9 January 2008
Daniel R. Lucey, MD, MPH
WHO posts 42 slides on containment strategy for the initial emergence of pandemic flu
The World Health Organization (WHO) posted 42 powerpoint slides, dated 7 January 2008, that provide an easily readable overview of their latest update of the interim protocol to attempt rapid containment of the initial emergence of the next human influenza pandemic. The slides were added to the right-hand side of the avian influenza section of the WHO website (www.who.int) under the document titled “WHO Interim protocol: Rapid operations to contain the initial emergence of pandemic influenza”. They can also be found under the “Updates” section at the top of the homepage of this website (www.BePast.org).
These slides provide insight into some of the many pragmatic issues the WHO and specific affected nation(s) may face at the start of the next flu pandemic. Each time a possible cluster occurs of persons with H5N1 avian influenza, or another potentially novel flu virus, then this evolving WHO protocol for rapid containment is likely to be considered in terms of feasibility and applicability. A critical consideration will be the time factor. Two mathematical modeling studies have resulted in the WHO anticipating that there may be only ~ 3 weeks “to start antiviral and non-pharmaceutical measures after the index cluster is detected” (slide 11). Possible prevention or mitigation of the pandemic has focused on the initial cluster(s) occurring in rural locations, rather than the more densely populated urban areas.
WHO recognizes that because such rapid containment has never been attempted there is no guarantee of success? Indeed, the feasibility of successfully implementing the protocol itself is controversial.
Multiple key concepts are illustrated in the slides. These include, for example, geographic containment of the outbreak by interventions in both a “containment zone” and a surrounding “buffer zone”. The WHO plan to provide asymptomatic persons with twenty (20) days of antiviral prophylaxis (slide 27), rather than 10 days, will directly impact how many people can be prophylaxed using stockpiles of anti-influenza drugs such as oseltamivir (tamiflu). Graphs depicting the estimated duration of interventions and “perimeter control” in the geographic containment zone, as well as surveillance efforts in both the containment zone and buffer zone, are also provided (slide 41).
The importance of successful communications throughout the rapid containment effort is emphasized as essential to ‘support and integrate all aspects of rapid containment’ (slide 38). These new WHO slides are themselves a step in the direction of successful transparent communications efforts and merit ongoing examination of the many difficult pragmatic and controversial issues that should be anticipated prior to the beginning of the next human influenza pandemic.
27 January, 2008
Daniel R. Lucey, MD, MPH
Pearls from the WHO “Smallpox and its Eradication”: The Role of Traditional Leaders in Northern Nigeria
This second in a series of insights (“pearls”) from the World Health Organization (WHO)’s 1988 Red Book titled “Smallpox and its Eradications” is quoted from chapter 17 (Western & Central Africa):
Northern Nigeria: the Role of Traditional Leaders
“In northern Nigeria, strong traditional tribal leadership both helped and hindered programme implementation. One advisor recalled his surprise when attending the first mass vaccination campaign in a town to find 6000 persons already in a line at 6 o’clock in the morning. As the day progressed, he proposed to the chief that a vaccination team should move to the market area to begin work there. The chief forbade this, indicating that if all vaccinations were performed in front of him, everyone would comply, but if he were not present at the vaccination assembly point, people would report they had been vaccinated when they had not. Vaccination in this and other largely Muslim northern cities continued until long after dark, as women were not allowed to leave their homes until nightfall.
On the negative side were such problems as those encountered during the investigation of the outbreaks in 1970 in and around Amayo. A village chief, when questioned about rumours of smallpox cases, denied all knowledge of them until, during the course of interrogation, his granddaughter emerged from the house with evident smallpox lesions. Because of fear that he would be deposed from his chieftaincy if it were found out that he had been hiding cases, he had suppressed information about the outbreaks.”
(page 866).
29 January 2008
Daniel R. Lucey, MD, MPH
European CDC Interim Report on Osletamivir (Tamiflu)-resistant (“H274Y”) Human Influenza A/ H1N1 Virus (not H5N1 avian flu)
On January 27th the European Centre for Disease Prevention and Control (ECDC) posted an 11-page document on their website providing an interim risk assessment of the “Emergence of seasonal influenza viruses typeA/H1N1 with oseltamivir resistance in some European Countries at the start of the 2007-08 influenza season”. Norway has the highest rates of resistance with 12 of 16 H1N1 virus isolates from symptomatic patients in November and December being resistant. The ECDC states that “H1N1 viruses are predominant in this winters epidemics worldwide, and these resistant viruses are a new phenomenon this winter” (p. 1). Thus, this is a concerning development, and warrants continued close monitoring. The full ECDC report can be found at: (http://ecdc.europa.eu/Health_topics/influenza/080127_.html)
Several of the key points in the ECDC report include:
- To date 19/148 (13%) of the Influenza A (H1N1) virus isolates from 10 European nations have “an amino-acid mutation histidine to tyrosine at position 274 in the neuraminidase protein, which in previous studies has been associated with a high level of resistance to oseltamivir” (page 3).
- All the H1N1 flu viruses tested this year, however, are still susceptible to the other anti-influenza drugs zanamivir, rimantidine, and amantidine (page 3).
- Epidemiological investigations of the 12 patients in Norway found no links between them, and no history of travel. Also, none of the 12 had been taking oseltamivir, or had been in close contact with persons taking this drug. Thus “it can be assumed that viruses carrying the H274Y mutation represent community influenza transmission in Europe (rather than importations or a focused outbreak)” (page. 3).
- Clinically, so far none of the patients with H1N1 influenza A virus resistant to oseltamivir are clinically any more ill than other patients with influenza (page 4).
- Some additional influenza virus isolate specimens from this month (January) have been sequenced by the Norwegian National Influenza Centre and show “evidence that the resistant virus is persisting”. (page 4). Thus, this oseltamivir-resistant virus is able to be transmitted person-to-person. Prior work with some other influenza viruses resistant to oseltamivir suggested that they had a reduced biological fitness that significantly impaired being transmitted person-to-person.
- “Oseltamivir resistance in influenza viruses is relative and despite its presence patients with oseltamivir-resistant viruses may still benefit from receiving oseltamivir (page 6. Reference cited is Moscona A. Oseltamivir resistance—disabling our influenza defenses. N Engl J Med 2005; 353:2667-72.).
- “The H274Y mutation has only been observed in viruses of the neuraminidase type 1 (N1). This mutation has been associated with a 400-fold reduction in the sensitivity of the virus to oseltamivir in vitro.” (Page 7).
- “In general, A/H1N1 viruses are associated with milder illness than other influenza A viruses” (page 7).
- “A/H1N1 viruses with the H274Y mutation have been seen before when they were detected in Japan in patients treated with oseltamivir. These viruses were not subsequently detected to be circulating in the community except at very low levels so they may be a somewhat different phenomenon” (page 7).
- In most countries in Europe oseltamivir is little used. “The numbers of prescriptions for treatment are negligible” (page 8).
- Looking forward, continued close monitoring of the possible spread and clinical outcomes related to these influenza viruses in Europe and on other continents is essential. National anti-influenza drug guidelines may need to be reviewed if the “H1N1-H247Y viruses continue to appear and spread” (page 9).
- To emphasize, this ECDC report pertains to human H1N1 human influenza viruses and does not involve any H5N1 avian influenza viruses.
31 January 2008
Daniel R. Lucey, MD, MPH
Increasing Numbers of European Nations (9) Report High Level (H274Y) Oseltamivir (Tamiflu)-Resistant Human influenza A H1N1 (not H5N1 avian flu)
On January 31, 2008 the journal “European Surveillance” posted online a rapid communication paper and accompanying editorial
describing oseltamivir (Tamiflu)-resistant seasonal H1N1 human influenza viruses in 9 European nations. Earlier this week such flu viruses were reported from isolates in four European nations. Of note, none of these influenza viruses are the avian flu virus H5N1. Today’s report by Nicoll and colleagues can be found at:
www.eurosurveillance.org/edition/v13n05/080131_2.asp.
This report updates that of January 27th and now includes a total of 437 influenza A (H1N1) virus isolates from 18 European nations. Of these, 50 (14%) show oseltamivir resistance by H274Y genotypic testing, or IC50 phenotypic resistance testing (see Table 1 of this paper by Nicoll et al.). One or more oseltamivir-resistance influenza H1N1 viruses were found in 9 of the 18 nations: Norway (26/37 virus isolates =70%), France (15/87=17%), UK (8/162=6%), Germany (3/42=7%), Finland (2/7), Portugal (2/6), Denmark (1/10), Sweden (1/13), and Netherlands (1/16).
These viruses with the H274Y mutation were reported to have IC50 values increased from ~ 1nM to over 400nM. As in the smaller initial report earlier this week, all these viruses remain sensitive to the three other anti-influenza drugs: zanamivir, rimantidine, and amantidine.
The majority of these oseltamivir-resistant viruses have been isolated from adults, although the ages of the patients range from 1 month to 61 years. Of note, none of these patients are known to have taken oseltamivir for therapy or prophylaxis, or to have been in contact with anyone taking oseltamivir. Thus, the authors conclude that this is “the first clear evidence that influenza A (H1N1) virus with the H274Y mutation can readily transmit between individuals”.
The accompanying editorial by Nicoll et al. emphasizes that these oseltamivir-resistant H1N1 influenza viruses are well-matched with the current influenza vaccine. The editorial by Lackenby et al., can be found at www.eurosurveillance.org/edition/v13n05/080131_2.asp
The January 31st New York Times (page A8, by Larence K. Altman) reports that in the USA the oseltamivir-resistant influenza A (H1N1 H274Y) strain has been found in 9/135 (6.7%) isolates of H1N1 viruses tested so far this flu season. The article also reported that the World Health Organization (WHO) on Tuesday (January 29th) held a two-hour teleconference with experts from multiple nations, according to a phone interview with Dr. Frederick Hayden, an influenza expert at WHO.
Further information from Europe, North America, and around the world will be forthcoming in the days and weeks ahead as influenza isolates are tested for oseltamivir-resistance. More are likely to be found. Fortunately, none of these viruses are the H5N1 avian influenza strain that has generated much concern as a possible pandemic precursor virus.
At the same time, the fact that this is the “first clear evidence” that significant person-to-person spread of oseltamivir-resistant (H274Y) seasonal human influenza A (H1N1) virus is occurring is worrisome. Previously, it was thought that the acquisition of this oseltamivir resistance typically conferred “less biologically fit” flu viruses that were not readily transmitted from person-to-person in a sustained manner.
Only the future will tell whether this phenomenon turns out to be an example of “past-as-prologue” in terms of other influenza viruses such as H3N2, H9N2, H7N7, H7N3, H7N2, H5N1 following the same pattern as oseltamivir-resistant H1N1 H274Y person-to-person transmission.
Feb 1, 2008
Daniel R. Lucey, MD, MPH
WHO/ECDC posts 18 FAQs on new oseltamivir-resistant transmissible Influenza A (H1N1) Viruses and Canada also reports their presence
Within the past 24 hours the World Health Organization (WHO) and the European Centers for Disease Prevention and Control (ECDC) posted on the WHO’s EPR website 18 frequently asked questions (FAQs) regarding the newly reported oseltamivir-resistant human influenza A (H1N1) viruses with the highly resistant H274Y mutation in the neuraminidase. The full 18 FAQs can be found at:
http://www.who.int/csr/disease/influenza/oseltamivir_faqs/en/index.html
Question 6 asks whether there is an explanation for the high frequency of oseltamivir resistance among the H1N1 human flu viruses. The answer begins with: “The frequency of oseltamivir resistance in H1N1 viruses in the current influenza season is unexpected and the reason why a high percentage of these viruses are resistant is currently unknown”.
Question 12 asks if the flu vaccine for this year is effective against this virus. The answer is yes. “”So far this flu season, A (H1N1) viruses are predominant in most parts of the northern hemisphere, and the majority are antigenically similar to A/Solomon Islands/3/2006, a vaccine virus. Immunization with this season’s vaccine remains an effective means of prevention against illness due to influenza viruses, including the oseltamivir-resistant H1N1 variants”.
Question 14 asks what potential implications these oseltamivir-resistant H1N1 human flu viruses have for the treatment of H5N1 avian flu cases? The answer is that so far “there are no reports of persons acquiring H5N1 infection from a patient with an oseltamivir-resistant H5N1 virus”. Moreover, oseltamivir resistance due to the same mutation has been reported in (only) three patients with H5N1 infection (but) they were being treated with oseltamivir. In contrast, none of the patients with highly-resistant H1N1 virus have been on treatment with oseltamivir.
In a related development the Canadian Press posted an updated article January 30th (Wednesday) stating that Canada’s National Microbiology Laboratory in Winnipeg reported that 8 of 81 (10%) influenza A (H1N1) viruses this flu season have the H274Y oseltamivir-resistance mutation. Of these, 6/8 were isolated from patients in Ottawa.
Of note, the one resistant H1N1 virus from British Columbia is from a child thought to have been infected in Sudan. If true, this suggests that such viruses might be in Africa as well as Europe and North America. No information regarding Africa or Asia has appeared yet, although updates from these continents can be anticipated soon. The full Canadian Press story can be found at:
www.cbc.ca/health/story/2008/01/30/tamiflu.html
Feb 4, 2008
Daniel R. Lucey, MD, MPH
Summary table of H5N1 avian flu viruses shared with WHO 2003-2007
On January 31, 2008 the World Health Organization (WHO) posted an informative updated table summarizing 8,815 human and animal H5N1 avian influenza specimens and viruses shared with them from 2003 until 2007. A total of 788 viruses were isolated and maintained in WHO labs, and 14 of these, originating in multiple nations, have been chosen for further development into H5N1 vaccine viruses.
The numbers of institutions receiving vaccine viruses, reverse genetics engineered or wild-type, are provided. This information can be found on the WHO website at:
www.who.int/entity/csr/disease/avian_influenza/TrackingHistoryH5N1_20080123.pdf This table is linked with the WHO’s original January 22, 2008 H5N1 Influenza Virus Tracking System database (interim version) that can be found at:
www.who.int/fluvirus_tracker/searchsample
This tracking system was developed on the request made to WHO noted in the “Interim statement of the intergovernmental meeting on pandemic influenza preparedness: sharing of influenza viruses and access to vaccine and other benefits” held 21-23 November, 2007. This two-page document on the WHO website includes the acknowledgment of “the urgent need for fair, transparent, equitable, and effective international mechanisms aimed at ensuring access to H5N1 vaccine and fair and equitable sharing of benefits, in support of public health amongst Member States taking into consideration the needs of developing countries (resolution WHA60.28)”.
The document also acknowledges “the fact that there has been a breakdown of trust in this essential system of the international collaboration and collective action” and that “the current system does not deliver the desired level of fairness, transparency, and equity”.
The January 31 pdf table appears to be oriented primarily according to the WHO laboratory to which the H5N1 influenza virus was provided (e.g., WHO CC Atlanta, WHO CC London, WHO CC Melbourne, WHO CC Tokyo, CHP HK ((Centre for Health Protection, Kowloon, Hong Kong (SAR), IP Paris (Unite de Genetique Moleculaire des Virus Respiratoires, Institute Pasteur, NAMRU-3, NIBSC, SJCRH, and UHK.
The nations from which the 14 influenza H5N1 viruses have been selected for further development into vaccine viruses (and the year the virus was shared with WHO) include: China (2005, 2006), Indonesia (2005), Viet Nam (2004), Cambodia (2007), China Hong Kong SAR (2003, 2006), Turkey (2005), Laos (2006), and Mongolia (2005). Of these 14 viruses, to date 8 are reverse genetics engineered vaccine viruses available for distribution. A total of 292 institutions have received one or more of these 8 WHO- developed vaccine viruses, while 47 institutions have received wild-type vaccine viruses.
