinical development of the influenza antiviral drug “peramivir” by Biocryst Pharmaceuticals, Inc., based in Birmingham, Alabama.
The website of Biocryst (www.biocryst.com) notes that in 2002 results of a Phase III clinical trial using an oral (pill) formulation of the drug failed to show statistical significance for the primary endpoint. The company is now developing peramivir for parenteral administration (intravenously (IV) or intramuscularly (IM)) due to the apparent low bioavailability of the oral formulation.
HHS funding is reported to be used for Phase 2 and 3 clinical trials using parenteral (not oral) administration of the drug. The Food and Drug Administration (FDA) has given “Fast Track” designation to peramivir and thus regulatory review will be accelerated.
The HHS news release today also states that their funding for clinical development of parenteral peramivir will include study of both “seasonal and life-threatening influenza, including highly pathogenic H5N1 influenza”.
Addition of an influenza antiviral neuraminidase inhibitor drug such as peramivir would be a welcome addition for clinicians to have given that Tamiflu can only be given orally and Relenza only by an inhaler. Moreover, some patients cannot absorb drugs adequately, particularly when critically ill. Furthermore, some patients cannot take Relenza via an inhaler especially if they have a preexisting lung disease.
18 January 2007
Daniel R. Lucey, MD, MPH
Indonesia to Ban Poultry in Residential Areas as H5N1 Virus Surges in Asia and Africa
Since December 2006 a surge in H5N1 avian influenza virus infections have been reported in poultry in multiple nations and a limited number of laboratory-confirmed human cases have occurred in Indonesia, Egypt, and China. Nations reporting new H5N1 outbreaks in animals include Thailand, Japan, South Korea, Vietnam, Indonesia, Egypt, and Nigeria. The outbreak in Thailand was reported by the Bangkok Post January 16th as the fifth round of H5N1 outbreaks since January 2004, and the first in six months, occurring on a duck farm in Phitsanulok province.
Indonesia has reported five (5) laboratory-confirmed human infections with the H5N1 avian flu virus to the World Health Organization (WHO) this month. One included a woman and her 18 year-old son. No other family members have tested positive and to date no other family clusters have been confirmed. Of note, there is still no evidence of a mutation or reassortment of H5N1 flu virus that has allowed sustained transmission of the virus from person-to-person-to-person-to person.
Indonesia has reported a plan to forbid domesticated birds in residential areas, according to The Jakarta Post January 17 (Headline News. “City “Workers Prepare for Bird Culls” by Theresia Sufa). The Jakarta Post article states that Jakarta Governor Sutiyoso “called on city residents to voluntarily slaughter all backyard fowls–especially chickens, ducks, and pigeons—to curb the spread of bird flu”. Sutiyosos’s statement “followed an announcement by Vice President Jusuf Kalla that the central government planned eventually to enforce a total ban on all poultry in residential areas nationwide”.
Currently, however, the critical issues of monetary compensation to poultry owners and laws to support the planned widespread culling of poultry in residential areas in Jakarta and across the Indonesian archipelago must be addressed. The societal and financial impact of such widespread culling could be profound.
International support in terms of compensation for loss of both small numbers of poultry and for owners of larger commercial poultry industries could be argued to be of multidimensional international benefit given the immense costs of a human influenza global epidemic if a highly pathogenic avian influenza virus acquires the ability to spread between humans in a sustained and efficient manner.
22 January 2007
Daniel R. Lucey, MD, MPH
3-Part CDC Plan to Deliver Antivirals, Masks and Respirators, and other Countermeasures after WHO Pandemic Flu Phase 4 is Declared
The US CDC recently posted their “Influenza Pandemic Operation Plan” (OPLAN) on their website (www.cdc.gov/flu/pandemic/cdcplan.htm). This 350-page plan, last updated 20 December 2006, provides insight into multiple aspects of pandemic flu preparedness. For example, Annex G (pages 245-258) details guidance on timely delivery of critical “Countermeasures” against a future pandemic influenza virus.
Appendix 1 (Strategic National Stockpile “SNS”) to Annex G provides the following background/assumptions (page 251):
1. “The World Health Organization (WHO) will declare Phase 4 of an influenza pandemic when there is a confirmed small cluster of limited human-to-human transmission of avian influenza, with spread being highly localized. The Federal government will engage Stage 2 of its response at this point.
2. The director CDC, in consultation with the Secretary HHS or his/her designee, will determine when to activate the Strategic National Stockpile (SNS) to begin the distribution of critical medical material based on the WHO Phase characterization and the severity of the disease.
3. All 62 CDC Public Health emergency Preparedness (PHEP) projects areas (all 50 states, the three large urban areas, the District of Columbia, Puerto Rico, the U.S. Virgin Islands, and the six Pacific Jurisdictions) have incorporated distribution of medical countermeasures into their pandemic plans.”
Delivery of countermeasures (p. 253) will occur in three (3) parts:
Part 1: Antiviral drugs: Estimated to take 7 days.
Part 2: Masks and respirators: to take the next 7-10 days after Part 1.
Part 3: More Personal Protective Equipment (PPE) including protective face shields, gowns, gowns, as well as intravenous antibiotics (for secondary bacterial pneumonias and other infections that will predictably occur to varying extents in patients who become infected with the pandemic influenza virus), mechanical ventilators and other equipment. To begin after Parts 1 and 2 are completed (i.e., after 14-17 days).
90% of this critical material deployed during Part 3 of the response will be shipped pro rata. 10% will be held back, however, and “allocated via a case-by-case approval process based on State needs and requests” and also to be available in the event of a second simultaneous emergency (either natural or human in origin).
Part 1 (antiviral influenza drugs) and Part 2 (masks and respirators) are to be distributed based on population (“pro rata”) “pushing product proactively to a single location in each of the CDC/SNS 62 project areas”.
Of note, these antiviral drugs are to be deployed “to the States prior to receipt of a request”, thereby ensuring “that States receive supplies before the need for assets becomes critical”. In addition, “Shipping product out at the first signs of a pandemic and before a State request will also ensure that the SNS staff and federal transportation partners are available in full capacity to aid in the federal response, and be ready to respond to other events” (e.g., a bioterrorist event or a second natural disaster).
One other notable difference between SNS policies already in place and this current pandemic flu plan is that the “Technical Advisory Response Unit (TARU) teams will not deploy. Once a project area accepts Federal assets, they will become the property of that project area (p.255).”
Detailed, successive, and complementary US and global plans for the next pandemic of human influenza should be welcomed because much as “waves” of pandemic influenza infections should be anticipated to occur, so should there be “Waves of Pandemic Preparedness” before the epidemic emergency begins.
31 January 2007
Daniel R. Lucey, MD, MPH
WHO H5N1 Flu Investigation Guidelines: 7 Days is the Patient’s Incubation Period Upper Limit, and -1 to +14 Days is the Time Frame for Contact Tracing
On January 29th the World Health Organization posted on their avian flu website a 15-page revision of their October 2006 document titled “WHO Guidelines for investigation of human cases of avian influenza A (H5N1). This update is particularly timely given that WHO announced today on their website that the government of Nigeria has reported their first human infection with H5 avian flu (confirmation pending).
Of note, for essential diagnostic, contact tracing, isolation and quarantine purposes this document states (page 4 last sentence) that “Based on currently available information and for purposes of conducting investigations, 7 days is considered to be the usual upper limit of the incubation period for human cases of A (H5N1)”. For example, this 7 day upper limit for the incubation period explains the WHO guidance to take a “travel history: for the 7 days before the onset of illness symptoms, asking particularly about contact within those 7 days with possibly H5N1-infected animals or humans.
An important distinction should be made, however, between this 7 day incubation period upper limit and the medically unrelated WHO guidance (middle of page 7) that contact tracing“ should focus on persons who had close unprotected (i.e., were not wearing PPE) contact with the case patient in the 1 day before through 14 days after the case patient’s illness onset.”
WHO states that the rationale for choosing the 1-day before until 14 days after illness onset is as follows (footnote on page 6):
(A): “Based on seasonal influenza studies which indicate virus shedding typically begins the day before symptom onset, comparable data are not available for H5N1”;
(B): “H5N1 virus is commonly detected in respiratory specimens during the first 2 weeks after illness onset. Although virus can be detected during the third week of illness for some patients with H5N1-related pneumonia, such patients would likely be hospitalized and isolated”.
Thus, the 7 days upper limit for an individual person’s incubation period from exposure to onset of symptoms, as advised by the WHO, is distinct from, and unrelated to, the 14 days upper limit for the number of days after illness onset in which contact tracing for potentially H5N1-exposed persons should be based. Given that 14 is the next multiple of 7 the risk for confusion exists in distinguishing between the upper limit of time for the incubation period and, separately, the operational upper limit of time recommended for contact tracing.