Browsing the WHO interim database posted at: www.who.int/fluvirus_tracker/searchsample
provides more specific data e.g., regarding the names of multiple institutions that have received shared isolates of specific H5N1 viruses. Variable parameters can be set for any given query of the data. For example, database parameters can be set for “country of origin”, “autopsy virus “ (e.g., Vietnam), “vaccine selected for vaccine development”, and 2008 updated data for more recent viruses from Myanmar and Pakistan. A more detailed focus can sometimes provide data on the clade and subclade of the virus isolate, and the sensitivity to the two anti-influenza drug classes for a specific virus isolate.
This interim WHO database appears to be an excellent start toward the goals specified in the interim statement resulting from the November 21-23, 2007 intergovernmental meeting. Ongoing additional information can be anticipated within this expanding global influenza A (H5N1) virus database. This information will hopefully help catalyze optimal transparency and international collaboration in the development of new vaccines and antiviral drug use against influenza H5N1 viruses present and future.
5 Feb 2008
Daniel R. Lucey, MD, MPH
2008-2009 Flu Vaccine composition meetings announced for this month at WHO and US FDA
At this time each year the 3-part (Influenza A H3N2 and H1N1, and Influenza B) composition of the influenza vaccine for the next flu season in the northern hemisphere is discussed at the World Health Organization (WHO), and separately at the US Food and Drug Administration (FDA) in Maryland. Recently, the WHO announced that their meeting this year will be held February 11-13 in Geneva. The FDA’s Vaccines and Related Biological Products Advisory Committee will meet Feb 21 in Gaithersburg, Maryland February.
The WHO conference next week is by invitation only. Its objectives will include not only making recommendations for next year’s vaccine in the northern hemisphere, but also to “analyze the antiviral susceptibility of seasonal influenza strains circulating and prepare a summary to support relevant national policy making”. In addition, the antigenic and genetic aspects of recent H5N1 influenza strains will be reviewed, and participants will “evaluate the need and select subsequently A (H5N1) virus(es) to develop new vaccine viruses”.
On February 21 the FDA’s advisory committee will meet at the Hilton Hotel, 620 Perry Pkwy in Gaithersburg. Oral presentations from the public will be scheduled between 11:20 a.m. and 11:50 a.m. and 2:45 p.m. and 3:15 p.m. Persons desiring to make formal oral presentations are advised by the FDA to notify the contact person (Christine Walsh or Denise Royster at 301-827-0314 or 301-443-0572) by February 6. The morning of February 21 will be devoted to the choice of influenza vaccine strains for the 2008-2009 influenza season. The afternoon will be devoted to the”clinical development of influenza vaccines for pandemic and pre-pandemic uses”.
Feb 8, 2008
Daniel R. Lucey, MD, MPH
European CDC Update: 81/208 (39%) of H1N1 Influenza A isolates from France are resistant to Oseltamivir (Tamiflu) this Flu Season (Note: Not avian flu H5N1)
On February 7 the European Centre for Disease Prevention and Control (ECDC) in Stockholm provided its weekly update on the evolving situation with high-level (H274Y) oseltamivir (“Tamiflu”) resistance in influenza A (H1N1) viruses. Most notably, as more H1N1 virus isolates have been tested this past week from France the proportion resistant has increased to 39% (81/208) compared with 17% (15/87) reported only one week ago on January 31st.
Norway continues to report the highest proportion of oseltamivir-resistant influenza A (H1N1) virus isolates with 42/66 (63%) resistant. This proportion is similar to last week in which a smaller sample size revealed a resistance rate of 26/37 (70%).
This weekly updated information is posted online (www.eurosurveillance.org/edition/v13n06/080207_3.asp) as a rapid communication in the journal “Eurosurveillance 2008; volume 13, issue 6 (Feb 7th) by Ciancio B, and colleagues from the Influenza Project Team of the ECDC (Stockholm, Sweden) and is titled: Oseltamivir resistance in human seasonal influenza viruses (A/H1N1) in EU and EFTA countries: an update”.
Today’s (Feb 8th) issue #252 online of the European Influenza Surveillance Scheme (EISS)-Weekly Electronic Bulletin reports that this flu season “of the total virus detections since week 40/2007 (N=6354), 80% were influenza A of which 98% were of the H1 subtype with a good match with the current vaccine strain. A/H1N1 viruses resistant to oseltamivir have been detected in a number of countries”.
Seven other European nations are reporting much lower percentages of oseltamivir-resistant Influenza a (H1N1) viruses, including: the UK (12/181=6.6%), Germany (7/82=8.5%), Finland (3/11), Sweden (1/13), Portugal (2/6), Greece (2/18), and the Netherlands (1/16). The table with these data is posted online, and is listed as reference # 3 in the paper by Ciancio, at: “http://ecdc.europa.eu/Health_topics/influenza/antivirals.html
So far, oseltamivir-resistance has not been found in Influenza B isolates, or the less common (this season to date) influenza A (H3N2) virus isolates. As with last week’s results, so far antiviral drug-resistance is limited to oseltamivir and does not include zanamivir, rimantidine, or amantidine. The etiology of these emerging oseltamivir-resistant influenza A (H1N1) viruses is still under investigation.
Ciancio et al., conclude their February 7th update by noting that “the WHO data (outside of Europe) are interesting, but still very preliminary. Resistant viruses have been detected in North America, China (Hong Kong) and Australia, although not yet in Japan, which is thought to have higher levels of oseltamivir than any other country.
In April 27, 2007 the WHO’s Weekly Epidemiological Record (WER) reported (NO. 17; p.150) that from Japan “During the 2005-2006 season, initial sequence analysis found known oseltamivir resistance mutations in none of 251 influenza A (H3N2) viruses, but in 4 of 178 (2.2%) influenza A (H1N1) viruses, all 4 of which possessed an H274Y mutation in the neuraminidase”.
On February 3, 2008 (this week) ProMED-Mail posted a January 31 report from the Hong Kong S.A.R. Centre for Health Protection (CHP) of the Department of Health that 4/45 Influenza A (H1N1) isolates that were resistant to oseltamivir.
The weekly (Thursday) updates from the European CDC are very helpful. They will likely continue to provide the cutting-edge of information and understanding of this evolving situation with influenza A (H1N1) viruses, this season’s predominant influenza strain so date. More global information is awaited to facilitate understanding the epidemiology and potential clinical significance.
An update from next week’s WHO influenza vaccine composition meeting (Feb 11-14) in Geneva is also anticipated given that the participants will also “analyze the antiviral susceptibility of seasonal influenza strains circulating and prepare a summary to support relevant national policy making”.
In the meantime, from a theoretical clinical and therapeutic perspective, if a patient was suspected of both:
A) Having a strong epidemiological link to a person or specific area of the world (e.g., Norway or France) having oseltamivir-resistant influenza A (H1N1) viruses, AND
B) Required therapy for a clinically serious, known or suspected influenza A (H1N1) infection, then at least a risk-benefit consideration of the above antiviral resistance (oseltamivir) and susceptibility patterns (rimantidine, amantadine, zanamivir) would be prudent. At the same time, an analysis of the potential for a rimantidine or amantidine-resistant influenza A (H3N2) virus infection would have to be made, as well as any contraindications to therapy with zanamivir (“Relenza”), given that this drug is only available in an inhaled form via a special “Diskhaler” inhalation device.
Health Department Reports that Influenza Has Arrived in New York City
If you haven’t had your vaccine yet, it’s not too late!
February 9, 2008 – Influenza has arrived in New York City, so if you and your family have not been vaccinated against the disease this season – now is the time to do it. Surveillance systems indicate that influenza is now spreading among New Yorkers, the Health Department reported today. There is plenty of vaccine available this year and there is still time to get vaccinated, so the Health Department is urging all New Yorkers to get vaccinated and reduce their risk.
“The best way to protect yourself or your loved ones from getting very ill is to get vaccinated,” said Dr. Thomas R. Frieden, New York City Health Commissioner. “Young children and older adults are at higher risk of hospitalization and death if they get sick. So don’t take the risk – get the vaccine today.”
Influenza is a highly contagious respiratory infection that, together with pneumonia, kills thousands of New Yorkers every year. Besides safeguarding people from days or weeks of debilitating sickness, the vaccine can prevent unnecessary school absences, doctor visits and hospitalizations. While anyone can get influenza, some groups are especially at high risk of complications and death:
• Children between 6 months and 18 years of age
• Adults 50 and older – especially those over 65
• Pregnant women
• People with chronic health conditions
• People in nursing homes and other long-term care facilities
• Health-care workers
• Anyone in close daily contact with children under 5 years old – especially those in contact with infants younger than 6 months
• Anyone in close daily contact with people who are over 50 years old or living with chronic health conditions
Influenza symptoms include a fever, dry cough and body aches – not a stomach ache or vomiting. And influenza is not just a bad cold. It is caused by a completely different virus. “If you do get influenza, cover your cough and stay home to minimize the spread of disease to others,” said Dr. Frieden.
It is still too early to tell the severity of this year’s influenza season. The Health Department is monitoring cases of influenza as well as strains that are drug-resistant. The agency will continue to provide guidance to healthcare providers throughout the season.
Scared of needles? There’s an alternative.
If you’re hesitant about getting a flu shot because of the needle, FluMist® is a nasal spray vaccine for healthy people between the ages of 2 and 49. Your doctor can tell you whether FluMist® is right for you.
Where to get vaccinated
Influenza outbreaks have occurred as late as May in New York City. Your regular health care provider should have a good supply of flu vaccine, so call and set up an appointment today.
Flu shots are available at no cost at Health Department clinics. No appointment is necessary. Any New Yorker can call 311 for clinic locations and other sites where flu vaccine is being offered, or use the flu clinic locator online at www.nyc.gov/health/flu.
New York City’s Health and Hospitals Corporation (HHC) also offers free and low-cost flu shots and FluMist® at public hospitals throughout the city. For information, visit www.nyc.gov/html/hhc/html/services/flushots.shtml.
Pneumococcal vaccine
People ages 65 and older and those between the ages of 2 and 64 with chronic medical conditions should ask their doctor about the pneumococcal vaccine (commonly referred to as the ‘pneumonia vaccine’).
11 February 2008
Daniel R. Lucey, MD, MPH
CDC reports flu vaccine not well-matched for Influenza A (H3N2) or Influenza B, and unexplained Tamiflu resistance found in 8% of Influenza A (H1N1) isolates
In a press conference transcript from last Friday, February 8, Dr. Joe Bresee, chief of the epidemiology and prevention branch of the Influenza Division at the Centers for Disease Control and Prevention (CDC) reported that only one of the three components of this year’s influenza (flu) vaccine is well-matched to circulating strains of the virus.
Influenza A (H3N2) and influenza B are not well-matched to their vaccine strains. Fortunately, however, the most common influenza type virus circulating so far this year, influenza A (H1N1), is a good match to its vaccine strain.
Dr. Bresee, and the CDC “FluView” website for Week 5 of this flu season (ending February 2nd), noted that 87% (46/53 influenza A (H3N2) virus isolates) were characterized as Influenza A/Brisbane/10/2007-like, a recent antigenic variant which evolved from the Influenza A/Wisconsin/67/2005-like virus that is in this year’s flu vaccine.
Dr. Bresee emphasized, however, that partial protection could still be conferred by this flu vaccine against the “drifted A/Brisbane strain”. Specifically, he cited military data from Europe in this regard…”we know that there are some Department of Defense data from last season when this H3N2 virus was predominant in Europe that showed that vaccinating people with the A/Wisconsin strain, which is, again, the virus that we have in our vaccine this year, was 52% protective against the drifted A/Brisbane strain”.
Nearly all (93%) of this year’s circulating influenza B viruses are of an entirely different lineage (the “Yamagata lineage”) compared with this year’s vaccine strain (“Victoria lineage”) of influenza B. Thus, vaccine-induced immunity is likely to be sub-optimal.
Fortunately, 96% (97/101) of the influenza A (H1N1) virus isolates characterized so far from isolates circulating in the USA are well-matched to the vaccine strain A/Solomon Islands/3/2006.
In terms of antiviral resistance, as of the week ending February 2nd, the CDC reported that 15 of the 331 influenza A and B viruses tested for antiviral resistance have demonstrated oseltamivir (Tamiflu) resistance. All 15 of these viruses are influenza A (H1N1) viruses (representing 8.1% of all H1N1 viruses so far this year).
This finding, still unexplained, is consistent with the reports this flu season from Europe (especially Norway and France), Hong Kong, and Canada of oseltamivir resistant influenza A (H1N1) viruses. No oseltamivir-resistant influenza A (H3N2) or influenza B viruses have been found yet this year in the USA.
Oseltamivir (Tamiflu) is the only oral recommended anti-influenza drug in the USA, given the high degree of adamantane antiviral drug resistance (specifically, to rimantidine and amantidine) among influenza A (H3N2) and influenza B. This year the CDC reported, as of February 2, that 8.3% of influenza A (H1N1) viruses, and 99% of influenza A (H3N2) viruses, are resistant to adamantane drugs
Thus, the only influenza virus type (A/H1N1) with any degree of oseltamivir (Tamiflu) resistance) is also the only one this year that is well-matched (96%) to the flu vaccine strain of influenza A (H3N2). The other two vaccine strains (influenza A/H3N2 and influenza B) are not well-matched to circulating strains, but they also have not exhibited any oseltamivir (Tamiflu) resistance to date.
12 February 2008
Daniel R. Lucey, MD, MPH
A new virus linked with a solid-organ transplant donor and the deaths of three transplant recipients
On February 6 the New England Journal of Medicine posted a paper by Gusavio Palacios and co-authors from Columbia University (NYC Mailman School of Public Health), the US CDC, and the Victoria Infectious Disease Reference laboratory (Australia) reporting the discovery of an arenavirus related to lymphocytic choriomeningitis viruses (LCMV) using a molecular technique termed “unbiased high-throughput sequencing”. The article can be found online at: http://content.nejm.org/cgi/content/full/NEJMoa073785. The accompanying editorial by Richard Whitley from Birmingham, Alabama that emphasized the potential new use of this “high-throughput DNA pyrosequencing” for the discovery of infectious disease pathogens.
This newly discovered virus was linked to the deaths of three Australian women after receiving either a transplanted kidney or liver. The donor had traveled to the former Yugoslavia for a three-month visit, and then 10 days after returning to Australia died of a cerebral hemorrhage. The cause of the cerebral hemorrhage was not definitively stated. All three transplant recipients, however, developed fever and encephalopathy before their deaths 4-6 weeks after transplantation. Further clinical information was limited. Chest infiltrates and graft rejection occurred in patients 1 and 2, and myoclonus in patient 2. Diagnostic tests for at least 24 pathogens were negative.
Evidence for a previously undiscovered Old World Arenavirus causing the cluster of three deaths began with RNA extraction from the brain, cerebrospinal fluid (CSF), kidney, liver, and serum from recipient # 1, and the CSF and serum of patient # 2. (Only the serum from patient # 3 was used for diagnostic testing). The authors reported that unbiased high-throughput sequencing initially detected the arenavirus. Then the infection was “confirmed” by means of culture, electron microscopy, and specific immunohistochemical and serologic tests.
The editorial by Whitley summarized the diagnostic methodology, termed “high-throughput DNA pyrosequencing”. He comments that this methodology has not been previously applied to pathogen discovery. Using the transplanted liver and kidney to form a library of 100,000 sequences, then subtracting human sequences leaves potential microbial sequences, such as those for this arenavirus. After obtaining these nucleic acid sequences the viral genome is cloned, and the virus propagated in tissue culture. Confirmation is obtained using serologic and molecular assays.
Although Koch’s postulates have not been fulfilled in the description of this new arenavirus, the authors note that the “virus is new and was not detected in 100 organ recipients who were not linked to this cluster”.
Clinicians are likely to anticipate the potential availability of more conventional serologic and molecular assays for this new arenavirus so that they can test for and understand the clinical spectrum of this pathogen, both in neurologic and non-neurologic diseases.
In addition, further application of this methodology of high-throughput DNA pyrosequencing for pathogen discovery could be applied to other unexplained diseases such as sarcoidosis, Kawasaki’s Syndrome, and many other diseases of unknown etiology.
16 Feb 2008
Daniel R. Lucey, MD, MPH
Europe: More oseltamivir-resistant Influenza A (H1N1). WHO posts evolving global resistance database results.
The European Centre for Disease Prevention and Control (ECDC) posted online 14 February 2008 an updated weekly table listing 202 virus isolates of oseltamivir-resistant influenza A (H1N1) from 13 European nations out of a total of 21 nations submitting 986 influenza A (H1N1) samples.
As in the preceding week, Norway and France had the highest percentage of these resistant viruses with 66% (63/95) and 39% (81/208), respectively. Of note, Luxembourg has now been found to have 23/93 (25%) resistant H1N1 influenza A viruses. The report and tabular list of the 21 European nations submitting samples, the 13 nations with one or more resistant viruses, the 8 nations without resistant viruses found to date, the number of total samples tested and the number found to be resistant can be viewed at:
http://ecdc.europa.eu/Health_topics/influenza/antivirals.html
http://ecdc.europa.eu/Health_topics/influenza/antivirals_table.html
The World Health Organization (WHO) has begun to post online a global update on oseltamivir-resistant Influenza A (H1N1). In a WHO document (table) dated 11 February 2008 and providing data from the last quarter of 2007 until 7 February 2008, several nations outside of Europe are reporting results of oseltamivir resistance testing by genotypic and/or phenotypic analyses. Nations reporting resistant viruses include: USA (15/179 = 8%), Canada (8/128=6%) Australia (2/36 = 6% although both cases are described as “probably imported” in a footnote to the table), China, Hong Kong SAR (5/67=7%).
Nations outside Europe reporting no oseltamivir-resistant influenza A (H1N1) include: Japan (0/71 isolates tested), Republic of Korea (0/27), New Zealand (0/88), Senegal (0/16), Thailand (0/8), Mongolia (0/4) and Algeria (0/2). The complete WHO document, that will be updated, can be found at:
www.who.int/csr/disease/influenza/h1n1_table/en/index.html
23 February 2008
Daniel R. Lucey, MD, MPH
WHO Director-General Chan welcomes new funding of $350 million/5 years for 7 Neglected Tropical Diseases in Africa, Asia, and Latin America
On 20 February 2008, the Director-General of the World Health Organization (WHO), Dr. Margaret Chan, issued a statement welcoming the announcement that same day ”to vastly increase funding for the integrated treatment of seven of the most important neglected tropical diseases…An intensified attack on these diseases delivers a blow against the poverty of millions of people”. This new funding is for $350 million over five years and was announced by the President Bush of the USA. The WHO statement by Dr. Chan is at: (www.who.int/mediacentre/news/statements/2008/s03/en/index.html)
These seven neglected tropical diseases (NTDs) include:
- Lymphatic filariasis (“elephantiasis”)
- Schistosomiasis (“snail fever”)
- Trachoma (severe eye infection)
- Onchocerciasis (“river blindness”)
- Hookworm (a soil-transmitted worm infection)
- Roundworm (also a soil-transmitted worm infection)
- Whipworm a third soil-transmitted worm infection)
The nations to receive this five-year funding (from FY 2009-FY 2013) will expand from 10 nations in 2008 to approximately 30 nations by 2013. The countries are located in African, Asia, and Latin America. WHO’s Dr. Chan compared the planned approach of integrated mass provision of medications to prevent and treat these neglected tropical diseases to the “approach to mass prevention similar to childhood immunizations. Efforts to increase coverage can begin immediately”.
The US President Bush called on other potential donors such as G-8 partners, foundations, public, private, and voluntary organizations to work toward adding an additional $650 million for the treatment of Neglected Tropical Diseases NTD). This document is posted at: www.whitehouse.gov/news/releases/2008/02/20080220.html
Dr. Peter Hotez, Editor-in-Chief of the medical journal “PLoS Neglected Tropic Diseases” called the $350 million donation “an important first step towards the Global Network’s goal of launching a $1-2 billion NTD fund”. He notes that “In 2005, the leaders of the major public-private partnerships devoted to fighting NTDs, together with a new NTD Department at the World Health Organization, designed a package of drugs known as the “rapid impact package” that treats the seven most common NTDs for a modest 50 cents per person per year”. His comments are at: www.plos.org/cms/node/329
This new global health initiative for an integrated approach against seven of the Neglected Tropic Diseases is welcome indeed. Moreover, it is hoped that this initiative, as well as others such as the President’s Malaria Initiative, and the President’s Emergency Plan for AIDS Relief, will be continued by successive US Presidents for the coming years, and if needed, decades.
26 February 2008
Daniel R. Lucey, MD, MPH
WHO Update: H5N1 Virus Antigenic Changes and Relation to Candidate Human Vaccines
This week the World Health Organization (WHO) posted on their avian influenza website a useful five-page update on “Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as human vaccines”. The WHO notes that stockpiles of H5N1 clade 1 and the more recent clade 2 are being created by multiple nations. Additional clinical trials of H5N1 viruses from clade 1 and clade 2 (including several subclades) are anticipated.
Genetic characteristics of H5N1 avian influenza viruses are based on phylogenetic relationships among the hemagglutinin (HA) gene of these viruses. There are now ten (10) such distinct phylogenetic “clades” (numbered 0-9) that have been found in animals and, to a much lesser extent, in humans. In addition, clade 2 H5N1 viruses have several subclades. The latest proposed H5N1 virus nomenclature system is posted at: www.who.int/csr/disease/avian_influenza/guidelines/nomenclature/en/index.html
Most human infections since 2003 have been due to clade 1 and clade 2 viruses, as follows:
Clade 1: Thailand, Vietnam, Cambodia, and China Hong Kong SAR
Clade 2.1: Indonesia
Clade 2.2: Azerbaijan, China, Djibouti, Egypt, Iraq, Nigeria, Pakistan,
and Turkey.
Clade 2.3.4: China, Lao People’s Democratic Republic, Myanmar,
and Vietnam.
WHO notes several examples of antigenic differences, using HA inhibition assays, between some H5N1 viruses and their respective clade or subclade-specific current vaccine candidates:
Clade 1: Some newer H5N1 virus isolates such as the A/duck/Vietnam/NCVD16/2007 are antigenically distinct from the vaccine candidate clade 1 viruses A/Vietnam/1194/2004, and A/Vietnam/1203/2004.
Clade 2.1: No virus isolates from 2007 are reported to be antigenically distinct, although Table 1 on page 3 shows one isolate from 2006 (“A/Indonesia/CDC625L/06 (Medan”) as having a low (80 vs 640 or 2560 for other clade 2.1 isolates) reference ferret antisera. The reference antigen used was “A/Indonesia/5/2005 (IND/5)”. The text and table in this document do not explicitly state whether this “Medan” virus isolate is from the northern Sumatra “Karo cluster” of genetically-related persons with H5N1 infection that occurred in May 2006.
Clade 2.2: “Some recently characterized clade 2.2 viruses from Egypt show evidence of antigenic heterogeneity” compared to currently recommended vaccine candidates. Table 1 names such viruses, for example: A/Chicken/Egypt/9403NAMRU3/07.
Clade 2.3.2: Viruses within this clade “are antigenically distinguishable from other 2.3 clades”.
Table 2 on page 4 of this document provides the “Status of H5N1 vaccine virus development as of 13 February 2008”. The initial third of this table lists reassortant viruses with “completed regulatory approval”. These include clade 1, clade 2.1, clade 2.2, and clade 2.3.4. All are listed as “available” except for the clade 2.1 A/Indonesia/5/2005 that “requires Indonesia Government permission”.
The final third of this table includes “viruses proposed by WHO for candidate vaccine preparation”. These include additional clade 2.1 (A/duck/Hunan/795/2002-like), clade 2.2 (from Egypt), and clade 2.3.2 viruses.
Overall, this document provides important new information about antigenic and genetic changes in the ongoing international spread of avian influenza H5N1 viruses and the implications for current and future vaccine candidates.
Feb 28, 2008
Daniel R. Lucey, MD, MPH
Oseltamivir-Resistant Influenza A (H1N1) reported in Japan, and persists in 15 nations in Europe, the USA and Canada
Today the European CDC and the WHO updated their online information regarding high-level resistance to oseltamivir (“Tamiflu”) by human seasonal Influenza A (H1N1) virus isolates. The WHO table of global data includes 5/100 (5%) virus isolates in Japan showing this high-level resistance, in contrast to no resistance earlier this flu season when this phenomenon was first reported from Europe. Today’s updated WHO global database can be found at: www.who.int/csr/disease/influenza/h1n1_table/en/index.html
The significance of these emerging oseltamivir-resistant human seasonal influenza A (H1N1) viruses is emphasized in today’s update on the website of the European Centre for Disease Prevention and Control (ECDC): “These are the first human influenza viruses resistant to oseltamivir found transmitting in the community anywhere in the world (boldtype added). Similar viruses have been seen before but usually following treatment and those viruses have not been able to transmit and infect and have rapidly disappeared…There is no evidence that the appearance of these new viruses are related to use of oseltamivir which is currently thought not to be widely prescribed in most European countries.” For the full 28 February ECDC report go to: http://ecdc.europa.eu/Health_topics/influenza/antivirals.html
The WHO global database update February 28 noted that the USA reported 9% of 453 influenza A (H1N1) virus isolates, Canada 9% of 211 isolates, and Hong Kong SAR, China 9% of 116 isolates as resistant to oseltamivir.
Oseltamivir-resistant influenza A (H1N1) viruses have now been reported in 15 European nations. These include Ireland (10.3% of 29 virus isolates tested), Switzerland (13.3% of 30 isolates), the Netherlands (26% of 50 isolates), France (38.6% of 207 isolates), Norway (66.1% of 124 isolates) and ten other nations.
Italy has tested 66 isolates, Spain 52 isolates, New Zealand 88 isolates, the Republic of Korea 54 isolates, and the Philippines 37 isolates without finding any oseltamivir resistance.
The origin remains unknown of these unprecedented human influenza viruses that are transmissible from person-to-person despite being oseltamivir-resistant. Testing results of much larger numbers of human and animal influenza virus isolates from nations in Asia, the Americas, and Africa will be very important to help assess the epidemiology of these highly-resistant (H274Y mutation) viruses.
Expanded testing of animal influenza viruses for oseltamivir-resistance could help assess the hypothetical issue of animals having been exposed to oseltamivir, and subsequently contributing to the emergence of oseltamivir-resistant human influenza A (H1N1).
6 March 2008
Daniel R. Lucey, MD
World Malaria Day Website Created by WHO
In the past week the World Health Organization (WHO) has activated a highly informative website dedicated to the upcoming first World Malaria Day on April 25, 2008. A number of organizations, such as the Roll Back Malaria (RBM) Partnerships, are collaborating on this website. This well-organized and informative website can be found at:
http://rbm.who.int/worldmalariaday/index.html
The website currently contains four “key messages” as well as personal statements regarding malaria by 14 highly-respected individuals from around the world. The four key messages are:
1. Malaria is deadly but beatable.
2. Investing in malaria control makes both humanitarian and economic sense
3. Investing in malaria is a cost-efficient way of achieving global health and development goals.
4. Collaboration is a key to success.
Two examples of the personal statements about malaria and the World Malaria Day that is now only seven weeks away include the following by Desmond Tutu, and by Dikembe Mutumbo:
“I support World Malaria Day. We can rid the world of the scourge of malaria. We have the means. We often lack the political will. Let us reverse this trend and make our world malaria free”
Desmond Tutu Archbishop Emeritus
The Desmond Tutu Peace Foundation
“… In the city of Kinshasa, DR Congo, my hometown, Malaria is still the principal cause of death that is recorded in many of the health centers. It is my sincere hope that the Africa of tomorrow will have equal access to quality health care. That is why I am personally working toward that goal. With the help of people of goodwill, like the Malaria Consortium, I have no doubt in my mind that we can achieve that goal. It is the right thing to do and it is in our common interest as citizens of the world. I am delighted to be working with the U.N Foundation which has donated Insecticide treated bed nets to the Biamba Marie Mutombo Hospital in the Congo. These nets will help combat malaria, so let us try to eradicate malaria from the planet in our lifetime”.
Dikembe Mutombo
NBA All Star for the Houston Rockets and founder of Dikembe Mutombo Foundation
At Georgetown University in Washington, DC students, faculty, and researcher partners from the Medical School, the Mortara Center at the School of Foreign Service, the O’Neill Policy Institute, in partnership with the NIH Fogarty Center, the WHO–DC Office, the UN Foundation, and other collaborators have organized a symposium on malaria April 25th.
Prior to World Malaria Day, undergraduate and graduate students are taking the lead on multiple fundraising events in order to send long-lasting insecticide-treated bed nets to malaria-endemic areas of Africa through the UN Foundation in DC (1800 Massachusetts Avenue NW). Their fundraising team is named the “Georgetown Hoyas: Operation Bug Off” and can be found at: www.nothingbutnets.net/georgetown.
March 10, 2008
Daniel R. Lucey, MD, MPH
Letter to Health Care Professionals from Manufacturer of Oseltamivir (Tamiflu) Updates Neuropsychiatric Information in Package Insert
The following information is quoted from page one of a three-page letter to health care professionals, dated “February 2008”.
“IMPORTANT PRESCRIBING INFORMATION
Dear Healthcare Professional:
Roche Laboratories Inc. would like to advise you of a recent update to the TAMIFLU ® (oseltamivir phosphate) package insert. The revisions to the product label are the result of recommendations made by the FDA Pediatric Advisory Committee meeting held on November 27, 2007. The revised PRECAUTIONS section of the TAMIFLU Capsules and Oral Suspension package insert now includes the following information and guidance under the Neuropsychiatric Events subheading:
Neuropsychiatric Events
Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of TAMIFLU to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.
In addition, the following statement has been revised in the What are the possible side effects of TAMIFLU? section of the TAMIFLU Patient Information:
People with the flu, particularly children and adolescents, may be at an increased risk of seizures, confusion, or abnormal behavior early during their illness. These events may occur shortly after beginning TAMIFLU or may occur when flu is not treated. These events are uncommon, but may result in accidental injury to the patient. Therefore, patients should be observed for signs of unusual behavior and a healthcare professional should be contacted immediately if the patient shows any signs of unusual behavior”.
Of note, the complete 22-page updated package insert (pi) for this antiviral medication (oseltamivir phosphate, or “Tamiflu”) can be found online at: www.rocheusa.com/products/tamiflu/pi.pdf
12 March 2008
Daniel R.Lucey, MD, MPH
Hong Kong closes all primary schools, kindergartens, and nurseries for two weeks due to human influenza outbreaks
The South China Morning Post newspaper (www.scmp.com) reported that on March 12: “All primary schools, special schools, nurseries and kindergartens will be closed for two weeks from today amid the city’s flu outbreak, the health chief announced…” It should be noted that the upcoming Easter vacation has been moved forward and will start earlier than had been already planned.
In an AP news report from Hong Kong today, carried also online at CNN.com, it was noted that three children, ages 2 years, 3 years, and 7 years have died of influenza-like illness in the past week. “Health Secretary Chow said that Yuen Kwok-Yung will head a panel of scientists studying the recent deaths” of the children.
Notably, Professor KY Yuen is an internationally renowned virologist and expert on influenza virus and the SARS virus, as well as a distinguished senior member of the microbiology and infectious disease community in Hong Kong, and senior Faculty member of the University of Hong Kong.
The website of the Hong Kong Centre for Health Protection (CHP) posted the March 12 daily update on influenza that included the following highlights (see: www.chp.gov.hk)
—“Hong Kong is currently at the height of influenza season, which is expected to last for some period”.