Lastly, 2 weeks (14 days) appears in the new WHO guidelines in one additional distinct situation, namely “enhanced surveillance” (page 10): “The duration of enhanced surveillance activities will need to be assessed for each investigation but typically would be expected to be undertaken for a minimum of 2 weeks (i.e., two incubation periods) after the last human case is identified.”
Understanding the rationale for the 7 day and 14 day (2 week) guidelines for each of the three specific situations described in this WHO document (on pages 4, 6, and 10) is essential to applying correctly these time periods to the investigation of human cases of H5N1 avian influenza.
12 February 2007
Daniel R. Lucey, MD, MPH
WHO Reports on 251 Persons with H5N1 Infection (2003-2006) and Confirms First Patient in Nigeria (2007)
The World Health Organization (WHO) 9 February issue of the weekly epidemiological record (WER) contains a detailed update on 251 WHO laboratory-confirmed patients with H5N1 avian influenza A infections from 25 November 2003-24 November 2006. On 3 February the WHO also confirmed the infection of the first patient in Nigeria (Lagos) with H5N1 virus infection.
The patient in Lagos, Nigeria’s largest city, was a 22 year-old woman who died on 16 January 2007. The definitive source of her infection is still under investigation. The 10 Feb 2007 issue of the International Herald Tribune carries an Associated Press article cites Tony Forman, the leader of the U.N. (FAO) team of experts assisting the Nigerian investigators, as attributing the human infection to exposure to a chicken purchased in a live bird market in Lagos just before Christmas. The young woman’s 52 year-old mother died on 4 January of similar flu-like symptoms, but tests for H5N1 have so far been negative for H5N1 infection, as have tests on other close contacts of the 22 year old patient.
Nigeria is the 11th nation to report lab-confirmed H5N1 avian flu infections in humans. The total number of lab-confirmed human infections with this virus is 271 of whom 165 (61 %) have died. The newspaper “Vanguard” published a report online on 5 February, by Chioma Obinna, stating that new outbreaks of H5N1 virus in avian populations have occurred in the states of Edo, Kwara, and Sokoto with at total of 17 states in Nigeria (including Lagos) having reported past H5N1 infections.
The WHO update summarizing clinical and epidemiological data on the initial 251 lab-confirmed patients with H5N1 influenza A virus infection contains 6 tables and 5 figures. Examples of the important findings include:
A: The overall case fatality rate was 60%.
B. Four days was the median time from symptom onset until hospitalization.
C. There was no statistical difference in median duration from symptom onset until hospitalization between persons who lived and those who died.
D. The media time from symptom onset until death was 9 days.
E. The median age was 18 years, with 52% of the 256 patients < 20 years and 89% < 40 years of age.
F. The gender ratio of cases was 1.0 (129 males/127 females).March 19-21, 2007 the WHO will hold its 2nd consultation on clinical aspects of human infection with H5N1 virus, in Antalya, Turkey.
6 April 2007
Daniel R. Lucey, MD, MPH
World Health Day: International Health Security Theme
On April 7 the World Health Organization (WHO) celebrates its founding with the annual World Health Day. This year the theme focuses on international health security. To initiate the events the new WHO Director-General, Dr. Margaret Chan, spoke at a high-level international meeting in Singapore on April 2nd. At the same time a multinational conference was held in Washington, DC at the Pan American Health Organization (PAHO) April 2-3.
Dr. Chan emphasized several key points:
- One of the greatest threats to international health security is “emerging and epidemic-prone diseases”.
- Modern activities that can contribute to such disease outbreaks include: the way we use and misuse antibiotics, how we produce and trade food, the high volume of air travel, and how we manage our environment.
- Outbreaks are a bigger threat today than 30 years ago in two ways. First, emerging infectious diseases are more numerous now. For example 39 human pathogens have been identified between 1973 and 2003. Approximately 75% of emerging human infectious diseases began as animal diseases. Second, the highly mobile and interconnectedness of the 21st century can amplify the damage caused by outbreaks. Examples include: the almost 2 billion airline passengers each year, interrelated financial markets, just-in-time production and global business sourcing, and electronic multimodality information exchange.
- In two months (June 2007), the new International Health Regulations (IHR), will allow WHO for the first time “to act on media reports to request verification and offer collaboration to an affected country. If this offer is refused, WHO can alert the world to an emergency of international concern using information other than official government notifications.” These new regulations should increase the ability of the WHO to act in a proactive manner to pre-empt “an outbreak early and stop it at its source—before it has a chance to become an international threat.”
- Misuse of antimicrobial drugs may result in a world “where mainstay antibiotics are no longer effective” and multidrug resistant viruses and bacteria can travel readily across international borders.
The complete transcript of Dr. Chan’s speech can be found on the WHO website under the section on World Health Day 2007 at: www.who.int/world-health-day/2007/toolkit/dg_message/en/index.html
10 April 2007
Daniel R. Lucey, MD, MPH
An overview of 3 parasitic infections: Chagas disease, schistosomiasis, and dracunculiasis
By Jessica Arabski, Mollie Hartung, Emily Iarocci, Akilah Jefferson, Cynthia Moreno and Elizabeth Morgan, Georgetown M.S. Graduate Program in Biohazardous Threat Agents and Emerging Infectious Diseases
Parasites depend on other organisms for survival and acquire resources at the expense of their hosts, which suffer health consequences as a result. Parasites such as protozoans and helminthes (worms) are a leading cause of disease in tropical, impoverished areas and enter the body through ingestion or penetration of the skin. The Centers for Disease Control and Infection (CDC) lists nearly 100 different parasitic infections affecting humans (www.cdc.gov). While many diseases exist, studying three prominent infections, Chagas disease, schistosomiasis and dracunculiasis, provides a broad overview of the parasites, hosts, symptoms, environmental factors, treatments and public health issues associated with parasitic infections.
Chagas disease, also known as American sleeping sickness, is caused by infection with the protozoan Trypanosoma cruzi. The illness is endemic in Mexico, Central America and South America, although cases have been documented as far north as the U.S. border. The parasite affects an estimated 11 million people annually, according to CDC. The Brazilian physician Carlos Chagas first discovered the infection in 1909.
Chagas disease is transmitted by certain species in the triatomine genus – part of the heteroptera, or “true bugs” order of insects – and survives on blood meals. The insects acquire the parasite after preying on an infected person or animal and then infect others during subsequent feedings. Triatomine are commonly found in mud and thatch houses, which provide spaces for the insects to hide during the day and are also prevalent in Central and South America, where most Chagas cases are isolated. Aside from direct contact with insect vectors, indirect infection can also occur through medical procedures such as blood transfusions and organ transplants, as well as consumption of food contaminated with insect feces. Congenital transmission is possible, too.
Chagas disease can assume both acute and chronic forms. The acute phase occurs directly after exposure and consists of mild non-specific symptoms such as fever, fatigue, muscle aches, diarrhea, vomiting, headaches, and localized swelling where the parasite enters the body, typically the facial area where the insect preferentially feeds. A trademark of acute Chagas disease is a symptom known as Romaña’s sign: swollen eyelids resulting from accidentally rubbing the feces the contaminated insect left behind into the eyes. Approximately five percent of patients – usually young children and the immunocompromised – develop a fatal infection of the heart or brain. Symptoms associated with the acute form of the illness usually last several weeks to months, although the untreated infection can persist and remain dormant for years. During the chronic phase, a third of those infected will develop cardiac and intestinal complications roughly 10 years after the original exposure. These symptoms can include enlargement of the heart, altered heart rate, heart failure and cardiac arrest, as well as enlargement of the esophagus or colon and complications related to eating or excretion.
Anti-parasitic treatments are effective against Chagas disease if administered early in the acute phase. Later delivery significantly diminishes effectiveness. Once the disease progresses to the chronic phase, treatment is restricted to alleviating symptoms.
While Chagas disease is a protozoan infection, schistosomiasis results from infection by flatworms, a type of helminth. The disease has a low mortality rate, but has high morbidity and causes incapacitating sequelae in millions of people each year. Formerly known as bilharzias after Theodor Bilharz, who identified the parasite in Egypt in 1851, schistosomiasis is acquired by humans through infection with Schistosoma haematobium, S. intercalatum, S. japonicum, S. mansoni and S. mekongi. A 2000 article in the tropical medicine journal Acta Tropica estimated that 85 percent of all cases occur in sub-Saharan Africa, although the parasite has also been isolated in southern Africa, Egypt’s Nile River valley, Brazil, Suriname, Venezuela, Antigua, the Dominican Republic, Guadeloupe, Martinique, Montserrat, Saint Lucia, Iran, Iraq, Saudi Arabia, the Syrian Arab Republic, Yemen, Southern China, the Philippines, Laos, Cambodia, Japan, central Indonesia, and Vietnam’s Mekong Delta.