—“Hospital admission rates due to influenza among children under 5 and elderly 65-year-old and older are rising, but below those recorded in peak seasons in 2006 and 2007”.
—“There are 20 suspected and 3 confirmed influenza outbreaks today. The suspected ones include 2 secondary schools, 11 primary schools, and 7 kindergartens/child care centres ….For the confirmed outbreaks, 2 are Flu A and 1 is Flu B, all affected primary schools”.
The findings of the expert panel headed by Professor KY Yuen will be scientifically informative and transmitted in an expeditious and transparent manner. At this time there does not appear to be any cause for panic, although the serious concern regarding the recent deaths of three children is certainly understandable.
The above comparisons by the Centre for Health Protection between hospitalizations this year for influenza in children under five years of age, and the past two flu seasons of 2006 and 2007 offers some overall quantitative context. Hopefully, the influenza incidence and severity of individual cases will have significantly declined after the current school closures that will continue into the following Easter school holiday recess.
13 March 2008
Daniel R. Lucey, MD, MPH
Courage Remembered: Five Years after the Initial WHO SARS Global Alert March 12, 2003, and Emergency Travel Advisory March 15, 2003
During this week five years ago, in the middle of March, 2003 the World Health Organization (WHO) issued their initial two statements (on March 12 and March 15) about the new disease that would become known as Severe Acute Respiratory Syndrome (SARS). In this present and likely future Age of Emerging Infections, the courage required to issue the press release on March 12, 2003 titled: “WHO issues a global alert about cases of atypical pneumonia” should be remembered.
Only in retrospect is it easy to say that issuing a global alert for a respiratory disease before it was even known to be a new “emerging” infection was the correct thing to do. At the time of this March 12, 2003 global alert it was noted stated that this “severe respiratory illness may spread to Hospital Staff” and examples were cited from one hospital in Hanoi, Vietnam, and one hospital in Hong Kong.
No precedent existed for such global alerts from WHO for other respiratory disease outbreaks, and there was no evidence that the pathogen was a new influenza virus that might signal the start of the next flu pandemic. In fact WHO stated in their March 12, 2003 global alert that: “No link has so far been made between these outbreaks of acute respiratory illness in Hanoi and Hong Kong and the outbreak of `bird flu,` A(H5N1) in Hong Kong SAR reported on 19 February” (2003).
Hopefully, this example from the WHO on March 12, 2003 will illustrate the concept of “Past as Prologue” when the next SARS-like respiratory disease emerges.
15 March 2008
Daniel R. Lucey, MD, MPH
Hong Kong reports human influenza A (H1N1) as the cause of death in one child and Influenza A (H3N2) as the cause of death in another child, and not an unusual human or avian flu virus.
On Friday, March 14, the Hong Kong Centre for Health Protection (www.chp.gov.hk) posted on their “Daily Update of Influenza Situation” website (http://sc.chp.gov.hk/gb/www.chp.gov.hk/epidemiology.asp?lang=en&id=448) an important update on their rapid investigation of the recent deaths of children with an influenza-like illness. No evidence of an unusual human influenza virus, an avian influenza virus, or dual infection with two flu viruses, was found as the cause of the death in two children recently reported to have an influenza-like illness.
Schools for young children in Hong Kong were closed in the middle of this week due to concern about influenza outbreaks, including those associated with the deaths of these two children.
The Centre for Health Protection specifically reported on March 14:
“Gene sequencing results available today on the 7-year-old boy who died in TMH confirmed that the H1N1 virus in the boy has the same genetic makeup as the circulating H1N1 (Brisbane) strains in Hong Kong. Earlier, gene sequencing results on the 3-year-old girl who died in TMH found that the H3N2 virus in the girl has the same genetic composition as the circulating H3N2 (Brisbane) strains as well. Both strains have been circulating in different parts of the world during the past few months. These results confirm that the 2 children did not die from a new virus that is more virulent than the circulating strains in the region”.
This March 14 report also noted that “During the year 2007, a total of approximately 1,400 children aged 12 years or below were hospitalized in hospitals under the Hospital Authority due to influenza (principal diagnosis). About 100 had suffered from more severe conditions including pneumonia, sepsis, myocarditis, encephalopathy or shock”.
In addition, across Hong Kong, “A new influenza surveillance arrangement with public and private hospitals has been set up to monitor the number of hospital reports on children aged 12 years or below who have fever, respiratory symptoms, and clinically more severe complications. From March 13-14, a total of 5 children have been reported through this new arrangement”.
Such daily updates on influenza in Hong Kong from the Centre for Health Protection, “with inputs from the Hospital Authority” of Hong Kong hospitals, are a reliable and valuable source of information.
18 March 2008
Daniel R. Lucey, MD, MPH
Hong Kong, Guangdong Province, and Macao experts meet March 17th to discuss influenza
Yesterday medical and public health officials met in Hong Kong at the Department of Health’s Centre for Health Protection (CHP) to discuss recent events regarding human seasonal influenza. Hong Kong closed all school for young children on March 13th due to concerns about influenza outbreaks occurring now during the peak of Hong Kong’s primary influenza season.
Closer cooperation between these public health officials in the Pearl River region and its delta emptying into the South China Sea, including Guangdong Province (the Pearl River runs through the province and its capital Guangzhou) and Hong Kong was one of the outcomes of the SARS crisis in 2003.
Information on more than 20 infectious diseases, not only SARS, began to be shared in a more rapid and transparent manner between these regional neighbors following the SARS epidemic. In 2005 an agreement was signed between Hong Kong, Macau, and Guangdong to work together to prevent and control multiple infectious diseases.
Meanwhile, in today’s (March 18) “Daily Update on Influenza Situation” posted on the homepage of the Hong Kong Department of Health Centre for Health Protection (CHP) (www.chp.gov.hk) it was noted that since the last update (March 17) “there is no new influenza outbreak. Last week, 24 confirmed influenza outbreaks were recorded.”A new influenza surveillance program was established in an arrangement with Hong Kong hospitals and the Department of Health March 13th. Since then, five lab-confirmed influenza infections have been reported in children aged 12 years or younger who also have clinically severe complications (e.g., severe pneumonia, severe sepsis, shock, encephalopathy, or myocarditis). Of these five children, three remain in stable condition in hospital, and the other two children have been able to be discharged from the hospital. The daily updates on the influenza events in Hong Kong (HK), particularly in children with severe complications, is an excellent way to rapidly convey information to the public and appears to be a very effective example of risk communication by the HK Department of Health.
24 March 2008
Daniel R. Lucey, MD, MPH
World TB Day and Global Tuberculosis Control 2008
Today is World Tuberculosis (TB) Day. On March 24, 1882 the renowned German physician and researcher, Dr. Robert Koch, announced in Berlin that he had discovered the bacteria that cause tuberculosis.
One week ago, on March 17, the WHO posted on their homepage a news release with links to the most recent comprehensive update on
TB titled: “Global tuberculosis control 2008”. A sobering finding highlighted in the report and news release is that, worldwide, less progress is being made in the diagnosis and control of TB. Data provided by 202 nations and territories formed the basis for this 12th annual WHO report on global TB. Data were compiled and presented from 2006, the most recent year for which information was available.
The striking scale of the global problem is conveyed by the fact that there were 9.2 million newly diagnosed cases of TB in 2006. Moreover, an estimated 1.5 million people died of TB that year. Approximately 500,000 persons in 2006 were diagnosed with multidrug-resistant TB (MDR-TB).
MDR-TB is one of two major obstacles to progress that were emphasized in this 2008 global TB report. “Given limited laboratory and treatment capacity, countries project they will provide treatment only to an estimated 10% of people with MDR-TB worldwide in 2008”. This March 17 WHO report and news summary can be found at:
www.who.int/mediacentre/news/releases/2008/pr07/en/index.html
A second major potential impediment to progress against TB worldwide is the overlapping and negatively-interacting dual epidemics of TB and HIV/AIDS. In 2006 there were an estimated 700,000 cases of TB among persons living with HIV. The WHO report estimated that 200,000 persons with HIV died with HIV-associated TB in 2006. As the HIV virus infects, damages, and destroys the immune system, it increases dramatically the risk of active tuberculosis disease caused by the TB bacteria. In 2006 nearly 700,000 TB patients were tested for HIV worldwide, far below the goal of 1.6 million persons that is part of the Global Plan to Stop TB 2006-2015.
A wide spectrum of information on tuberculosis and its impact on global health is available on the WHO website at:
www.who.int/topics/tuberculosis/en/index.html
25 March 2008
Daniel R. Lucey, MD, MPH
Human Influenza Outbreak in Hong Kong Stabilizing
Today the Hong Kong Centre for Health Protection (CHP) posted on their website under the “Daily Update on Influenza Situation” the following highlighted information: “The number of children hospitalized for influenza with complications during the past 2 weeks shows a stable trend and is comparable with previous years”.
Also highlighted was the fact that Hong Kong is still “within its traditional influenza season, which is expected to last for some time”. No new influenza outbreak had been recorded since the last update. “Last week, one confirmed influenza outbreak was recorded”.
Since the March 13, 2008 new influenza surveillance arrangement went into effect to monitor children 12 years of age and younger with fever, respiratory symptoms, and more severe complications such as severe pneumonia, severe sepsis, shock, encephalopathy, or myocarditis, there have been 24 such reports. Of these, 6/24 children have had laboratory-confirmation of influenza virus infection (2 with Influenza A and four with Influenza B viruses). Of note, all six children have already been discharged from hospital.
The remaining 18/24 children had at least preliminary tests for influenza viruses that were negative, and 9/18 have been discharged from hospital.
Close monitoring of the influenza outbreak, particularly pertaining to severe complications in children, will continue to provide such admirably transparent risk communication facts both within and beyond Hong Kong.
28 March 2008
Daniel R. Lucey, MD, MPH
Emergency Operation Centre inaugurated at the European CDC
At the beginning of this month (March 4) a state-of-the art Emergency Operations Centre (EOC) was opened at the Stockholm headquarters of the European Centre for Disease Prevention and Control (ECDC).
The homepage of the ECDC (www.ecdc.europa.eu) carries a description of the opening ceremony of the EOC. An easily accessed video news report is included as part of an audiovisual package. The importance of the EOC is stated succinctly on the ECDC homepage: “The EOC provides ECDC with the tools it needs to link to its key partner and to monitor developments as they occur 24 hours a day, 7 days a week.”
Participants in the opening ceremony of the EOC included representatives of the European Parliament, European Commission, and individual European Union (EU) Member States.
The EOC was recognized as serving to facilitate the ECDC’s ability to “work closely with health experts in the Member States, the European Commission and WHO”.
This ECDC EOC in Sweden will quite likely contribute to emergency preparedness worldwide and, as such, should be highly appreciated.
29 March 2008
Daniel R. Lucey, MD, MPH
CDC Conference Report on Anthrax Advises “Early and Aggressive Pleural Fluid Drainage”.
In the most recently published (April 2008) issue of the CDC’s Emerging Infectious Diseases (EID) Journal contains a paper by four CDC authors, lead by Stern EJ, titled: “Conference Report on Public Health and Clinical Guidelines for Anthrax”. The meeting took place 24 months ago in Atlanta, on March 13-14, 2006. The goal of the conference “was to convene subject matter experts for a review of research developments and clinical experience with anthrax prophylaxis and treatment and to make consensus recommendations for updating guidelines for PEP, treatment, and clinical evaluation of patients with anthrax”. The full paper can be found online at:
(www.cdc.gov/eid/content/14/4/e1.htm) This author participated in this conference as the representative for the Infectious Disease Society of America (IDSA)
This specific newsletter will emphasize only one of the key findings in this conference report, namely the recommendation for:
“Early and aggressive pleural fluid drainage is recommended for all IA (Inhalational Anthrax) case-patients and is consistent with the standard of care for empyema or complicated pneumonia. This recommendation is based on the experience that chest tubes or early serial drainage of pleural effusions seemed to be beneficial in the successful clinical therapy of the surviving IA patients in 2001 and in the recent 2006 IA case…Analysis of serial pleural fluid samples from the 2006 IA case showed high pleural fluid lethal toxin levels. The positive outcome of this case likely resulted from a combination of the mechanical effects on respiration from fluid drainage and the reduction in lethal toxin levels by removing pleural effusions”.
This a long-awaited and welcome recommendation that will very likely contribute to improved outcomes for future patients with inhalational anthrax.
This author has advocated for such pleural drainage on multiple occasions since 2004, e.g., in the anthrax chapter(s) of “Principles and Practices of Infectious Diseases” edited by Mandell, Bennett, and Dolin; in a Newsletter on this www.BePast.org website 24 May 2005 titled “Drainage of pleural fluid in patients with inhalational anthrax: a critical need to be anticipated as part of combination therapy”, in a videotaped presentation at the NIH (at the invitation of Dr. Mike Bray), in a presentation to medical staff at the Baltimore Clinician Biosecurity Network, and in the chapter on anthrax in the 2007 Cecil’s Textbook of Medicine.
The May 24, 2005 newsletter on www.BePast.org stated that pleural fluid drainage “could be therapeutic for at least two reasons:
(1) Removal of toxin-producing anthrax bacteria around the lung. When the organism was found in the pleural fluid by staining or culture, then the criteria defining an “empyema” is met and drainage of the infected pleural fluid (empyema) is the standard of care for any type of bacterial infection.
(2) The blood pleural effusions due to anthrax can be large, as well as recurrent, and could contribute to impaired lung function at a time when the anthrax infection is becoming a systemic infection…”
Hopefully, this recommendation for “early and aggressive” pleural fluid drainage will be formally incorporated when the actual “updated CDC guidelines for treatment and prophylaxis of anthrax…” are eventually “published in detail in other CDC publications…”
This critical point distinguishing the now published 2006 “conference report” from the anticipated future official CDC updated guidelines is stated at the end of the initial paragraph of this April 2008 paper by Stern and colleagues from the CDC.
31 March 2008
Daniel R. Lucey MD, MPH
Hong Kong Reopens Schools and Issues Guidelines on Face Masks and Checklists During Ongoing Flu Season
Today the Hong Kong Government stated that all schools could reopen. At the same time, they also provided detailed influenza precautions given that the current human influenza season is still ongoing.
The Health Department Centre for Health Protection (CHP) recently posted a 13-page document titled “Prevention of Influenza: Action Checklist for School Resumption”. This document can be found at: www.chp.gov.hk/index.asp?lang=en. It includes detailed advice for before school resumes organized under the headings of:
A. Ensure a clean and hygienic school environment
B. Communicate well with staff/students
C. Communicate well with parents
After school resumption detailed advice is provided under the following headings:
A. Check body temperature
B. Maintain Environmental Hygiene
C. Maintain personal hygiene and healthy lifestyle
D. Observe health condition of students and staff recovering from influenza
E. Keep sick leave records of staff and students
F. Taking care of sick students in school
A sample letter to parents is provided. Advice includes: Check body temperature and do not send children to school if they have a fever (> 37.5 C if ages 0-6 years, and 37.2 C in older children if an oral thermometer is used). Also, keep children who are ill out of school until fever has subsided and symptoms have improved for at least 2 days.
Additional guidance, with illustrations, is provided for how to perform hand-hygiene and how to wear a surgical mask properly.
The Department of Health on March 28th posted online
www.dh.gov.hk/english/press/2008/080328-2.html the following advice regarding the wearing of masks at school:
“If students develop flu-like symptoms in school, the school should provide them with surgical masks and keep them in an isolation room temporarily. The parents should be informed at once to pick the students up to seek medical care.
Staff taking care of the sick students should adopt protective measures, which include performing hand hygiene before and after contact with the students and wearing surgical masks. Details can be found in the Annex V: Use Mask Properly under the Prevention of Influenza: Action Checklist for School Resumption (March 2008) which was distributed to school management…
In case of suspected influenza outbreak in school, the school management should report to the CHP so that epidemiological investigation and necessary preventive measures can be taken. CHP will also advise the school if wearing surgical masks is necessary.”
The Hong Kong response to the seasonal human influenza outbreaks, their impact on school-age children and their parents, the decision to close schools March 13 and to reopen them March 31, is an excellent model of transparent risk communication from which lessons can be learned by the USA and other nations.
8 April 2008
Daniel R. Lucey, MD, MPH
Zanamivir (Relenza) influenza drug adds to its “Warnings and Precautions” based on reports of neuro-behavioral symptoms.
The US Food and Drug Administration (FDA) posted the following information on their website on last week regarding the influenza neuraminidase inhibitor zanamivir (“Relenza”).
Relenza (zanamivir)
Audience: Pediatric and infectious disease healthcare professionals
[Posted 04/01/2008] GlaxoSmithKline informed healthcare professionals of changes to the WARNINGS AND PRECAUTIONS sections of prescribing information for Relenza regarding information from postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who are receiving neuraminidase inhibitors, including Relenza. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Relenza to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms which can include seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease.
Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient.
[March, 2008 – Letter – GlaxoSmithKline]
A similar letter to health care professional concerning potential neuro-behavioral reactions to the other FDA-licensed neuraminidase inhibitor oseltamivir (“Tamiflu”) was sent by its manufacturer Roche Laboratories, Inc. in February 2008 (see the March 10, 2008 “Washington Newsletter” on www.BePast.org).
This information regarding zanamivir (Relenza) and oseltamivir (Tamiflu) should be made available to patients, including in formats anticipated for use in pandemic influenza preparedness.
Further research, from multiple nations, is needed to help determine to what degree, if any, there is a causal relationship between these neuraminidase inhibitors and these neuro-behavioral symptoms.
26 April 2008
Daniel R. Lucey, MD, MPH
The Jakarta Post reports on 3-day live simulation exercise drill of a pandemic influenza outbreak
The Saturday, 26 April issue of The Jakarta Post newspaper reports online that the April 25-27 live field simulation of an outbreak of pandemic influenza has begun in Jembrana regency in Bali, Indonesia.
Friday, April 25, was the first day of the simulation exercise. The Jakarta Post article (written by Emmy Fitri) reported that “The pandemic simulation began with a villager visiting a community health center complaining of a prolonged cold and respiratory problems. Several residents were reported to have similar symptoms. An investigation team from a local health agency was deployed to detect the possible spread of the virus by checking residents’ temperatures”.
“The village was then sealed off to prevent the virus from spreading. Police and military officers were deployed to bar people from entering or leaving the village. In the meantime, the local administration set up a makeshift hospital on a soccer field to treat patients with anti-viral prophylaxis or oseltamivir, effective in tempering the early onset of avian influenza.”
This 3-day simulation was aptly described by the Indonesian Health Ministry’s director general for communicable disease control, I Nyoman Kandun, by an Indonesia saying “sedia payung sebelum hujan”. This saying was translated as “putting up our umbrellas before it rains”.
The cost of the 3-day simulation exercise ($500,000 USD) was funded by the US Centers for Disease Control and Prevention.
The Jakarta Post reported that today, Saturday April 26, the second day of the exercise, “people will be referred to Tabanan Hospital in Tabanan and later Sanglah Hospital in Denpasar for further treatment.
On Sunday, April 27th, the third and final day of the simulation, the Post reports that “staff at the airport will simulate thermal scans on all people entering and leaving the airport and will spray their vehicles with disinfectant.
The evaluation and assessment of this 3-day live field simulation will prove valuable for improving international preparedness against the beginning stages of the next human influenza pandemic, and indeed for other infectious disease outbreaks as well.
28 April 2008
Daniel R. Lucey, MD, MPH
Indonesia completes 1,000-person, 3-day pandemic flu (“Flu Yang Mematikan”) simulation exercise with involvement of Bali airport
The Jakarta Post continued to report on Sunday and Monday, April 27-28 the unfolding of the unprecedented 3-day pandemic influenza preparedness exercise in Denpasar, Bali, Indonesia. Emmy Fitri continued the series of articles over the past several days in The Jakarta Post on the approximately 1,000-person simulation that ended on Sunday, April 28th at the Ngurah Rai International Airport.
On Saturday, April 26th, the second day of the large-scale exercise, villagers living at the epicenter of the outbreak learned that “the avian influenza has become Flu Yang Mematikan (deadly influenza)” according to Fitri’s article April 27th in the Post.
The World Health Organization (WHO) had a representative, Subhash Salunke, in Indonesia for this unique simulation drill. Subhash commented on the importance of this simulation, being quoted in the Post as saying “It’s a learning process for all and this simulation will contribute a lot to the global community”.
Sunday, April 27th, was the third and final day of the simulation exercise and the Ngurah Rai International Airport in Dengpasar, Bali was involved. Emmy Fitri’s article in today’s issue of The Jakarta Post online (www.TheJakartaPost.com) describes how security was heightened, and vehicles were stopped for identification of occupants by security officials wearing surgical masks.
Persons who had traveled from the village where the new pandemic flu strain was detected were directed to report to a special tent for a health check. Persons with a fever or who had an influenza-like-illness (ILI) were sent to a field hospital.
A photo in today’s (April 28) issue of The Jakarta Post showed a participant in the simulation exercise inside a “makeshift emergency room” at the airport, surrounded by persons acting as health care providers and dressed in gowns, gloves, goggles and masks.
The airports’s health care unit head, Nur Hasan, noted that the “airline associations had been invited to take part in the simulation”.
Lessons learned from this groundbreaking multidisciplinary simulation will be helpful in preparing for the subsequent exercises planned in Indonesia as well as a model for other nations.
29 April 2008
Daniel R. Lucey, MD, MPH
“The Intolerable Global Burden of Malaria”:
Slides by Dr. Joel Breman on World Malaria Day
On the first World Malaria Day April 25th, 2008 Dr. Joel Breman of the NIH Fogarty International Center in Bethesda, Maryland delivered a keynote address at the Georgetown University Malaria Symposium with over 40 powerpoint slides addressing the spectrum of malaria.
Dr. Breman has kindly made available these slides for educational purposes on this website (www.BePast.org) under the section at the top of the homepage listed as “Featured Links”.
Excellent color slides are included that illustrate the microscopic appearance of the malaria parasite, maps showing where malaria is endemic today, the latest prevention and treatment interventions against the anopheline mosquitoes and the Plasmodium parasites, and data on the recent decrease in malaria deaths in Zanzibar and Eritrea.
Emphasis is given to malarial deaths due to Plasmodium falciparum, particularly in children under the age of five years and in women who are pregnant. The co-existence of the “overlapping burden of Neglected Diseases and malaria” is also illustrated.
Dr. Breman is one of the Guest Editors of the 42-paper special issue of the December 2007 American Journal of Tropical Medicine and Hygiene titled: “Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives. This state-of-the art update builds on similar special issues of this journal co-edited by Dr. Breman that were also dedicated to malaria in 2001 and 2004.
We are very appreciative of Dr. Breman’s willingness to allow his slides from World Malaria Day last Friday to be posted on this website. We hope his slides will serve to emphasize that every day is “World Malaria Day” in many places around the globe.
May 4, 2008
Daniel R.Lucey, MD, MPH
WHO reports outbreak of over 1800 cases of enterovirus 71 in China
On May 1st the World health Organization (WHO) posted on their website a summary of the outbreak of Enterovirus (EV) 71 in China. Of the 1884 patients diagnosed between the start of March and April 29th, 20 fatalities have occurred in Fuyang city in Anhui Province, China.
The clinical disease caused by EV-71 is termed “hand, foot, and mouth disease (HFMD)”. It is NOT related to “foot and mouth disease (FMD)” of animals. The human disease HFMD typically involves a rash on the palms and soles with vesicles and inflammation in the mouth.
The 20 deaths have been linked to “serious complications such as neurogenic pulmonary edema”. Fortunately, the case fatality7 rate (CFR) has dropped from 11% during March 10-31 to 0.2% between April 17-29.
Of note, initial testing for respiratory diseases did not show the cause of the illness. Further testing and “several expert consultations were conducted at the national level” and on April 23rd Enterovirus-71 was confirmed as the cause of the illness, and in some cases, death of affected infants and young children.
No specific antiviral medication, or vaccine, is available for enteroviruses, including EV-71. The WHO “Fact sheet” on enteroviruses (non-polio type) states that “Males more often develop clinically recognizable diseases than females. Transmission is usually by the faeco-oral or by the respiratory route when there is an associated respiratory illness. The virus may be excreted in the stool for many weeks…and may possibly be transmitted in the community by contact with contaminated food or water”.
Appropriate target prevention and control measures have been instituted in Fuyang city and Anhui Province, according to the May 1st WHO posting on their disease outbreak website.
An appropriate travel history should be obtained for any patients or their contacts presenting to clinics or hospitals in the USA, or anywhere else, for patients presenting with clinical evidence of HFMD, especially with respiratory compromise.
May 7, 2008
Daniel R. Lucey, MD, MPH
China: Enterovirus 71 cases increase to 15,799 as Ministry of Health mandates reporting of all cases
The number of persons with Enterovirus 71 (EV-71) infection, one cause of Hand, Foot, and Mouth disease (“HFMD”), have increased sharply in Anhui province, and appeared in other provinces of China. The government has taken several steps to control the outbreak including mandatory central reporting, and establishing a special virus laboratory in Fuyang city, Anhui province.
In a report from Beijing (Xinhua news agency) posted online at www.chinaview.cn today (May 7), it was stated that “China is confident that it can control the spread of the disease with effective prevention methods”, according to the health ministry spokesman Mao Qun’an at a joint press conference today between the Ministry of Health and the World Health Organization (WHO).
This same spokesman was cited in the China View online article as reporting that “two kindergartens in Beijing have reported some cases recently, and local health officials have closed two schools already”. Notably, however, Mao emphasized that this disease is seen each year in Beijing and there has not been “a remarkable rise” in cases or fatalities so far this year in Beijing. He stated that the HFMD outbreak will not affect the Beijing Olympics.
CNN reported online (cnn.com) today from Beijing that “authorities reported 15,799 cases of the disease on Tuesday” (May 6). Importantly, some of this striking rise in the number of cases is due to the recently mandated reporting of all HFMD cases to central health authorities. CNN also reported that in the eastern province of Anhui, “the provincial government has quarantined people exposed to the virus and limited movement into and out of Fuyang, where the outbreak was first reported in mid-March”.
A total of 28 deaths so far have been attributed to EV-71. Most, but not all, have been in Anhui province. The latest deaths have been reported from Hunan province in central China and in Guangxi Autonomous Region in southwestern China.
Vigilance for EV-71 has been reported to have increased in Hong Kong, Taiwan, and India. A larger number of EV-71 infections are possible as the warmer summer months approach in China and elsewhere. This is an evolving situation.
May 9, 2008
Daniel R. Lucey, MD, MPH
Sanofi Pasteur announces that H5N1 influenza Clade 2.2 bulk antigen enters US pandemic flu stockpile
In a press release April 28, 2008 Sanofi Pasteur, “the vaccines division of sanofi-aventis Group, announced that the U.S. Department of Health and Human Services (HHS) has accepted bulk vaccine antigen…to protect against a new strain of avian influenza”.
“The antigen lot accepted today will protect against a clade 2.2 strain of H5N1 virus (A/Barheaded goose/Qinghai Lake/01/2005) that is …the first to be identified in an outbreak of migratory birds…This strain of avian influenza H5N1 is the strain that currently predominates in birds of Europe, the Middle East, and Africa.”
Of note, this is not a vaccine; instead, it is bulk antigen from which a vaccine can be made. Thus, the actual number of doses of vaccine that can be made from this bulk concentrate form depends on the amount of antigen required for each vaccine dose.
For example, sanofi pasteur’s FDA-licensed (2007) Clade 1 H5N1 vaccine requires 90 mcg per dose of vaccine. In contrast, the usual seasonal human influenza vaccine requires only 15 mcg per dose of vaccine.
Accordingly, (only) 6.4 million doses of vaccine can be made from this Clade 2.2 H5N1 bulk antigen if 90 mcg are required per dose. In contrast, 38.4 million doses of vaccine can be made from this Clade 2.2 bulk antigen if only 15 mcg are required per dose.
Ongoing research on H5N1 vaccines that are “antigen sparing” will hopefully make possible the use of 15 mcg per dose, or less, and thus increase the number of vaccine doses. This need to maximize H5N1 vaccine doses is particularly important if two doses are necessary to induce protective immunity, as is generally accepted at this time.
14 May 2008
Daniel R. Lucey, MD, MPH
OSHA posts for comment preliminary draft guidance on use of masks and respirators for pandemic flu planning
On May 13, 2008 the Occupational and Health Safety Administration (OSHA) of the U.S. Department of Labor posted online a preliminary, non-binding, draft guidancedocument for public comment on the use of masks and respirators for pandemic influenza planning. This is NOT a final or official document, but is an informative preliminary contribution to this very important issue of respiratory personal protective equipment (PPE). The entire document can be found at: www.osha.gov/dsg/guidance/stockpiling-facemasks-respirators.html
This document is well-organized. It contains three (3) useful tables:
Table 1: “Advantages and Disadvantages of Respirators and
Facemasks” including unit cost ($) of each type.
Table: 2: “Stockpiling Estimates for Respirators and Facemasks”
Table 3: “Stockpiling Estimates for Facemasks for Use by Ill Patients”
There is one additional conceptually helpful table (unnumbered): “Example of Stockpiling Needs and Comparative Costs for a Single High Exposure Risk Employee”.
In the beginning of the document four (4) specific degrees of risk of occupational exposure to pandemic influenza virus are defined. These four levels of risk then help determine the suggested type of respirator or facemask.
The four levels of occupational exposure risk are defined as:
- ” Very high exposure risk occupations are those with high potential exposure to high concentrations of known or suspected sources of pandemic influenza during specific medical or laboratory procedures”.
- “High exposure risk occupations are those with high potential for exposure to known or suspected sources of pandemic influenza virus”.
- “Medium exposure risk occupations include jobs that require frequent, close contact (within 6 feet) exposures to known or suspected sources of pandemic influenza virus such as coworkers, the general public, outpatients, school children or other such individuals or groups.”
- Lower exposure risk (caution) occupations are those that do not require contact with people known to be infected with the pandemic virus, nor frequent close contact (within 6 feet) with the public. Even at lower risk levels, however, employers should be cautious and develop preparedness plans to minimize employee infections.
In the second paragraph of this informational, non-regulatory draft document these four exposure risks can, in general, be advised to wear the following respiratory protection (PPE) during the first AND second (successive) “waves” of pandemic influenza:
“As is explained in more detail in this guidance, employers should consider stockpiling facemasks and respirators. More specifically, it is recommended that employees at very-high risk and high risk of exposure to pandemic influenza use respirators, while employees at medium risk of exposure use facemasks. Neither facemasks nor respirators are recommended for employees at lower risk of exposure to pandemic influenza.”
This draft document goes on to give specific examples of persons engaged in specific work within each of the four exposure risk categories (very high, high, medium, and lower). For example, the “High Exposure Risk” category, requiring respirators (e.g., N-95 or above), includes:
—“Health care delivery and support staff exposed to known or suspected pandemic patients (for example, doctors, nurses, and other hospital staff that must enter patient’ rooms).”
—Staff transporting known or suspected pandemic patients (for example, emergency medical technicians).”
—“Staff performing autopsies on known or suspected pandemic patients”.
Examples of “Medium Exposure Risk”, for which facemasks rather than respirators would be generally recommended, include:
—“Employees with high-frequency contact with the general population (such as schools, high population density work environments, and some high volume retail)”.
Examples of “Lower Exposure Risk (Caution), for whom no respirator or facemask is generally recommended, include:
—Employees who have minimal occupational contact with the general public and other employees (for example, office employees).”