Humans acquire schistosomiasis in freshwater bodies contaminated with infected human excretion. Feces and urine carry schistosome eggs that hatch once in water and seek a host in the form of specific snail species. The parasite multiplies asexually by the thousands and develops into a larval form that leaves the snail and is capable of infecting humans, who are exposed through ingestion, wading, bathing, washing laundry, or numerous economic activities involving fresh water. The flatworm penetrates the skin and grows inside the blood vessels, eventually producing eggs that migrate to the liver, intestines, or bladder and are passed in excretion. In some rare instances, eggs disseminate to the brain or spinal cord, resulting in seizures and paralysis. Schistosomiasis symptoms represent an immune response to parasite eggs rather than to the actual flatworm. Typical manifestations include a rash or itchy skin several days after infection, followed by non-specific symptoms such as fever, chills, coughing, and muscle aches roughly one to two months later. People repeatedly infected over the course of many years develop liver, intestinal, lung, and bladder damage. Schistosomiasis can also contribute to anemia and stunted growth.
Because schistosomiasis is acquired through contaminated water, the disease is often a symptom of poverty and represents lack of access to potable water. Globally, 200 million people are infected with the disease, according to the CDC. World Health Organization (WHO) statistics estimate the mortality at 11,000 deaths and the burden of disease representing 1.7 million Disability Adjusted Life Years annually. These figures, however, fail to consider sequelae and indirect health problems including liver disease, hydronephrosis, portal hypertension, haematemesis and other kidney problems, as well as cancer of the bladder.
A WHO Expert Committee on the Control of Schistosomiasis developed a morbidity control strategy based on chemotherapy in 1984. Previous control strategies revolved around snail elimination. In tandem with chemotherapy and snail control, other control measures include health education, adequate sanitation, and provision of potable water. According to the Special Programme for Research and Training in Tropical Diseases, a joint effort of WHO, the United Nations and World Bank, this control strategy is difficult to administer in communities with resource constraints. Many infected areas remain unidentified. The drug praziquantel, used in chemotherapy, is generally well-tolerated and effective.
Like schistosomiasis, dracunculiasis, also known as Guinea worm disease, is an illness found in impoverished areas with unclean water. Spread by the roundworm Dracunculus medinensis, the disease is endemic to the Sudan, which represents over 50 percent of all cases, according to CDC. The parasite is also considered endemic to Ghana and Nigeria, and has been isolated in Benin, Burkina Faso, Côte d’Ivoire, Ethiopia, Mali, Mauritania, Niger, Togo and Uganda. The latest information on the global eradication program against dracunculiasis can be found on the WHO website at: www.who.int/dracunculiasis/en/
Dracunculiasis typically results from ingestion of fresh water contaminated with microscopic crustaceans called copepods, or water fleas, carrying the roundworm Dracunculus medinensis. In their aquatic habitat, copepods consume D. medinensis larvae, which develop in the organism’s gut and assume an infectious form in 10 to 14 days. When a human ingests infected water, stomach acid dissolves the flea, but the larvae remains viable and, once freed, migrate to the small intestine. The larvae burrow through the intestinal wall and enter into body cavity, where the organism remains for about a year until developing into a mature, female roundworm two to three feet in length. A painful blister develops when the worm is ready to emerge and the area ruptures within 24 to 72 hours. Because the parasite grows vertically in hosts and approaches the lower limbs, approximately 90 percent of the worms emerge from the leg and foot area, according to CDC. The emerging worm can be pulled out centimeter by centimeter each day and wrapped around a small stick. A complete extraction can take weeks to months.
Dracunculiasis symptoms appear days to hours before the worm emerges from the skin, an event that, as noted, typically occurs a year after initial infection. Symptoms include fever, as well as swelling and intense burning in the area of emergence, which is designated by blistering and is key to perpetuating the cycle of infection. Regular activity, or potentially the desire to quell burning, can lead a person to accidentally or intentionally expose blisters to water. In response, the worm immediately produces larvae, which copepods will consume, thus allowing the parasite – and infection – to persist. Aside from transmission, the blisters associated with dracunculiasis have other implications, as they frequently become infected, leading to secondary bacterial infections. These infections extend the period of incapacitation and in some cases even lead to disabling complications such as locked joints and permanent crippling. When a worm emerges, a person often cannot work for three months, on average. This period typically coincides with planting or harvesting season. Because dracunculiasis occurs in areas that already face poverty, the economic ramifications of immobilization are profound.
Medication to end or prevent infection by D. medinensis larvae has not yet been developed. Surgical removal prior to blister formation is possible, however. Aspirin, ibuprofen and other analgesics can help reduce swelling and antibiotics can prevent secondary bacterial infections. Abstaining from standing pond water prevents infection. When in endemic areas, safe alternatives include using filtered water or water from underground sources. The provision of clean water is imperative to preventing dracunculiasis infections. Furthermore, political stability is key to eradication, as war clearly disrupts public health efforts.
A brief study of Chagas disease, schistosomiasis and dracunculiasis provide a broad overview of the diverse scientific and public health issues associated with parasitic infections. While parasitic infections come in many forms, what they all share in common is a detrimental relationship with a human host. Disrupting parasite-host interaction – whether through improving sanitation conditions, ensuring the availability of potable water, fostering political stability conducive to disease control efforts or a number of other measures – is an often daunting but pivotal prerequisite for halting infections.
References:
1. Chitsulo L., et. al. The global status of schistosomiasis and its control. Acta Tropica, 2000, 77(1):41-51.
2. Fact sheet: Chagas disease. Centers for Disease Control and Prevention. Division of Parasitic Diseases.
http://www.cdc.gov/ncidod/dpd/parasites/chagasdisease/factsht_chagas_disease.htm.
3. Fact sheet: Dracunculiasis. Centers for Disease Control and Prevention. Division of Parasitic Diseases. http://www.cdc.gov/ncidod/dpd/parasites/dracunculiasis/factsht_dracunculiasis.htm.
4. Fact sheet: Schistosomiasis. Centers for Disease Control and Prevention. Division of Parasitic Diseases. http://www.cdc.gov/ncidod/dpd/parasites/schistosomiasis/factsht_schistosomiasis.htm.
5. Schistosomiasis. Special Programme for Research and Training in Tropical Diseases. World Health Organization. http://www.who.int/tdr/diseases/schisto/default.htm.
6. “Strategic direction for research: Schistosomiasis.” Special Programme for Research and Training in Tropical Diseases. World Health Organization. http://www.who.int/tdr/diseases/schisto/direction.htm.
14 April 2007
Daniel R. Lucey, MD, MPH
WHO posts a 1996-2007 Update on H5N1 Influenza in Animals and Humans and Convenes a Conference on Clinical Aspects of H5N1.
The World Health Organization (WHO) has updated their detailed chronology of events related to the H5N1 Avian Influenza A virus on their website. Notably, this very useful 17-page reference is divided into two columns. The first column of data pertains to animals and the other to human-related H5N1 events. This most recent update was posted April 2, and includes events fro 1996 through March 2007.
WHO has also posted a one-page overview of the “2nd WHO Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus.” This conference was held March 19-21 in Antalya, Turkey and included 100 international participants. The 1st such WHO Consultation was held May 2005 in Ha Noi, Vietnam. Results of the conference last month in Turkey will be shared via a publication, according to the WHO website.
Currently, however, WHO has stated that some of the anticipated information to come from this conference includes updated knowledge and understanding of:
1. The incubation period of the virus
2. Clinical and pathological manifestations of the disease
3. The length of virus shedding
4. Patient responses to antiviral drugs, and other treatments
In terms of recent human infections, Egypt has reported the largest number of laboratory-confirmed H5N1 patients. In 2007 Egypt has reported to WHO 16 patients, four of whom have died. The most recent death was reported on the WHO website April 11th and involved a 15 year-old female from the Cairo governate. The total number of laboratory-confirmed H5N1 virus human infections is now 291. Of these, 172 (59 %) have been fatal.
Hopefully, the March 19-21 WHO Consultation will further our understanding of why this extremely high case fatality rate of nearly 60% occurs and what additional interventions might result in a marked reduction.
20 April 2007
Daniel R. Lucey, MD, MPH
US FDA Approves Initial Human Vaccine against H5N1 (Clade 1) Avian Influenza Virus for the Strategic National Stockpile (SNS)
This week the Food And Drug Administration (FDA) announced approval of the first human vaccine to prevent infection with the H5N1 avian influenza virus. This vaccine is made by sanofi pasteur, Inc., and will be manufactured in Swiftwater, Pennsylvania. It will not be available commercially. Instead, it will be purchased by the US government for storage in the Strategic National Stockpile (SNS) for potential future use for prioritized recipients.
In a press release on April 17, the FDA Commissioner, Dr. Andrew C. von Eschenbach stated: “The threat of an influenza pandemic is, at present, one of the most significant public health issues our nation and world faces. The approval of this vaccine is an important step forward in our protection against a pandemic.” www.fda.gov/bbs/topics/NEWS/2007/NEW01611.html
Although generally well tolerated in terms of side effects (e.g., pain at the injection site, headache, muscle pain, and “a general ill feeling”, according to the FDA) by the approximately 400 healthy adult volunteers, the immune responses induced by the vaccine were less than optimal. For example, only 45% of the vaccines who received the highest dose of the vaccine (90 micrograms of H5N1 antigen), intramuscularly on two occasions one month apart, produced antibody levels (titers) considered to be protective against human influenza infection. Thus, this vaccine is a starting point from which to compare future H5N1 vaccines.