In my view, based on personal observations and experience with SARS in Toronto and Asia in 2003, the “Medium Exposure Risk” group will be the most controversial once the pandemic actually begins (as opposed to pre-pandemic guidance such as this document), if a facemask rather than a respirator is recommended.
May 16, 2008
Daniel R. Lucey, MD, MPH
Stockpiling estimates for facemasks for ill patients during waves of pandemic flu
The May 13th proposed draft guidance from the Occupational Safety and Health Administration (OSHA) (www.osha.gov) of the U.S. Department of Labor contains an informative and heuristic section on estimating facemask usage for patients in workplaces classified as “High Exposure Risk” for pandemic influenza. “
The rationale is to decrease the relative amount of virus being expelled into the air by persons with (pandemic) influenza. “During periods of pandemic influenza activity, facemasks should be offered as part of a respiratory hygiene/cough etiquette strategy to patients who are coughing and/or sneezing, have a fever or have other symptoms of influenza-like illness when they present for health-care services”.
Specific numbers of facemasks needed are presented in Table 3 of this document. For example:
Occupational setting Facemasks needed
Hospital (inpatient)* 2 per patient per day
Essential visitors** 3 per visitor per day
Emergency Rooms 1 per ill person
Outpatient office/clinic 2 per patient visit
Long term care 1 per patient per day
Home healthcare 1 per patient visit
Emergency medical services 1 per ill person
· For inpatients the primary use for the facemask is postulated to be when transporting them to and from their room. This OSHA draft document states that once the inpatient is appropriately isolated, either in a private room or by placement in a room with other patients with pandemic influenza (“cohorting”), then they do not need to wear a facemask.
** “Essential” visitors might “include parents of pediatric patients who need to stay with the patient in their room but will not apply to visitors of all patients. Hospitals will likely encourage social distancing during an influenza pandemic and may restrict visitors…”, according to this draft document.
Importantly for planning purposes, this document also makes estimates of facemasks needed for ill persons in the occupational setting of “first responders”.
For example, for “Corrections” facilities 2 facemasks per ill inmate per day are estimated, while ill persons in an occupational setting of “Law enforcement” or “Fire department” 1 facemask per ill person is estimated.
These estimates for facemask use (NOT N-95 respirators) by ill persons significantly raises the size of the facemask stockpile, but should be integrated into pandemic planning by responsible officials and organizations.
While working at the Washington, DC Department of Health in the spring of 2004, we ordered (and received) 2 million facemasks as a stockpile for the city in the event of a large-scale respiratory illness. While this was recognized as simply a start in the needed direction, even this number of masks will not be sufficient for DC during the first wave of pandemic influenza. More will be needed.
May 23, 2008
Daniel R. Lucey, MD, MPH
WHO Director-General Dr. Margaret Chan Opens 61st World Health Assembly citing 3 Global Crises
The 61st World Health Assembly is meeting this week from May 19-24 in Geneva, Switzerland. The Director-General of the World Health Organization (WHO), Dr. Margaret Chan, made an address to the Assembly on May 19th in which she identified three global crises and provided updates on multiple specific diseases.
The three global crises, also cited as “international security threats”, that are “looming on the horizon” include:
1. Food security
2. Climate Change
3. Pandemic Influenza
“Food security is in a crisis…the crisis arises from a so-called “perfect storm” of converging factors.” It is estimated that 50-70% of disposable income is spent on food in poor households. This means fewer funds for health care, especially for families who are uninsured.
Climate change will be linked to “ a growing number of environmental refugees. If land becomes parched or salinated, if coastal and low-lying areas are permanently under water, these people cannot simply go home. Environmental refugees thus become a new wave of settlers, possibly adding to international tensions.”
“Pandemic influenza is the third global crisis looming on the horizon. The threat has by no means receded, and we would be very unwise to let down our guard. As with climate change, all countries will be affected, though in a far more rapid and sweeping way.”
Dr. Chan went on to give brief updates on multiple specific diseases, such as HIV/AIDS, Malaria, TB, polio, and non-communicable diseases such as diabetes, asthma, cancer, and heart disease. She also addressed maternal and newborn health, the Integrated Management of Childhood Illness, the Millennium Development Goals, and the “global tobacco epidemic”, among other issues.
In contrast to a “perfect storm”, Dr. Chan highlighted what she termed the opposite phenomenon, a “perfect rainbow”. The example she cited was the “harmonious way” in which multiple factors were coming together in a collaborative effort to control neglected tropical diseases.
For example “safe and powerful drugs are being donated or made available at very low cost. Integrated approaches have been devised for tackling several diseases at once.” Furthermore, “A strategy of mass preventive chemotherapy, aimed at reaching all at risk, rivals the protective power of immunization…With a comparatively modest, time-limited financial push; many of these diseases can be controlled by 2015. Some can even be eliminated by that date.”
The full text of Dr. Chan’s address can be found on the WHO website at: www.who.int/dg/speeches/2008/20080519/en/index.html
30 May 2008
Daniel R. Lucey, MD, MPH
Bangladesh reports first human infection with H5N1 avian influenza
The World Health Organization (WHO) reported on its website May 28th that Bangladesh has confirmed its first patient with H5N1 avian influenza. Like a small numbers of reported patients with H5N1 infection from other nations, this patient was only identified retrospectively, having become ill on January 27th.
These occasionally identified patients should remind us again that there are certainly more (unrecognized) patients than the official global total provided by the WHO of laboratory-confirmed H5N1 infections.
This patient was a 16 month-old boy who had been exposed to slaughtered and live chickens in his home in Komalapur, Dhaka. Fortunately, he has fully recovered. All of his family members have reportedly stayed healthy. Lab tests for H5N1 avian flu infection on them are in process. Presumably, these would be antibody assays given that approximately four months have elapsed since the child’s illness.
In a report yesterday, May 29th on the website of the US Geological Survey (USGS) National Wildlife Center it was noted that “H5N1 was first reported in Bangladesh in March 2006 and has spread to 47 of the country’s 64 districts.” WHO spokesman Gregory Hartl was quoted as saying:” When a disease is so widespread in poultry, it is really a matter of time before you get a human case. It shows the need to control the disease in animals if you are going to reduce the chances of transmission to humans”.
June 11, 2008
Daniel R. Lucey, MD, MPH
Indonesia Continues Preparedness for Avian Influenza and Communicable Diseases
Bali, Indonesia is the location of a two-day conference that began Wednesday, June 11th on how to prevent the spread of communicable diseases via air travel. Sixty delegates are representing ten Asia Pacific nations and other geographically distant countries such as Morocco. In addition to Indonesia, other Asian nations participating include Malaysia, Singapore, the Philippines, China, Japan, and Bangladesh. Avian Influenza is one of the specific diseases that will be a focus of the conference, according to an article in The Jakarta Post today. The conference was opened by Tri Sunako, the Air Transport Director of the Indonesian Transportation Ministry.
This conference follows on the April 25-27 outdoor exercise in Bali simulating the start of the next human pandemic of influenza. This remarkable multidisciplinary simulation was coordinated with both national and international partners, including the World Health Organization (WHO). At the end of this three-day event, several additional similar, albeit smaller, simulation exercises were announced for the future in other parts of Indonesia.
Similarly, on Thursday, May 15 the National Committee for Avian Influenza Control (Komnas FBPI) and the Tangerang administration initiated a campaign to prevent the spread of avian flu. This broad-spectrum public awareness campaign about avian flu incorporates use of posters and banners placed in poultry markets, public transportation sites, mosques, churches, and schools, according to an article in The Jakarta Post on May 16, 2008. The newspaper also reported that the Tangerang area has had 14 cases of H5N1 avian influenza and is thus one of the hardest hit areas in Indonesia.
June 22, 2008
Daniel R. Lucey, MD, MPH
Indonesia Reports Two Additional H5N1 Human Infections
The World Health Organization (WHO) posted on their avian influenza website June 19 that the Indonesian Ministry of Health (MOH) reported two additional patients with H5N1 influenza A infection. This is welcome news given recent concern that such H5N1 human infections might not be reported publicly as frequently as has been done in the past by Indonesia.
Both human cases were fatal. They were from different areas in or near Jakarta, and were not epidemiologically linked. One patient was a 16 year-old female from south Jakarta in Jakarta province who had symptom onset May 7, was hospitalized five days later (May 12) and died on May 14.
The second patient was a 34 year old female from Tangerang district, Banten Province (west of Jakarta). She developed symptoms on May 26, was hospitalized seven days later (June 2) and died the next day on June 3. Indonesia has now reported 135 laboratory-confirmed cases of H5N1 infection. Of these, 110 (81%) have been fatal.
Both patients illustrate again the very rapid progression of H5N1 influenza disease with an interval from symptom onset until death of only 7-8 days in these two patients.
Efforts to decrease the case fatality rate (> 80%) are ongoing not only in Indonesia, but in all nations with human cases, given the rapid progression to death in many patients. Even in Egypt, which is often cited admirably for having one of the lower case fatality rates (CFR) in this disease, 22 deaths out of 50 lab-confirmed cases have occurred, resulting in what is still an extremely high CFR of 44%.
June 24, 2008
Daniel R. Lucey, MD, MPH
WHO announces Infection Control Network Meeting in Geneva June 26-27
The Infection Control Network for Readiness and Response to Communicable Diseases Emergencies will meet at the end of this week in Geneva, Switzerland according to an announcement on the website of the World Health Organization (www.who.int). The goal of the network is to establish the essential infection control and prevention measures for health care during both communicable diseases crises and during routine health care.
Scheduled participants in this June 26-27 meeting WHO experts from the Geneva headquarters as well as regional and country offices, and other experts from outside of WHO. Some of the documents currently posted under “WHO tools for infection control in health care include:
—Interim Infection Control Recommendations for Care of Patients with Suspected or confirmed Filovirus (Ebola, Marburg) Hemorrhagic Fever (March 2008).
—Infection prevention and control of epidemic-and pandemic-prone acute respiratory disease in health care WHO interim Guidelines (2007).
—WHO guidelines on hand hygiene in health care: a summary (2006).
Citing the example of SARS in 2003, the following is stated under the background section for infection prevention and control in health care for preparedness and response to outbreaks: “If outbreaks hit health care settings without a culture of safe practices, the risk of disruption to health care systems can be high. Among many important lessons derived from the SARS pandemic, being prepared and having a culture of safe health care practices that can prevent and control pathogen dissemination is key to coping with outbreak situations.
Results of the second meeting of the Infection Control Network in Geneva this week are awaited, particularly with regard to communicable disease crises.
26 June 2008
Daniel R. Lucey, MD, MPH
US Funding Development of New Diagnostic Tests for Influenza A H5N1 Virus in Humans with Results within 3 Hours
The US Centers for Disease Control and Prevention (CDC), in conjunction with the Office of Biomedical Advanced Research and Development Authority (BARDA) have funded two US companies to develop “low-cost influenza tests that can differentiate seasonal human influenza viruses from avian influenza within three hours”. The press release can be found on the HHS website at www.hhs.gov
HHS stated that currently testing for H5N1 infection in humans “can take up to 24 hours”. The proposed new, faster tests (within 3 hours) for H5N1 virus infection “could be performed in a hospital or a commercial laboratory and would expedite the diagnosis of large numbers of patients”.
The two companies receiving the awards are Nanogen, Inc, San Diego, California and Meso Scale Diagnostics, LLC, Gaithersburg, Maryland.
The availability of such significantly faster diagnostic tests for human H5N1 virus infection could be of immediate clinical use to nations already experiencing human infections with H5N1 virus. Hopefully, these new tests would be sufficiently sensitive to detects the different clades and subclades of H5N1 including clade 2.1 in Indonesia, clade 2.2 in Africa, and clade 2.3 in China and some other parts of Asia.
Such faster diagnostic tests could be performed at “points-of-care” where persons with suspected H5N1 virus infection are seen and clinically evaluated. A positive test result could significantly improve clinical care and infection control measures. In addition, if one outcome of such new tests is that an effective antiviral drug (e.g., oseltamivir (Tamiflu)) is given earlier to patients who have H5N1 virus infection, then the extremely high case fatality rate recorded in all nations to date should be decreased.
27 June 2008
Daniel R. Lucey, MD, MPH
WHO Holds Public Health Security Exercise
One year after the International Health Regulations (IHR) entered into force on 15 June 2007 the World Health Organization (WHO) announced a 2-day simulated public health security exercise (“PHSX”) “to test specific aspects of WHO’s response to a potential PHEIC (public health emergency of international concern) and the procedures, protocols and communication methods that would be used when notified of such a threat”.
Prior to the June 11-12, 2008 exercise, the WHO posted a four-page “Frequently Asked Questions (FAQs)” about this event on their website homepage (www.who.int).
Although the results of this exercise have not yet been reported, the WHO described the design of the event beforehand as follows:
“Through a series of simulated events, a pathogen will emerge whose symptoms mimic many possible aetiologies, making it hard, at first, to understand the nature and gravity of the disease outbreak. The pathogen is first discovered in Country A, which responds rapidly and reports the outbreak to WHO, as per its IHR obligations. With this notification, WHO forms an event management group, spanning the Country and Regional Offices and Headquarters, to assess the pathogen and the public health threat it might pose. Subsequently, cases are discovered in Country B and C”.
The evaluation phase of the exercise will be performed in real time by “evaluators drawn from Asia, North America, and Europe”. The subsequent lessons learned from this two-day simulation exercise “will be shared with WHO offices across the world and with Ministries of Health and the National IHR focal Points, with whom WHO will be working closely during any public health emergency with the potential to become a PHEIC” (public health emergency of international concern).
The results and lessons learned from this and future such WHO simulation exercises will likely be of major interest to public health emergency planners everywhere.
June 28, 2008
Daniel R. Lucey, MD, MPH
Roche Announces New Plan for Businesses to Stockpile Oseltamivir (Tamiflu) for Pandemic Flu Preparedness
In a press release June 26, the manufacturer (Roche) of the anti-influenza oral drug “Oseltamivir (Tamiflu)” announced a new option for U.S. businesses to stockpile this drug as part of their pandemic influenza preparedness plan.
According to Roche, under this plan “businesses pay a nominal fee to “reserve” their own stockpile of Tamiflu, which Roche will store and rotate to keep in “date”. The contract must be renewed each year.
If a business chooses to take delivery of their stockpile, then the press release states “they can purchase their dedicated product from Roche at the prevailing wholesale price. Roche will guarantee delivery within 48 hours in most circumstances”.
The manufacturer also notes in their Jun 26 press release: “The most frequently reported adverse events in clinical studies were nausea, vomiting, and diarrhea.”
In addition, Roche stated: “In post-marketing experience, rare cases of anaphylaxis and serious skin reactions have been reported. There have been post-marketing reports (mostly from Japan) of self-injury and delirium with the use of Tamiflu in patients with influenza. The reports were primarily among children. The relative contribution of the drug to these events is not known. Patients with influenza should be closely monitored for signs of abnormal behavior throughout the treatment period”.
Roche reports that they have received orders for oseltamivir (Tamiflu) to date from 300 companies out of the 800 U.S. based businesses that have made inquiries. The result of this new plan will likely be to increase the number of companies with such stockpiles, despite the waning concern in some sectors regarding the urgency of preparing for the next human influenza pandemic.
3 July 2008
Daniel R. Lucey, MD, MPH
A large, ongoing measles epidemic in Switzerland associated with limited enthusiasm for MMR vaccination
Philip E. Tarr, MD, Infectious Diseases Service, Kantonsspital Bruderholz, University of Basel, Switzerland; philip.tarr@unibas.ch
Since November 2006 there has been a large epidemic of measles in Switzerland, with >3000 reported cases as of June 18th 2008. An outbreak of limited size and duration in San Diego in January 2008 was linked to the “importation” of measles into the US by a 7-year old child who returned to the US from a family vacation in Switzerland. The Swiss federal office of public health now asks international visitors to consider vaccination before travelling to Switzerland.