This initial H5N1 human vaccine does not include any vaccine adjuvant, such as alum or MF-59. Also of potential importance, it uses a Clade 1 form of the H5N1 virus that was prevalent during the early outbreaks in 2003-2004 in Vietnam and Thailand. More recent outbreaks in 2005-2006 in other nations have involved predominantly a Clade 2 form of the virus (and subclades of Clade 2, according to the WHO H5N1 avian flu website postings). Clade 2-based H5N1 vaccines have already begun to be developed, but none are published yet in the medical literature.
Writing on the vaccine’s approval in the New York Times on April 18, 2007 (page A21), Andrew Pollack quoted Norman Baylor, head of the vaccine office at the FDA as describing this vaccine as an “interim measure”, and that future H5N1 vaccines would hopefully have higher than 45% efficacy, and ideally only require one shot and less H5N1 antigen.
The vaccine’s efficacy is estimated based on the antibody levels produced by the immune response after two shots of the vaccine. No human volunteers were exposed to the actual H5N1 virus after receiving either the vaccine or the placebo. It would be considered unethical to expose human volunteers to a virus that currently has approximately a 60% mortality rate based on the nearly 300 persons with laboratory-confirmed H5N1 virus infections reported by the World Health Organization (WHO).
The initial publication in the medical literature regarding this vaccine was 13 months ago in the March 30, 2006 issue of the New England Journal of Medicine.
April 30, 2007
Daniel R. Lucey, MD, MPH
Yellow Fever: Ongoing Emergence in Africa and South America
Yellow fever is a flavivirus that can cause a wide spectrum of clinical manifestations ranging from mild symptoms to fever and jaundice (hence its name) to severe illness, bleeding, hepatitis, and death. It is a vector-borne disease that is transmitted to humans primarily via domestic mosquitoes, most notably the same species that can also transmit dengue virus, namely Aedes aegypti.
There are three types of yellow fever transmission cycles: sylvatic (occurring in the jungle), intermediate, and urban (see the table and diagram below). All three cycles exist in Africa, but in South America, only sylvatic and urban yellow fever occur.
| Type of Spread | Pattern of Spread | Occurrence location | Who is affected | Outcome | |
| Sylvatic (Jungle) | Infected monkeysàmosquitoesàhumans | Tropical rainforests | Young men working in the forest | Sporadic cases | |
| Intermediate | Semi-domestic mosquito infect monkeys and humans | Humid or semi-humid savannahs of Africa | Habitants of rural villages | Small-scale epidemics due to increased contact between humans and infected mosquitoes | |
| Urban | Domestic mosquitoes (Aedes aegypti) carry virus from person to person | Areas with high human population density in both Africa and South America | Both travelers and habitants of these areas | Large explosive epidemics spreading outward from the initial source |
The disease is endemic to regions of Africa and the Americas, and it is once again making resurgence in parts of these continents. Although there is an effective vaccine available, there has been an increase in the number of infected people over the last two decades. Thus, yellow fever has reemerged as a serious public health concern. Yellow fever causes epidemics that can affect up to 20% of the population. When epidemics occur in unvaccinated populations, case-fatality rates may exceed 50%. No antiviral treatment for yellow fever virus. As cited on WHO and ProMed websites, from September of 2006 until the present, there have been either documented or suspected cases in the following countries: Togo, Bolivia, Peru, and Angola.
WHO recommends vaccination as the most effective preventative strategy. In regions of current outbreaks, mass vaccination campaigns have been underway as an attempt to control the situation. The vaccine is part of the global emergency yellow fever vaccine stockpile. In the past, such mass vaccination campaigns have been an effective method of yellow fever control. This combined with efforts to control the disease vector—through spraying as well as behavioral modifications—had led to significant decreases in occurrence of the disease. However, such campaigns must be met with sustained effort in order to ensure continued success.
Alicia Chou, Pete Harlan, Jordan Kanter, and Stephanie Hrycaj, Georgetown University, M.S. Graduate Program in Biohazardous Threat Agents and Emerging Infectious Diseases “Emerging Infectious Diseases: The Past as Prologue (MICB-524)”. Course Instructor: Daniel R. Lucey, MD, MPH. EROne Institute, Department of Emergency Medicine, Washington Hospital Center, Washington, DC. Website: www.BePast.org
References:
Yellow Fever: http://www.who.int/csr/disease/yellowfev/en/
http://www.who.int/csr/disease/yellowfev/global_partnership/en/index.html#control
http://www.who.int/csr/don/2007_02_12/en/index.html
10 May 2007
Daniel R. Lucey, MD, MPH
Defense Department Issues N-95 Respirator Guidance – Including Reuse If Necessary, During A Time of Pandemic Flu
On May 9th the Department of Defense (DoD) announced in a press release posted on the primary US government website for all pandemic influenza news (www.pandemicflu.gov) that “DoD Teams with Other Agencies to Prepare U.S. for Pandemic Flu Outbreak”. This news release included both the DoD “Implementation Plan for Pandemic Influenza” dated August 2006, and a link to “Pandemic Influenza: Clinical and Public Health Guidelines for the Military Health System”, dated 23 April 2007. These new guidelines are posted on the “DoD Pandemic Influenza Watchboard” at: www.dod.mil/pandemicflu
On pages 7-9 of this Clinical and Public Health Guideline are defined what the DoD terms “Pandemic Influenza Precautions (PIP)”. Included in the 10 separate PIP sections is one section that describes the “minimal personal protective equipment (PPE) recommended to enter any patient room/area”. Within the five subsections of this PPE section is the following information pertaining to N-95 respirator use and possible reuse:
“If necessary, a disposable N-95 respirator can be reused by the same individual with the following precautions: (1) a protective covering such as a medical mask or a clear plastic face shield should be worn over the respirator to protect it from surface contamination; (2) the respirator should be carefully stored between uses; (3) wearer should wash his/her hands before and after handling the respirator and the device used to shield it. Use surgical masks when N-95 respirators (or higher) are unavailable. Discard masks when exiting patient room/area.”
May 20, 2007
Daniel R. Lucey, MD, MPH
Indonesia reports 15 new patients with H5N1 influenza over 3 months based on testing at National Laboratory in Jakarta
The WHO reported May 16 that since January 31, 2007 Indonesia has confirmed 15 additional patients with H5N1 avian influenza, with 13 fatalities. Indonesia now has the largest number of lab-confirmed H5N1 virus human infections (96), and the largest number of deaths (76). Globally, WHO has confirmed 306 patients with H5N1 infection, of whom 185 (60%) have died.
The 15 Indonesian patients ranged in age from 14-39 years. WHO noted that 8/15 had no known source of infection, while the remaining 7 did have a known exposure to dead or sick poultry. At this time there is no report of person-to-person transmission in any of these 15 patients. They lived in 10 separate parts of Indonesia ranging from different parts of Jakartato three different areas of Sumatra, three different parts of Java, and Riau. The number of days between symptom onset and hospitalization ranged from 1-20 days. The number of days from hospitalization until death ranged from 1-7 days.
Importantly, Indonesia has now gained the formal approval of the WHO to complete all laboratory testing for H5N1 virus infection within the country and therefore no longer need to send specimens for testing to WHO-collaborating laboratories outside of Indonesia. Future testing for H5N1 will continue to be performed at the National Laboratory in Jakarta, in collaboration with the Eijkman Institute.
This decision followed discussion between Indonesia and WHO, and a formal assessment of the laboratory capacity in Indonesia by scientists from the WHO Collaborating Centre in Tokyo and the national influenza centres of India, Thailand, and the WHO Regional Office for SE Asia and the WHO Country Office of Indonesia. In this regard, Indonesia has again taken a leadership role on H5N1 influenza-related issues similar to its recent approach and discussions with WHO regarding sharing of H5N1 virus isolates and H5N1 vaccine development and access to such vaccines for developing nations such as Indonesia.
Time will tell if additional nations seek and obtain approval from WHO to complete all H5N1 laboratory testing internally, without having to send specimens for confirmatory testing to international WHO reference laboratories. Regardless, the need for epidemiological and clinical information to be transmitted rapidly to WHO remains as important as ever, especially with regard to any possible clusters of human infections.
25 May 2007
Daniel R. Lucey, MD, MPH
WHO Updated Protocol for Rapid Operations to Contain Initial Emergence of Pandemic Flu Includes 20 Days (not 10) of Antiviral Prophylaxis
The World Health Organization (WHO) this month updated their interim protocol on “rapid operations to contain the initial emergence of pandemic influenza”. It contains several significant changes from the last major update in May 2006. The 22-page document is posted on the WHO avian influenza website at: www.who.int/csr/disease/avian_influenza/guidelines/draftprotocol/en/index.html
This conceptually and operationally valuable document includes sections on: ‘The decision to launch a containment operation; The containment strategy; Activities in the Containment Zone; Activities in the Buffer Zone; and Duration of the Containment Operation’.
Of the multiple pragmatic issues discussed in each of these sections of the document is the statement that “All persons in the Containment Zone considered unlikely to be infected would be given 20 days of antiviral prophylaxis. Although a 10-day course is the usual period for prophylaxis of seasonal influenza, extending prophylaxis for 20 days would allow for:
—Simpler logistical considerations: since it may take several days to distribute antivirals throughout the Containment Zone, extending the period of prophylaxis will increase the duration of time during which most or all of the population in the Containment Zone is on prophylaxis or treatment at the same time.
—Uncertainty about the characteristics for the emerging virus: the virus may have a longer incubation period than seasonal strains of influenza.
—Packaging considerations: oseltamivir is packaged in blister packs of 10 tablets.”
While this rationale is clear for 20 days of prophylaxis, i.e. 20 tablets of oseltamivir IF that is the drug used, this policy would mean that the current WHO antiviral stockpile of “3 million treatment doses (i.e. 2 doses per day for 5 days” (stated on page 12 of this WHO document) would be reduced if 20 tablets were used by each person for prophylaxis rather than 10 tablets (i.e. one tablet per day for 10 days.
Vigilance for actual influenza disease in persons initially given once-daily prophylactic doses, which would require changing to twice daily doses of oseltamivir as therapy, would be critical. In addition, .monitoring for oseltamivir resistance, as much as possible in real time, would also be important. “Such antiviral resistance would be more likely to develop in persons on once-daily prophylactic doses who are actually infected with the new pandemic flu virus and thus would require twice-daily dosing for a minimum of five days and possibly several more days. Further aspects of this new WHO interim protocol will be discussed subsequently.
28 May 2007
Daniel R. Lucey MD, MPH
WHO Factors to Consider in Launching a Pandemic Flu Containment Operation including Clustering of 5 or more Closely Related Cases or Two or More Generations of Transmission.
The World Health Organization (WHO) included in their updated interim protocol for “Rapid operations to contain the initial emergence of pandemic influenza” (May 2007) several key factors to consider in deciding whether to launch such an operation. The quantitative epidemiologic criteria defining evidence of efficient and sustained human-to-human transmission are particularly noteworthy.
Three main types of technical factors were presented by the WHO, in considering whether to launch a containment operation,
1. Virologic factors: Lab evidence of a novel influenza A virus is key. In particular, sequencing of the virus to determine if it has either:
A. Both avian and human influenza virus genes, or
B. An increased number of mutations that might suggest advanced adaptation to humans.
2. Epidemiologic factors: A 2nd key issue is whether there is “Evidence of efficient and sustained human-to-human transmission (e.g. clustering of 5 or more cases closely related in time and space or two or more generations of transmission)”. Notably, the severity of the influenza illness in these initially diagnosed is not deemed by WHO to be “an important consideration for initiating or not initiating a containment operation” (page 7).
3. Operational, logistical, security and political factors: All of these issues are important “because they will determine the feasibility of initiating and maintaining a timely and effective containment operation” (page 8).
The WHO emphasizes that any containment operation would “require the full agreement of the national authorities who would also be responsible for leading and managing the national activities related to the containment operation”. In addition to national authorities, WHO would also “consult with external experts about the situation and provide input and relevant advice to national authorities”.
Of interest, WHO also states that in this plan that has been updated from 12 months earlier (May 2006) “Potential changes in the pandemic phase will be decided separately by the WHO Director-General” (page 8).
Thus, launching a pandemic flu containment operation does not necessarily mean that the current WHO Phase 3 Pandemic Alert would have to be raised to a Phase 4 (small cluster(s)), or Phase 5 (larger cluster(s)). Instead, the individual situation would be assessed and a final decision about any WHO
pandemic influenza Phase change would be made by the Director-General.
The epidemiologic threshold cited in this document for initial evidence of efficient and sustained human-to-human transmission appears designed to optimize the probability of detecting the earliest signal that a novel influenza virus has acquired a “newly advanced adaptation to humans”.
Such “clustering of 5 or more cases closely related in time and space or two or more generations of transmission” brings to mind the situation in an Indonesian family involving H5N1 infection in May 2006, which fortunately did not turn out to involve significant new gene mutations or human-to-human transmission outside of the 7-8 members infected with the Clade 2 H5N1 virus.
Early intervention will likely be critical to any successful containment operation in the future, and heightened vigilance for an initial emergence of the next pandemic flu virus appears to be one of the highlights of this WHO protocol.
5 June 2007
Daniel R. Lucey, MD, MPH
TB and Air Travel: WHO Guidelines and Recommendations
In 2006, the World Health Organization (WHO) published the 2nd edition of their document “Tuberculosis and Air Travel. Guidelines for Prevention and Control”. This document, posted on the WHO website and also listed on the CDC website, offers 17 recommendations (see pages 28-29) divided between those for: Passengers and air crew (# 1-2); Physicians (# 3-7); Public Health Authorities (# 8-11), and Airline Companies (#12-17).
Given recent events regarding the airline travel of a person from the USA to Europe and subsequent flights within Europe and from Europe to Canada with tuberculosis infection of the lung that turned out to be extremely-drug resistant (“XDR-TB”), meaning that his tuberculosis bacteria not only met the criteria for being “Multi-Drug Resistant (“MDR-TB”) but was resistant to additional antibiotics that defined it as “XDR-TB”, the five WHO recommendations (# 3-7) for physicians are emphasized below:
3. Physicians should inform all infectious TB patients that they must not travel by air on a flight exceeding eight hours until they have completed at least two weeks of adequate treatment.
4. Physicians should inform all MDR-TB patients that they must not travel by air—under any circumstances or on a flight of any duration—until they are proven to be culture-negative.
5. Physicians should advise TB patients who undertake unavoidable air travel of short duration (less than eight hours) to wear a surgical masks when possible or to cover the nose and mouth when speaking or coughing at all times during the flight.*
6. Physicians should inform the relevant health authority when they are aware of an infectious TB patient’s intention to travel against medical advice.
7. Physicians should immediately inform the relevant health authority when an infectious TB patients has a recent history of air travel (i.e. within three months).
This recommendation (see # 5 above regarding wearing of a surgical mask) is applied only on a case-by-case basis and subject to prior agreement of the airline(s) involved and the public health authorities at departure and arrival.
18 June 2007
Daniel R. Lucey, MD, MPH
Indonesia reports 100th patient with H5N1 avian flu (80% mortality), asymptomatic infected chickens, and possible mutation facilitating poultry-to-human spread
On June 15th the World Health Organization (WHO) posted on their avian flu website that the Indonesian Ministry of Health reported the death on June 12th of a 26 year-old man with laboratory-confirmed H5N1 avian influenza virus infection. This young man was from Riau province. He is the 100th lab-confirmed patient with H5N1 virus infection in Indonesia, of whom 80 have died. Globally, there have been 311 lab-confirmed human infections and 191 deaths in 12 nations.
While this 26 year-old man did have documented exposure to ill and dead poultry the Jakarta Post newspaper (online at www.thejakartapost.com) carried an Associated Press article on June 17 titled “Bird flu-infected chickens in Indonesia showing no symptoms”. The article quoted the Agriculture Ministry director of animal health, Musni Suatmodjo: “Chickens are testing positive for the H5N1 virus, but they are staying health”.
Previously, most chickens with H5N1 avian flu virus infection became ill and often died rapidly, facilitating surveillance efforts to identify and cull infected flocks and identify persons exposed to these infected poultry.
While ducks have been noted in the past to be able to have asymptomatic H5N1 virus infection yet still shed the virus and be infectious, this has not been the case with the majority of chickens to date. Such a development could make animal health and human public health efforts to control the spread of H5N1 virus much more difficult.
In addition, on June 6th Reuters carried an article from Jakarta quoting the head of Indonesia’s commission on bird flu, Bayu Krisnamurthi, stating that preliminary data suggested that the H5N1 virus might be able to spread more easily from poultry to humans: “In the past it took exposure of high intensity and density to the virus to get infected. There are now suspicions, early indications that this has become easier”.
A microbiologist at the bird flu commission, Wayan Teguh Wibawan, was also quoted by Reuters explaining that: “Virus samples from poultry cases have increasingly shown a similarity in their amino acid structures to virus samples extracted from humans…This makes it easier for the virus to attach to human receptors”.
Such information that the H5N1 virus might be mutating in a functionally important manner that facilitates spread of the virus from poultry to humans is very important. Analyses of these latest H5N1 virus isolates have not yet been reported from any laboratories outside of Indonesia.