In past years, office- and hospital based physicians in Switzerland hardly saw any cases of measles – similar to the experience of physicians in the US. Now Swiss physicians need to know and be able to recognize measles again. Clinical experience during the epidemic has been consistent with well recorded knowledge: The rash may appear as confluent as early as on day 2 or 3; careful oral examination almost always reveals Koplik spots on the buccal mucosa that are considered pathognomonic for measles. Complications have been relatively mild, including pneumonia in approx. 5% of cases, no deaths, and only a small number of possible cases of encephalitis. In 28% of over 16 year old persons, however, a visit to the emergency room and/or hospitalization was required. While the median age of persons with measles in Switzerland has been 10 years, complications were more common in adolescents and adults.
Measles immunization, most commonly utilizing the combination measles mumps rubella (MMR) vaccine, is universally recognized as safe, generally well tolerated and highly effective: The protective effect of a single dose is >90%, and 2 doses are 99% protective. Why then is the incidence of measles currently observed in Switzerland by far higher than in any other European country?
In contrast to the US that has a well-established system for the compulsory administration of vaccines to school children and college students, compulsory vaccination is considered to be ethically unacceptable in Switzerland (of note, the same conclusion was reached by authorities in the United Kingdom in 2004). Only a small proportion of the Swiss population describes itself as categorically opposed to vaccines. However, >10% of parents are “skeptical” towards MMR vaccination. Unlike the situation in the 1960s and 70s when non-vaccination was associated with inadequate access to health care, low levels of income and education, parents who do not vaccinate their children in Switzerland today tend to higher levels of education and income. Non-vaccination appears to be epidemiologically linked to the utilization of “alternative” medical services and the pursuit of a “healthy” lifestyle (of note, in this regard, Switzerland clearly has the highest consumption per capita of “organic” food products in Europe).
Immunization advice in Switzerland is typically given by general practitioners who need to consider public health policy (official vaccine recommendations), the parent’s individual expectations and desires, and societal values including personal autonomy. While immunization rates in Switzerland have increased in the past year – most likely in the context of a major public health effort in response to the epidemic – they are still too low to prevent measles epidemics. Therefore, novel prevention approaches are needed in order to increase the immunization rate to 95% in Switzerland, the level required for measles elimination.
14 July 2008
Daniel R. Lucey, MD, MPH
Does Francisella tularensis exist in nature in Acanthamoeba?
In 1989 Kersti Gustaffson from Umea, Sweden reported that Francisella tularensis was able to grow in the laboratory in a culture medium preconditioned with a protozoan parasite amoeba named Acanthamoeba palestinensis (Canadian J Microbiology 1989; 35:1100-1104).
In 2003 Hadi Abd and colleagues from Umea, Sweden and from the Karolinska Institute in Stockholm reported that Francisella tularensis
could grow in the laboratory inside Acanthamoeba castellanii protozoa themselves, rather than only in the presence of conditioned culture media. The authors concluded that “ubiquitous protozoa might be an important environment reservoir for F. tularensis” (Appl Environ Microbiol 2003 (Jan) 69: 600-606.
In 2004 Crystal Lauriano and colleagues in the USA and Canada published their finding that an F. tularensis gene (mglA) regulated transcription of virulence factors critical for survival within both amoeba and macrophages. They concluded that “mglA is a global regulator of factors necessary for virulence and presumably also for environmental persistence”. (PNAS 2004;101 (12):4246-4249).
Multiple other papers have been published from additional labs studying the in vitro co-culture of F. tularensis and Acanthamoeba organisms. So far, however, to my knowledge there are no publications in either the English or Swedish language literature supporting the hypothesis that F.tularensis and Acanthamoeba actually co-exist in nature.
18 July 2008
Daniel R. Lucey, MD, MPH
Hong Kong Notifies Physicians to Anticipate Summer Influenza Peak
Hong Kong has some of the world’s best Influenza virologists and most experienced public health officials. Over the years they have established a clear pattern of two annual peaks in seasonal influenza cases in humans. The largest peak, as in many places in the northern hemisphere, is in the winter, typically in the February-March time frame. A smaller, second peak in seasonal human influenza occurs in Hong Kong in the summer, specifically in the June-July time frame.
The Hong Kong (HK) Department of Health’s Centre for Health Protection (CHP) issued a “Dear Doctor” letter to physicians in HK this week on 15 July advising “Vigilance against seasonal influenza”. Signed by Dr. SK Chuang this letter is posted on the government website of the Department of Health at: www.dh.gov.hk/english/useful/useful_ld/useful_ld.html
The letter states that influenza infections increased between the week ending 14 June and the week ending 5 July, with influenza A (H3N2) cases outnumbering influenza A (H1N1) and influenza B cases. Dr. Chuang also notes that an increase in the hospital admission rates for the very young (4 years of age or younger) and the elderly (65 years of age and above) have begun to rise. Physicians are reminded by the Department of Health to report respiratory diseases in institutional facilities in order to activate outbreak control measures.
Such examples of the frequent “Dear Doctor” letters from the Hong Kong Department of Health, addressing a wide range of medically related issues and posted online chronologically, is an excellent model of proactive public health communications.
22 July 2008
Daniel R. Lucey, MD, MPH
Indonesian health care providers emphasize need for point-of-care tests for H5N1 avian influenza
An Indonesian team of 14 co-authors published an important paper last month (June) describing a series of 27 laboratory-confirmed patients with H5N1 avian influenza infection admitted to the Sulianti Saroso Infectious Diseases Hospital in Jakarta between September 2005 and December 2007. The first author is Sardikin Giriputro and the paper is published in the Annals of the Academy of Medicine Singapore 2008; 37: 454-457.
Of the 27 lab-confirmed fatalities, ranging in age from 1-40 years, 21 were fatal (78% CFR). The 27 cases were from a total of 296 suspect cases managed at this Infectious Disease hospital in Jakarta during this 27-month time frame (average 11 suspect cases and one lab-confirmed case per month). The non-specific nature of the initial symptoms, chest x-ray, and sometimes uncertain epidemiological link to H5N1 AI-infected animals or their environment can make rapid diagnosis and institution of anti-influenza therapy with oseltamivir problematic.
Importantly, the authors state:
“Early recognition is critical as it has been recognized from a global review of cases of H5N1 influenza that delays in treatment with antiviral agents result in much higher mortality. For a large and diverse country such as Indonesia, this is likely to remain a challenge for some time. The only conceivable solution is the development of cheap, effective, point-of-care tests for H5N1 influenza that are as easy to use as a pregnancy test for example. These could be used by a rural primary healthcare clinic or district hospital in any developing country. This is clearly a challenge for the global scientific community. Even if such tests were available, however, the next challenge would be ensuring that they are widely distributed and that the resources are available for primary and secondary healthcare providers to have immediate access either to antivirals or to rapid evacuation to tertiary facilities that can treat these patients to achieve good outcomes.”
This statement of need for a rapid diagnostic test for avian influenza is similar to that announced last month (June 12) on the website of the US Government’s Department of Health and Human Services (www.hhs.gov), and also later on the US Government’s single website for all pandemic influenza information (www.pandemicflu.gov):
“HHS Secretary Mike Leavitt today announced that the Centers for Disease Control and Prevention (CDC) has awarded $12.9 million for the development of low-cost influenza tests that can detect and differentiate seasonal human influenza viruses from avian influenza within three hours.
“The early detection of emerging pandemic influenza is critical to the nation’s pandemic response,” Secretary Leavitt said. “Early detection will aid in improving patient survival, overall health outcomes, and use of containment measures in the event of an influenza pandemic.”
Currently, the process for testing for avian influenza A (H5N1) can take up to 24 hours…”
Taking the Indonesian perspective and the US HHS Secretary’s perspective into a larger perspective embracing both developing and developed nations, one can hope that:
Given the emerging genetic and antigenic diversity of H5N1 avian influenza viruses into multiple different clades and subclades, the future first generation of affordable, rapid diagnostic tests for H5N1 avian influenza will work equally well for all H5N1 viruses, including the Clade 2, subclade 1 (Clade “2.1”) H5N1 avian influenza virus that is predominant today only in Indonesia.
28 July 2008
Daniel R. Lucey, MD, MPH
Disease due to F. tularensis “Fx1” Infection
The clinical history of a patient with a microbiologically atypical Francisella tularensis infection, termed “Fx1”, was presented in a microbiology journal by co-authors from Texas and Umea, Sweden over a decade ago. As part of a new series on this website of patients and clinical syndromes of past of particular interest, this patient’s clinical course is summarized below.
The patient was a 55 year-old man who lived in Galveston, Texas on a beachfront cottage. He had diabetes and had been on prednisone, 20mg each day for an unstated duration, “for inflammatory nodular skin lesions of unknown etiology”. The severity and treatment of his diabetes was also unstated. He was hospitalized in June 1991 with a three week history of weakness, shortness of breath on exertion, chest pain, and restfulness. He was found to have diffuse wheezing in both lungs and moderate enlargement of his liver and spleen. On his third day in the hospital he developed a high fever (39.8 C), headache, and an increased peripheral white blood cell count.
Work-up revealed two positive blood cultures obtained with his fever that grew a Francisella species termed “Fx1”. An MRI brain scan was interpreted as showing brain abscesses with a maximum size of 12mm. The initial spinal fluid exam culture was not commented on, but there were 25 white blood cells (92% of which were mononuclear cells), an elevated protein of 107 mg/dl and a glucose of 84mg/dl (without a peripheral blood glucose being reported and thus unable to be interpreted as within normal limits or not).
A chest X-ray after the fever appeared revealed “new pleura-based infiltrates in the right lower lung”. No sputum was produced. Extensive testing that included an echocardiogram, an EEG, and a 4-vessel cerebral angiogram was negative. The patient was treated with “expanded-spectrum cephalosporins”. Subsequently, both his fever and his right lower lung abnormality resolved. No information was provided on any further brain imaging or longer-term clinical follow-up. His presumptive diagnosis was bacteremia, pneumonia, and brain abscesses due to the “Fx1” bacteria.
Serologic testing for Francisella was negative when performed two weeks after the positive blood culture. The patient lived with a “tick-infested dog”, but no results of testing for Fx1 infection of the dog, the ticks, or any other potential environmental sources were presented.
The two positive blood cultures grew a small, gram-negative coccoid bacteria (“termed “Fx1”) in the aerobic bottle after three days using the BACTEC blood culture system. Importantly, the Vitek NHI panel suggested an (incorrect) identification of the Fx1 Francisella bacteria as Hemophilus Actinomycetemcomitans with a 99% confidence level (see page 1998 under the “Growth and biochemical results” section of this paper). . While this “Fx1” bacterium was susceptible in vitro to ceftriaxone, ciprofloxacin, imipenem and chloramphenicol, it was resistant to penicillin, ampicillin, amoxicillin-clavulanate, aztreonam, cephalothin, and trimethoprim-sulfamethoxazole.
This patient is the only one published, to this writer’s knowledge, with infection due to this Fx1 Francisella bacteria (in subsequent years further identified as Francisella tularensis novicida (or “novicida-like”).
The importance of mis-identification of this bacteria as Hemophilus Actinomycetemcomitans (with 99% confidence level by Vitek NHI panel), should be emphasized in the event of an environmental contamination with Francisella “Fx1”. In such a situation, explicit public health and medical recommendations must be made to perform surveillance and testing of any clinical specimens (e.g., blood, skin, sputum, pleural fluid, lung, spinal fluid, or brain) from ill patients who could have been exposed to this contaminated environment who have Hemophilus Actinomycetemcomitans bacteria identified in the clinical laboratory, given that the true identity of such bacteria could well be an atypical Francisella tularensis species such as Fx1.
31 July 2008
Daniel R. Lucey, MD, MPH
“Fx2” Francisella tularensis infection
Of historical interest, two patients with a microbiologically atypical Francisella tularensis infection, one designated “Fx1” and the other “Fx2”, were reported in 1996 (Clarridge JE et al. Characterization of two unusual clinically significant Francisella strains. J Clinical Microbiology 1996; 34: 1995-2000). The preceding newsletter described the patient with “Fx1”, while this one will briefly summarize the clinical course of the patient with “Fx2” infection.
The patient was a 43 year-old man who was admitted to the hospital in 1995 with a one week clinical history of fever, shortness of breath, and occasional vomiting and diarrhea. Over the previous 6 months, he had an unidentified illness that caused a 45-pound weight loss. He had evidence of left-sided pneumonia on physical exam and chest X-ray. His labs revealed pancytopenia (decreased white cells, red cells, and platelets).
Blood cultures on admission grew the Fx2 Francisella species. He was treated with 2 weeks of ampicillin-sulbactam for the diagnosis of pneumonia and bacteremia. The fever resolved and the blood cultures became negative. A bone marrow aspirate and biopsy showed no evidence of granulomas or cancer (or iron stores). Moderate hepatosplenomegaly lead to a liver biopsy that did show granulomas, lymphohistiocytic infiltration and abundant plasma cells. Special “stains and cultures” of the liver and bone marrow tissue however, were negative. Serology (acute and convalescent) was negative for Francisella.
Epidemiologically, the patient had a dog, (but no mention of any ticks). He used well water for cooking and bathing, but culture of this water did not show any Francisella bacteria. He lived in a rural area in Liberty County, Texas.
The blood culture turned positive after 6 days in the aerobic bottle of the Bac-t-Alert blood culture system. In vitro, it was resistant to the ampicillin-sulbactam that he was treated with for two weeks. Fx2 was also resistant to ceftriaxone (unlike Fx1), aztreonam, piperacillin, and erythromycin. It was susceptible to ciprofloxacin (like Fx1), gentamicin and amikacin. The Vitek NHI microbiologic identification panel suggested that Fx2 was “unidentified but possibly Cardiobacterium hominis, Hemophilus Actinomycetemcomitans, or Neisseria subflava”. The Vitek GNI identification system suggested Fx2 could be “Acinetobacter lwoffii”.
The patient is the only one, to my knowledge, ever reported with this Fx2 infection, subsequently identified as Francisella tularensis novicida (or “novicida-like”).
As with the Fx1 Francisella tularensis novicida (like) bacteria described in this same paper (and summarized on this website earlier this week), the mis-identification of Fx2 by microbiologic laboratory systems emphasizes the importance of explicitly performing surveillance for the above named (quite unusual) non-Francisella bacteria (e.g., Hemophilus. Actinomycetemcomitans (as with Fx1) Acinetobacter, Cardiobacterium hominus) anytime a possible environmental contamination is thought to have occurred with Francisella tularensis bacteria that could include Fx2 (or Fx1).
6 August 2008
Daniel R. Lucey, MD, MPH
The Jakarta Post reports 13 persons suspected with bird flu in North Sumatra, but lab tests still pending.
In a short article Wednesday, August 6th in The Jakarta Post reported that a total of 13 persons were undergoing evaluation and treatment for SUSPECTED (but not lab-confirmed) avian influenza in northern Sumatra.
The location in northern Sumatra is Air Batu village, Air Batu subdistrict, Asahan regency. All 13 persons were seen at Abdul Manan hospital.
Two of the 13 patients were transferred to Adam Malik Hospital in the provincial capital of Medan. These two children (7 years old and 8 months old) were reported by a hospital official in Medan, Sinar Ginting, to be in critical condition with high fever, cough, and other respiratory symptoms. This same official said that one week earlier chickens had died suddenly in the neighborhood where these children lived. Sinar Giting also was quoted as saying: “Officials from the local health agency have examined the chickens and found they were positively infected with H5N1 virus”.
An AFP article posted in the Singapore Straits Times cited a nurse treating some of these patients as reporting that 3 of the 13 persons had died; however, no deaths have so far been reported in the Jakarta Post. This Straits Times article also stated that human specimens have already been sent to the major referral laboratory in Jakarta for avian influenza testing.