It should be noted that both Indonesian officials quoted by Reuters emphasized appropriately that these data are only preliminary. Hopefully, independent analyses will be performed and made public soon, given the potential importance of such findings for control efforts in both the animal and human public health domains.
July 16, 2007
Daniel R. Lucey, MD, MPH
Containment Zone WHO Strategy for Pandemic Flu Initial Emergence
The World Health Organization’s latest interim protocol for “rapid operations to contain the initial emergence of pandemic influenza” includes a “Containment Zone” and a surrounding “Buffer Zone” that have been detailed in a 20-page document on the WHO website (www.who.int).
The fundamental containment strategy is to rapidly identify the initial (“index”) cases forming a cluster of persons infected with a new pandemic flu virus while still limited to a localized geographical area and initiate routine control measures. Then, a “Containment Zone” will be drawn around this area with the index cluster of patients and both widespread antiviral drug prophylaxis and non-pharmaceutical interventions such as social distancing will be recommended.
The five (5) critical activities within the Containment Zone include (see page 12 of the WHO May 2007 document):
- Extensive antiviral prophylaxis (20 days of antivirals would be given, not 10 days).
- Perimeter control (“it is critical to discourage to the extent possible all non-essential movement of persons in and out of the Containment Zone” and to include “exit screening procedures”. page 13).
- Multiple non-pharmaceutical measures (including “isolation of ill persons, voluntary quarantine of exposed persons, social distancing measures such as school closures and cancellation of mass gatherings, & other measures to minimize persons density (e.g. staggered work and market hours”. page 14).
- Surveillance and laboratory testing
- Detailed assessment of the novel virus
The three (3) primary activities in the “Buffer Zone” that will be drawn outside of the “containment zone” include (see page 14of 20):
- Active and comprehensive surveillance with laboratory testing.
- Isolation and treatment of suspect cases
- Antiviral prophylaxis of contacts of suspect cases
Additional specific guidelines are provided in this 20-page document. At the same time, nine (9) annexes to this document “will be added shortly” (page 18) and will further help international planners anticipate and prepare better for the next human influenza pandemic.
7 July 2007
Daniel R. Lucey, MD, MPH
FDA Clears First Rapid Diagnostic Test for Malaria
In an “FDA News” release posted on the FDA website (www.fda.gov) June 26, 2007 the US Food and Drug Administration (FDA) announced that they had cleared for marketing in the laboratory setting the “first authorized U.S. rapid test for malaria”. In the July 13 issue of the CDC’s Morbidity and Mortality Weekly report (MMWR) (2007:56 (27): 686) a “Notice to Readers: Malaria Rapid Diagnostic Test” (RDT) appears that describes in a one page summary this new malaria test known as “Binax NOW Malaria (Inverness Medical Innovations, Scarborough, Maine).
This new rapid malaria test (RDT) can provide results in 15 minutes following placement of several drops of whole blood on a dipstick. Of note, this test is intended for laboratory use only by hospital and commercial laboratories and not by individual clinicians or patients. According to the FDA, “Results still need to be confirmed using standard microscopic evaluation” for malaria (plasmodium) protozoan parasites. The FDA reported that the “Binax NOW test was 95 percent accurate compared with standard microscopic diagnosis in a multi-center study outside the United States in areas where malaria is prevalent”.
The Centers for Disease Control and Prevention (CDC) MMWR 13 July publication adds that this malaria rapid test detects two different malaria antigens: “HRP2, which is specific to Plasmodium falciparum, and a malaria aldolase found in all four human species of malaria parasites. Although the test can identify P. falciparum, it cannot distinguish between Plasmodium vivax, Plasmodium ovale, or Plasmodium malariae or detect mixed infections”.
In an unrelated recent noteworthy publication for clinicians on malaria, in the May 23/30, 2007 issue of the Journal of the American Medical Association (JAMA) Kevin Griffith and colleagues provide a systematic review on the treatment of malaria in the United States. They note that artemisinin anti-malaria drugs “are not yet available” in the USA.
Artemisinin anti-malarial drugs are available in some nations outside the USA, and combination therapy using artemisinins in certain clinical settings has been discussed in detail by the World Health Organization (WHO) in documents posted on their website (www.who.int).
22 August 2007
Daniel R. Lucey, MD, MPH
WHO Updates Clinical Advice on Human H5N1 Virus Infections
This week the World Health Organization (WHO) released new guidance on practical clinical issues in the care of patients with H5N1 avian influenza infections. The 22-page document, including 95 references, builds on the WHO Consultation conferences on Human H5N1 infections convened in Antalya, Turkey in March 2007 and in Hanoi, Viet Nam in May 2005. Annex 1 lists the nine international members of the “Document drafting group” and the 12 international external reviewers.
This document, posted on the WHO website at: www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage07/en/index.html, also includes two quite useful standardization documents. These are a “WHO H5N1 Clinical Case Summary Form” and a lab form that includes space for data on virus detection results (RT-PCR and Virus Culture), virus susceptibility testing, and plasma antiviral concentration.
Among the multiple clinical “pearls” for this emerging disease are:
- “The duration of A (H5N1) viral replication in humans appears to be prolonged and has been documented to last up to 15-17 days after illness onset (see references 4, 12, 13). In the absence of corticosteroid administration, immuno-competent A (H5N1)-infected persons probably cease to excrete the infectious virus 3 weeks after illness onset, but further virological shedding data are needed to verify this.” (Page 2 “Site of Care” section).
- “In contrast to uncomplicated seasonal influenza, oseltamivir treatment is also warranted for patients presenting late with A (H5N1) virus infection because viral replication is more prolonged than with seasonal influenza”. (Page 5 “Antiviral Treatment” section).
- “Continued fever and clinical deterioration may suggest ongoing viral replication, although the possibilities of bacterial superinfection and other nosocomial complications should be evaluated. If no clinical improvement has been observed after a standard 5-day course, the oseltamivir therapy may be extended for a further 5 days” (page 6).
- Regarding potential inhaled therapy with the neuraminidase inhibitor zanamivir (Relenza), “stringent hospital infection control measures must be adhered to if any drugs are administered by a nebulizer to patients with human A (H5N1) illness to prevent possible transmission of A (H5N1) viruses by aerosol.”
- Regarding potential combination antiviral therapy with an adamantine drug (rimantidine or amantidine) plus a neuraminidase inhibitor (oseltamivir or zanamivir), this should only be considered if there is “pneumonic disease or clinical progression” and when locally circulating A (H5N1) viruses (such as Clade 2.2 and Clade 2.3) are likely to be susceptible to adamantanes (but NOT Clade 1 viruses as found so far in Cambodia, Thailand, or Viet Nam). Preferably, serial respiratory samples should also be collected for serial virological monitoring” (page 7 “Other viral agents” section).
- Regarding “virological monitoring: “When possible, collection of serial respiratory samples (throat swabs and , if available, tracheal aspirates) for detection of A (H5N1) virus (before treatment, day 4-5, and day 7-8 after treatment is initiated) should be considered to analyze viral clearance or persistence and antiviral resistance” (pages 7-8).
- A detailed section on ventilatory support is provided (pages 12-14) including the observation that “There appears to be a high incidence of pneumothorax in critically ill A (H5N1) virus-infected patients.” (Page 12).
- Regarding infection control, it is noted emphasized that “Administration of supplemental oxygen via mask may also contribute to dispersion of potentially infectious aerosols. Oxygen masks with an expiratory port and HEPA filter will reduce aerosol production” (page 14).
Hospitals, health care clinics, and public health agencies would benefit by reviewing and discussing this document with all persons and departments that could become involved with the care of a patient (e.g., a traveler in August 2007 to the USA from an H5N1 endemic area of the world) in order to have an updated standard operating protocol (SOP) for the optimal care of such patients and to minimize the infection control risk to persons providing this medical care.
7 September 2007
Daniel R. Lucey, MD, MPH
Cutaneous Anthrax: Key References for Clinicians
This week two persons in Danbury, Connecticut (USA) were diagnosed with cutaneous anthrax. The reported source of the infection is imported animal hides being used to make African drums. Today’s New York Times also reported that “six samples collected from a three-story house and a barn in the backyard tested positive for anthrax… (Page A27, Sept 7, by Thomas Kaplan)”
According to the Connecticut Post (ConnPost.com) article September 5th by Robert Miller “staff from Danbury Hospital and the state Department of Public Health emphasized the cases posed no health risk whatsoever to the general public”.
This event can reinforce the importance for clinicians of having useful references readily available with regard to cutaneous anthrax, 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 most recent (6th) edition (2005) of the textbook “Principles and Practice of Infectious Diseases” edited by Mandell, Bennett, and Dolin (pages 2485-2491 and 3618-3624)
4 October, 2007
Daniel R. Lucey, MD, MPH
As with the Anthrax attacks of 2001 remember that skin lesions have occurred with aerosol-transmitted Tularemia.
If a bioterrorism attack were to occur using aerosolized Francisella tularensis bacteria, then inhalational tularemia (“pneumonia”) would occur. Oculoglandular and oropharyngeal manifestations were also included with pneumonic tularemia as part of a preliminary case definition in 2005 following a possible airborne exposure in the US. As with the skin manifestations of anthrax in persons exposed to the spores sent through the mail in 2001, however, skin lesions can occur with airborne tularemia and thus should be considered in the search for symptomatic patients following a possible aerosol attack.
One of the largest reported civilian outbreaks of airborne tularemia, involving at least 676 persons, occurred in northern Sweden in the autumn of 1966 and winter of 1967 (Dahlstrand, Sverker et al. “Airborne Tularemia in Sweden” Scandinavian Journal of Infectious Diseases 1971;3:7-16). The cause of this outbreak was attributed to inhalation of dust from hay that contained Francisella tularensis from vole feces. Of note, infected skin ulcers were found in 44 of the 405 patients (11.6%) who had serologically confirmed infection with F. tularensis.
In addition, 142 (35%) of these 405 serologically-confirmed patients with airborne tularemia showed skin manifestations “generally occurring 2-3 weeks after onset of the disease. In approximately 50% of the cases where a description of the manifestations was available there was an erythema multiforme-like exanthem on the hands, arms, or legs, while approximately 20% had symptoms of erythema nodosum with reddish-blue, tender infiltration on the legs” (p. 13-14).
The authors of the 1971 publication from Sweden contrasted the more common occurrence of infected ulcers after infection with F. tularensis by direct contact with an infected hare or via mosquitoes than by airborne exposure. In 2007, however, the lesson for biopreparedness is that nearly 12% of patients exposed to naturally-occurring airborne Francisella tularensis developed infected ulcers and thus our initial case definitions and clinical surveillance algorithms used in the search for symptomatic patients should include skin lesions.
If a bioterrorism attack occurs with Francisella tularensis optimized in terms of size (small), concentration (high), strain (virulent), and/or antibiotic resistance (multidrug), then an even higher percent of persons may have skin lesions.
October 5, 2007
Daniel R. Lucey MD, MPH
Beware of misidentification of Francisella tularensis as Actinobacillus or Hemophilus species and the risk of aerosols in the Clinical Laboratory
The causative agents of tularemia include Francisella tularensis subspecies tularensis and Francisella tularensis subspecies holarctica. In the event of a natural outbreak of tularemia or a bioterrorism attack clinicians should be aware of potential misidentification of these organisms by clinical laboratories.
The CDC/ASM/APHL “Basic Protocols for Level A Laboratories for the presumptive identification of Francisella tularensis” posted at: http://emergency.cdc.gov/agent/tularemia/ emphasizes that:
A. ‘The most common misidentification of F. tularensis is Haemophilus influenza and Actinobacillus species’.
B. “Identification of isolates by using commercial identification systems is not recommended due to the high probability of misidentification. The Vitek NHI panel may give as high as 99% confidence to the identification of Actinobacillus actinomycetemcomitans with strains of F. tularensis”.
C. Another important reason that commercial identification systems should not be used to identify Francisella tularensis is because of the “potential of generating aerosols” that could put laboratory workers at risk for one or more of the multiple tularemia clinical syndromes.
Given the rarity of Actinobacillus infections in most US hospitals, if a commercial identification system was used then consideration of a misidentification of F. tularensis should be considered if the patient’s clinical presentation is consistent with tularemia.
In the clinically unlikely event of a “cluster” of Actinobacillus isolates involving more than one patient, then a coordinated evaluation of the patients and their bacterial laboratory isolates, by both clinicians and laboratorians, should be completed rapidly to rule out tularemia.
31 October 2007
Daniel R. Lucey, MD, MPH
WHO Updates Pandemic Flu Rapid Response and Containment Plan
This month the World Health Organization (WHO) updated their May 2007 version of their pandemic influenza rapid response and containment protocol. This update provides significantly more information than prior versions, especially with the inclusion of the following seven annexes:
Annex 1: Ethical issues during rapid containment
Annex 2: Rapid containment communication
Annex 3: Antiviral prophylaxis issues (including pediatric dosing of oseltamivir)
Annex 4: Non-pharmaceutical interventions (NPI) (e.g., social distancing p.33)
Annex 5: Checklist for NPI planning
Annex 6: Laboratory preparedness for rapid containment
Annex 7: Major roles and responsibilities for countries and WHO
The WHO plan still emphasizes a “Containment Zone” around the initial patients with the new pandemic flu virus, and a “Buffer zone” surrounding this Containment Zone.
Five (5) Key activities in the WHO Plan for the “Containment Zone” include:
- Extensive antiviral prophylaxis and treatment
- Perimeter control (p. 16)
- Multiple non-pharmaceutical interventions (e.g., social distancing)
- Surveillance and laboratory testing
- Assessment of the novel influenza virus
Three Key activities for the “Buffer Zone” include:
- Active and complete surveillance with laboratory testing of all suspect cases
- Isolation and treatment of all suspect cases
- Antiviral prophylaxis and quarantine of contacts of suspect cases (p. 20).
14 November 2007
Daniel R. Lucey, MD, MPH
US Funds Development of an Inhaled Form of Gentamicin
In the event of a bioterrorist attack, the Centers for Disease Control and Prevention considers six Category A biological agents as the most likely culprits. These agents include botulinum toxin, anthrax, viral hemorrhagic fevers, plague, smallpox, and tularemia. The high morbidity and mortality give these biohazardous threat agents a particular potential for public health impact.
On October 5, 2007, Nanotherapeutics, Inc. was issued a four year contact for $20 million to develop NanoGENTTM, an inhalational form of the antibiotic gentamicin. The funding was provided through the National Institute of Allergy and Infectious Disease (NIAID) and Biological Advanced Research and Development Authority (BARDA), with preclinical funding from Project BioShield. Project BioShield was signed into law on July 21, 2004 by President Bush to provide new tools that will improve medical countermeasures against chemical, biological, radiological, or nuclear attacks. A full description of this Health and Human Services contract may be found at: http://www.hhs.gov/news/press/2007pres/10/pr20071005c.html.
NanoGENTTM, an inhaled formulation of the broad-spectrum antibiotic, gentamicin, provides a potential treatment for bioterrorist threat agents, such as those that cause tularemia and plague. Gentamicin is a bactericidal aminoglycoside antibiotic that binds to the 30S ribosome of gram-negative bacteria and thereby inhibits protein synthesis.
According to the manufacturer, NanoGENTTM provides several potential advantages over traditional delivery mechanisms such as intravenous administration. These include: 1) higher shelf-life stability, 2) better control of particle size and deposition efficiency, 3) control of cell uptake and targeting, 4) controlled release-rates, and 5) increased systemic bioavailability. Descriptions of these advantages may be found on the Nanotherapeutics, Inc. website at: http://www.nanotherapeutics.com/ nanotechnology.php.
Perhaps the most beneficial advantage of inhalational gentamicin might occur during situations requiring mass post-exposure prophylaxis, such as large-scale biological agent release. This advantage is in the relative ease of administration and non-invasive nature of the drug delivery system. Further “advantages of inhaled therapy include direct drug delivery to the diseased organ, targeting to alveolar macrophages harboring the bacteria, reduced risk of systemic toxicity, and improved patient compliance.” More detailed information regarding these advantages may be found in the following publication: Pandey, R., and Khuller, G.K. “Antitubercular inhaled therapy: opportunities, progress, and challenges.” J Antimicrob Chemo. (2005) 55: 430-435. Potential disadvantages that occurred with older versions of inhaled antibiotics several decades ago, including aminoglycosides, must be anticipated and monitored for closely.
The lack of FDA-licensed vaccines or immunoglobulin for either tularemia or plague, as well as the potential for person-to-person transmission of plague pneumonia, leave antibiotics as the only presently available therapeutic countermeasure. Therefore, novel forms of antibiotics, such as NanoGENTTM, may contribute to the advancement of our current biodefense countermeasures.
Megan Hofmeister, Christine SooHoo, Courtney Tauscher, Ray Webber, and Wade Greening
Graduate Students in the Master of Science (M.S.) Program in Biohazardous Threat Agents and Emerging Infectious Diseases, Department of Microbiology and Immunology, Georgetown University Medical Center. MICB-523 Course: “ Biodefense Public Health Countermeasures” taught by Daniel R. Lucey, MD, MPH, Director of the Center Biological Counterterrorism and Emerging Diseases, EROne Institutes, Washington Hospital Center,Washington, DC.
4 December 2007
Daniel R. Lucey, MD, MPH
Health Requirements and Recommendations for Travelers to Saudi Arabia during the Hajj
The US Centers for Disease Control and Prevention (CDC) posted updated information on their website that is “current as of today, December 04, 2007” that pertains to this year’s Hajj, a pilgrimage to the Islamic holy places in Saudi Arabia. This year the Hajj begins December 18th.
CDC recommended vaccinations include the meningococcal vaccine, influenza vaccine, hepatitis A vaccine, hepatitis B vaccine, typhoid vaccine, and polio vaccine or adult booster. In addition, “routine immunizations” should be up-to-date including measles, mumps, rubella (“MMR”), and diphtheria, pertussis, and tetanus (“DPT”).
CDC also provides detailed information on how to decrease the risk of heat injury and other illnesses. Meningococcal disease symptoms and risk factors are listed, in part because of meningitis outbreaks associated with the Hajj in 1987 and 2000, as cited in this CDC document.
The final sentence of this CDC four-page document states: “For the official documentation of full requirements for entry into Saudi Arabia for the Hajj, see the World Health Organization (WHO) Weekly epidemiological record, November 2, 2007”.
This WHO Weekly Epidemiological Record (“WER” No. 44, 2007, 82, pages 385-388 can be found at: www.who.int/wer) states that “the Ministry of Health of Saudi Arabia has issued requirements for the forthcoming Hajj season as follows”. Clear, specific information is provided regarding: (I) Yellow Fever, (II) Meningococcal meningitis, (III) Poliomyelitis, (IV) Influenza vaccination, (V) Disease surveillance and health regulations at borders (airports, ports), and (VI) Foods.
For example, for meningococcal meningitis prevention it is stated: “ Visitors from around the world arriving for the purpose of “Umra” or pilgrimage or for seasonal work are requested to produce a certificate of vaccination with the quadrivalent (ACYW135) vaccine against meningococcal meningitis, issued not more than 3 years and not less than 10 days before arrival in Saudi Arabia.”
“Arrivals from countries of the African meningitis belt, namely: Benin, Burkina Faso, Cameroon, Chad, Central African Republic, Cote d’ Ivoire, Eritrea, Ethiopia, Gambia, Guinea, Guinea-Bissau, Mali, Niger, Nigeria, Senegal, and Sudan” will also be given chemoprophylaxis against meningococcal disease “at points of entry to all arrivals from these countries to lower the rate of carriers among them. Ciprofloxacin tablets (500mg) will be given to adults, rifampicin to children and ceftriaxone to pregnant women” (p. 386).
Under section V (Disease surveillance and health at borders) it is stated that “People aged less than 15 years and traveling to Saudi Arabia from polio-affected countries will be vaccinated with OPV regardless of previous vaccination history. All adult travelers from Afghanistan, India, Nigeria, Pakistan, and Sudan should also receive 1 dose of OPV at border points” (p. 387).
Regarding influenza vaccination “The Ministry of Health of Saudi Arabia recommends that pilgrims be vaccinated against influenza before arrival, particularly those with pre-existing conditions (e.g., the elderly, people with chronic chest or heart diseases or cardiac, hepatic, or renal failure)”.
In reading these preventive public health measures involving screening for diseases and documentation of vaccinations, administration of one or more vaccines to specific populations, and antibiotic prophylaxis against meningococcal disease for certain highest-risk persons (including different antibiotics for adults, children, and pregnant women) one is reminded of emergency preparedness and response activities in recent years against infectious diseases and biohazards in the US, and other nations.
Some of the best practices and lessons learned are potentially shared in these public health settings, even thought they might appear widely different in their respective contexts.
16 December 2007
Daniel R. Lucey, MD, MPH
Pakistan Reports 8 Suspected H5N1 Avian Flu Patients and Myanmar reports First Confirmed H5N1 Patient
On Saturday, December 15, the World Health Organization (WHO) posted on their avian influenza website a report from Pakistan’s Ministry of Health that there are 8 patients with suspected H5N1 avian influenza virus infection in the Peshawar region. These are the first reports of human infections with the H5N1 virus. Epidemiological investigations and containment are being undertaken by the Pakistani Ministry of Health with technical support from the WHO. The source of infection and whether or not human-to-human transmission has occurred is being determined. Initial reports state that at least some of these 8 persons are family members (brothers).
The initial laboratory diagnosis of the H5N1 virus was performed in the Pakistani National Laboratory and samples have been sent to a WHO reference laboratory.
Outbreaks in poultry have been reported in Pakistan since 2006, especially in the “poultry belt” of the North-West Frontier Province. Outbreaks in wild birds have been reported since earlier this year in the Islamabad Capital Territory, according to the WHO.
On Friday, December 14, the WHO posted on this same website that Myanmar had reported their first H5N1-positive patient, a 7-year-old girl from Shan State (East). Fortunately, the patient has recovered following hospitalization November 27th. Poultry are suspected to be the source of her infection, but epidemiologic investigations are ongoing by Myanmar officials with support from the WHO.
The laboratory diagnosis of H5N1 virus infection was made in the National Health Laboratory in Yangon, and then at the National Institute of Health in Thailand, and in the WHO reference lab in Tokyo.
Further details of these initial reports of human H5N1 avian influenza in Pakistan and Myanmar are anticipated. Lastly, plane travel by persons with possible H5N1 virus exposure emphasizes once again the importance of hospitals, clinics, and public health officials to be prepared to safely and rapidly evaluate such persons and their close contacts. Such preparedness should include the Americas. In the Washington, DC and National Capitol Region written draft protocols for patients with potential H5N1 virus exposure and infection should be readily accessible. As in the time of anthrax in 2001, the goal should be “Preparedness not Panic”.
21 December 2007
Daniel R. Lucey, MD, MPH
WHO News Briefing Update on Pakistan H5N1 Infections in Humans
In a Reuters news story posted online this morning by Stephanie Nebehay the World Health Organization (WHO) held a news briefing in Geneva that included an update on the initial outbreak in Pakistan of H5N1 avian influenza virus in humans. This interim update is reassuring in that no further suspected cases of human H5N1 infections have been reported since December 6th. This 15-day period is longer than the generally estimated upper limit for the incubation period of the virus in humans (10 days).
Referring to the WHO team in Pakistan working with national experts on the H5N1 outbreak investigation, Dr. David Heymann,the highly respected leader of the WHO SARS global response and an expert with over 30 years experience in infectious dis ease outbreaks with WHO and CDC, is quoted by Reuters as stating:
“The team feels that this could be an instance of close contact human-to-human transmission in a very circumscribed area and non-sustained, just like happened in Indonesia and Thailand”.
In a separate situation in China, Dr. Heymann was quoted as stating that the report of a father and son being infected with the H5N1 avian influenza virus earlier this month also does not appear to represent any form of sustained person-to-person transmission. Specifically, Dr. Heymann reported that blood tests for the H5N1 virus taken from 600 contacts of these two persons in Jiangsu Province did not show any evidence of infection with the virus.
Even given this reassuring interim update, the genetic sequences of the H5N1 viruses from these patients in Pakistan and China will be of value in detecting any potentially significant mutations and to categorize the viruses into the appropriate clade and subclade of H5N1 virus lineage.
31 December 2007
Daniel R. Lucey, MD, MPH
First World Malaria Day: April 25, 2008
At the 60th World Health Assembly (WHA) earlier this year the proposal was made to create the first “World Malaria Day” on April 25, 2008. At the eleventh plenary meeting of the WHA on 23 May 2007 it was resolved that “World Malaria Day shall be commemorated on 25 April…in order to provide education and understanding of malaria as a global scourge that is preventable and a disease that is curable…” (See full text on malaria issues from the 2007 WHA at: www.who.int/gb/ebwha/pdf_files/WHA60/A60_R18-en.pdf)
Some of the exciting recent developments in the multidisciplinary effort to prevent, treat, and control malaria include: use of long-lasting insecticide-treated bed nets, indoor residual spraying with appropriate insecticides, new combination antimalarial medications, rapid diagnostic tests, investigational vaccine testing, and expanded educational outreach. Updated information on many of these efforts can be found on the malaria section of the World Health Organization (WHO) website (www.who.int/topics/malaria/en/).
Since 2001, April 25th each year has been known as “Africa Malaria Day”. This designation grew from the Abuja Declaration made by leaders of 44 nations at the African Summit on Malaria in Abuja, Nigeria April 25, 2000.
In anticipation of World Malaria Day students and faculty at Georgetown University in Washington DC, like many universities around the world, are planning a series of events to increase malaria awareness and to raise funds to purchase long-lasting insecticide-treated bed nets. In partnership with the UN Foundation in Washington a student-named team, the “Georgetown Hoyas: Operation Bug Off” was formed in mid-November 2007. Interested persons can join at: www.nothingbutnets.net/Georgetown
On Friday, January 25, 2007 one of the first in a series of presentations on malaria at Georgetown University will be given from 10 am-11:30 am in the MICB-524 class “Emerging Infectious Diseases: Past as Prologue” in the conference room (NE 315) of the Medical-Dental Building. The class is open to all graduate and undergraduate students as well as other interested members of the Georgetown and Washington, DC community. Additional events are being planned for both before and after World Malaria Day April 25th.