Laboratory results are anticipated soon that will address whether any of the human illnesses are due to H5N1 virus.
August 10, 2008
Daniel R. Lucey, MD, MPH
Indonesia reports that all of the suspected cases of avian flu tested negative in Asahan district, North Sumatra
On Saturday, August 9, the director general of the Indonesian Ministry of Health, Nyoman Kandun, was quoted by the media (Agence France Presse (AFP)) in Jakarta as reporting that “All specimens collected from suspect cases have given negative results. They are all recovered”, in reference to the suspected H5N1 infection in 13 persons from Asahan district in North Sumatra.
The Program for Monitoring Emerging Diseases (ProMED-mail) posted this report as well as the statement that: “Until further notice, ProMed-mail will not report suspected human cases of avian influenza in Indonesia until they have been confirmed by the Indonesian Ministry of Health.
21 August 2008
Daniel R. Lucey, MD, MPH
Bacterial pneumonia after influenza infection as the primary cause of death in the 1918-1919 pandemic: Need for bacterial vaccine and antibiotic stockpiles in 2008-2009.
Four papers and editorials (1-4) published this month have emphasized the importance of including the ability to prevent, diagnose, and treat bacterial pneumonias as part of pandemic influenza preparedness.
A major contribution to this literature is provided by the data published online this week for the upcoming October 1, 2008 issue of the Journal of Infectious Diseases by Morens,Taubenberger, and Fauci from the NIAID/NIH. They reviewed publications in English, German, and French that described bacteriologic data and autopsies from 8,398 persons in 15 nations who died during the 1918-1919 influenza pandemic. They also studied lung tissue blocks from 58 more influenza fatalities from 1918-1919 preserved in the National Tissue Repository of the Armed Services Institute of Pathology, as well as bacteriologic data from 35 pleural fluid culture series, and 42 blood culture series.
These authors concluded from this comprehensive review that:
“The majority of deaths in the 1918-1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings.”
The specific bacteria involved likely included three for which safe and effective vaccines exist today: Hemophilus. Influenza (“formerly “Bacillus influenza” in 1918), the pneumococcus, and the meningococcus. Additional pneumonia-causing bacteria cited in this paper included Staphylococcus and Strep pyogenes (“Strep hemolyticus” in 1918), for which there are no current FDA-licensed vaccines. Unlike in 1918, however, antibiotics exist today that can treat all of these bacteria, even in their drug-resistant forms.
Morens and colleagues noted, however, that “the extraordinary severity of the 1918 pandemic remains unexplained”. Interestingly, they suggest that the current H5N1 avian influenza virus ‘may have pathogenic mechanisms that are atypical because the virus is poorly adapted to humans’.
Of note, bacterial pneumonia has not been linked to the extremely high case fatality rates (e.g., 81% in Indonesia, 67% in China, 44% in Egypt) in the initial several hundred patients with laboratory-confirmed H5N1 virus infection. Instead, the recent update on H5N1 virus infection in humans from the World Health Organization (WHO) Writing Committee (published January 17, 2008 in the New England Journal of Medicine) has reported that: “The primary pathologic process that causes death is fulminant viral pneumonia” (5).
Logically, Morens and colleagues at the NIH go on to state that in their Journal of Infectious Diseases paper: “If the next pandemic is caused by a human-adapted virus similar to those recognized since 1918, we believe the infection is likely to behave as it has in past pandemics, precipitating severe disease associated with prevalent colonizing bacteria”.
Therefore, the implication of their findings for pandemic influenza preparedness I is that these critical efforts should not only focus on the influenza viral pathogen: “The present work leads us to conclude that in addition to these critical efforts, prevention, diagnosis, prophylaxis, and treatment of bacterial pneumonia, as well as the stockpiling of antibiotics and bacterial vaccines should be among the highest priorities in pandemic planning”.
In my opinion, one might only add that the technology to isolate in culture most viruses, including the influenza virus itself, did not exist in 1918. Thus, viral co-pathogens (e.g., adenoviruses, cytomegalovirus, parainfluenza virus, metapneumovirus, or other pulmonary or systemic viral pathogens that may have also contributed to the morbidity and mortality of the pandemic, would not have been identified. Such potential viral co-pathogens, in addition to the influenza virus and “prevalent colonizing bacteria”, should be sought in future human pandemics and when possible in experimental animal models, including those studying the still-enigmatic H5N1 avian influenza virus.
References:
- Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness. J Infect Dis 2008; 198 (1 October). Accessed online Aug 20, 2008.
- McCullers JA. Planning for an influenza pandemic: Thinking beyond the virus. (Editorial commentary). J Infect Dis 2008; 198 (1 October). Accessed online Aug 20, 2008.
- Brundage JF, Shanks GD. Deaths from bacterial pneumonia during 1918-1919 influenza pandemic. Emerg Infect Dis 2008 (August) vol 14. No 8. pages 1193-1199. accessed 20 Aug 2008 at: www.cdc.gov/eid
- Gupta RK, George R., Nguyen-Van-Tam JS. Bacterial Pneumonia and Pandemic influenza planning. Emerg Infect Dis 2008 (August) vol 14. No 8. pages 1187-1192. accessed 20 Aug 2008 at: www.cdc.gov/eid
- WHO Writing Committee. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358: 261-273.
23 August 2008
Daniel R. Lucey, MD, MPH
WHO reports that 107/107 (100%) of influenza A (H1N1) human viruses this flu season are resistant to oseltamivir (Tamiflu) (Note: This is not avian H5N1)
The World Health Organization (WHO) reported on their influenza website 20 August 2008 a three page document listing the results of Influenza A (H1N1) virus resistance to oseltamivir (Tamiflu) in 2008 for nations in the southern hemisphere as well as the northern hemisphere. Of note, in the southern hemisphere’s current flu season 107/107 H1H1 human influenza isolates that have been tested from South Africa and 10/10 H1N1 human flu isolates from Australia have been found to be resistant to oseltamivir by genotypic analysis.
The explanation is uncertain, especially given the fact that only one of the 107 patients in South Africa was reported to be receiving oseltamivir. In Chile, 4/32 H1N1 isolates (13%) were resistant to oseltamivir, specifically the H274Y resistance mutation. No increase in virulence of the H1N1 influenza illness was noted.
In Hong Kong, a second peak of influenza typically occurs in July-August each year, albeit smaller than the usual peak in the winter months (December-March) of the northern hemisphere. From the second quarter of 2008 until 20 August, a total of 583 influenza A (H1N1) virus isolates from patients in Hong Kong have been tested and 97 (17%) have been found to be resistant to oseltamivir.
During the past winter flu season in the northern hemisphere,, from the last quarter of 2007 until 31 March 2008, WHO’s update on 20 August showed Influenza A (H1N1) resistance to oseltamivir rates to be: e.g., Norway 178/265 (67%); France 231/496 (47%); Russian Federation 58/128 (45%), Ukraine 23/67 (34%); Switzerland 10/53 (19%); USA 126/1026 (12%); Hong Kong 79/666 (12%); UK 37/346 (11%); Spain 2/106 (2%).
As discussed in several “Washington Newsletters” on this website earlier this year (January 30, Feb 1, Feb 8, Feb 19, Feb 28, 2008)), the surprising and unexplained sharp increase in Influenza A (H1N1) resistance to oseltamivir was reported by the European CDC and WHO at the start of 2008 ).
Of particular concern is the fact that such oseltamivir resistant human influenza A viruses are being transmitted person-to-person. Previous observations were that some, but not all, oseltamvir-resistant influenza viruses had an impaired biological “fitness” such that their ability to spread from person to person was impaired.
Given that influenza A (H1N1) viruses can become resistant to oseltamivir AND be transmitted person-to-person-to person, how likely is it that avian influenza A (H5N1) will acquire the ability to become resistant to oseltamivir AND be transmissible from person-to-person-to person?
Rare instances of such H5N1 avian influenza viruses resistant to oseltamivir have already been reported in the scientific literature (e.g., from Vietnam). Fortunately, neither these H5N1 viruses nor any others have acquired the ability to be spread in a sustained manner from person-to-person-to person.
This 20 August report from the WHO should be grounds to develop faster additional novel anti-influenza medications that could be used for prevention and treatment, both of current human influenza viruses and potential pandemic human threats such as avian influenza viruses H5N1, H7N7, H7N3, H7N2, H9N2 and other flu viruses of avian origin not yet recognized to infect humans.
Lastly, ongoing international work to identify the mechanism of acquiring oseltamivir resistance by human Influenza A (H1N1) viruses should be strongly supported in order to make appropriate interventions as soon as possible.
8 September, 2008
Daniel R. Lucey, MD, MPH
Past and Future Newsletters on Tularemia
No bioterrorism events in the USA due to Francisella tularensis, the causative bacterial agent of the disease “tularemia”, have occurred in the 21st century. Fortunately, this absence of disease includes during the incubation period of tularemia following detection of F.tularensis by Biowatch filters in some US cities. For example, public reports (online) of such events have occurred at least one time in the months of September or October in or near Houston (2003), Washington, DC (2005), San Jose (2005), and St. Louis (2006).
During this September and October (2008) this Newsletter and website (www.BePast.org) will increase its information and commentary on tularemia: its history, diagnosis, prevention, and treatment. This focus will build on past newsletters on tularemia posted on this site.
For example, newsletters posted here have commented on in vitro work co-culturing the protozoan parasite Acanthamoeba with F. tularensis (14 July 2008), algorithms to diagnose the index case(s) of tularemia after a bioterrorism event (October 1 and 3, 2005; October 4 and October 6, 2007), and the environmentally rare, but in-vitro well studied “Fx1” and “Fx2” isolates of F. Tularensis novocida-like stains (July 30-31, 2008).
15 September 2008
Daniel R. Lucey, MD, MPH
New H5N1 virus Clade 2.3.4 (‘Fujian-like lineage’) available for vaccine development
During the past week the World Health Organization (WHO) posted on their avian influenza “vaccines and antivirals” website that a new recombinant H5N1 avian influenza virus has been developed from a Clade 2.3.4 isolate named A/duck/Laos/3295/2006. The WHO stated that it is available under a Materials Transfer Agreement (MTA). This new recombinant vaccine virus was developed by a laboratory at the US Food and Drug Administration (FDA/CBER).
Currently, the only US FDA-licensed H5N1 vaccine is based on a clade 1 virus isolate. Most human infections today are no longer due to clade 1 H5N1 viruses. Instead, most human infections are due to Clade 2 viruses, either clade 2.1 (found primarily in Indonesia), clade 2.2 (“Qinghai lineage’), or clade 2.3.
Although some degree of cross-clade protection may occur with certain H5N1 vaccines, the degree of protection may not be as high as with the clade (or subclade) of H5N1 that is used to make a given vaccine. Thus, at this point in time it appears quite reasonable to develop H5N1 vaccines against all of the major clades (Clade 1 and 2) and subclades (e.g. Clade 2.1, 2.2., 2.3). In this regard the availability of this recombinant clade 2.3.4 (‘Fujian-like lineage’) H5N1 vaccine virus represents progress.
The subclade 2.3.4 has also formerly been referred to as a ‘Fujian-like lineage’ H5N1 virus. The WHO reference for this nomenclature equivalence is listed on their avian influenza website in a document from August 2007 titled “Towards a unified nomenclature system for the highly pathogenic H5N1 avian influenza virus”. See www.who.int/csr/disease/avian_influenza /guidelines/nomenclature/en/ibndex.html
H5N1 highly pathogenic avian influenza infection of ducks in Laos has continued, with the most recent report to posted on the OIE website (www.oie.int) on September 14, 2008. Two outbreaks were reported in ducklings in Nambok and Xay (the latter was traced to a duckling from the the Nambok outbreak). The ducklings in Nambok were in a small commercial unit within a village with backyard poultry. The WHO website lists two humans with laboratory-confirmed H5N1 virus infections in Laos, both of which occurred in 2007. Worldwide, the WHO currently reports 387 human H5N1 virus infections, with 245 fatalities (63% case fatality rate).
Comments would be welcome by e-mail regarding the Materials Transfer Agreement (MTA) issue(s) and whether a difference exists regarding MTA requirements for H5N1 viruses of animal versus human sources.
24 September 2008
Daniel R. Lucey, MD, MPH
Tularemia Risk Communication:
CDC’s “Communicating in the First Hours”
The US Centers for Disease Control and Prevention (CDC) has previously posted on their website a series of risk communication documents related to major emergency threats including the CDC Category A bioterrorism candidate agents such as tularemia, anthrax, and pneumonic plague. These documents, termed “Communicating in the First Hours”, can be found at www.bt.cdc.gov/firsthours/tularemia
For tularemia a five-page pdf is posted that addresses seven (7) points as part of “Health and Safety Information”. These points are:
- What is happening?
- What is tularemia and can it spread from person to person?
- What are symptoms of tularemia?
- What to do if you have symptoms of tularemia and were recently in the xxx area.
- What to do if you are or have been near the xxx area and do not have any symptoms of tularemia.
- What to do to protect yourself
- What is being done and how to get more information.
This 5-page pdf, dated December 28, 2005, can be found online at:
www.bt.cdc.gov/firsthours/pdf/messages_tularemia.pdf
28 September 2008
Daniel R. Lucey, MD, MPH
WHO updates Candidate H5N1 vaccine virus list for potential use as human vaccines
On Thursday, September 24, the World Health Organization (WHO) posted on their avian influenza website (Vaccines and Antivirals section) an update titled “Antigenic and genetic characteristics of H5N1 viruses and candidate H5N1 vaccine viruses developed for potential use as human vaccines”. The prior summary was from February 2008.
This five (5) page pdf document included the following list of “Reassortants with completed regulatory approval”, all of which are available, except for the Clade 2.1 A/Indoensia/5/2005 that WHO states requires “Indonesian Government permission”:
Clade 1 A/Viet Nam/1203/2004
Clade 1 A/Viet Nam/1194/2004
Clade 1 A/Cambodia/R0405050/2007
Clade 2.1 A/ Indonesia/5/2005 (NOTE: “Requires Indonesian Government Permission”)
Clade2.2 A/Bar-headed goose/Qinghai/1A/2005
Clade 2.2 A/whooper swan/Mongolia/244/2005
Clade 2.2 A/turkey/Turkey/1/2005
Clade 2.3.4 A/Anhui/1/2005
Clade 2.3.4 A/Japanese white-eye/Hong Kong/1038/2006
Clade 2.3.4 A/duck/Laos/3295/2006
WHO also provides a list of four H5N1 viruses that are “Reassortants prepared and awaiting regulatory approval”: These include a clade 2.2 virus from India (chicken/2006), a clade 2.1 virus from Hunan (duck 2002), a clade 2.3.2 virus from Hong Kong (magpie/2007), and a clade 4 virus from Guiyang (goose/2006).
As with the prior WHO summaries on this topic in August 2006, March 2007, and February 2008 this is a valuable document in terms of the ongoing evolution of H5N1 influenza viruses and the respective evolving development of candidate vaccines.
As in other publications, WHO notes that clade 1 viruses initially caused human infections several years ago in Cambodia, China Hong Kong SAR, Thailand and Vietnam; recently Clade 1 viruses have been found again in poultry in Cambodia, Thailand, and Viet Nam.
Clade 2.1 viruses continue to cause human and animal infections in Indonesia.
Clade 2.2 viruses have been the most widespread geographically, causing animal infections in over 60 nations in Asia, Europe, and Africa. Human infections with Clade 2.2 viruses have been lab-confirmed in Azerbaijan, Turkey, Egypt, Nigeria, Pakistan, Iraq, Bangladesh, Djibouti, and China.
Clade 2.3.4 viruses have caused human infections in China, Lao PDR, Myanmar, and Viet Nam.
Clade 4 and Clade 7 viruses have been reported in some birds in Asia.
Currently, the USA has only one Clade 1 (Viet Nam 2004) based H5N1 vaccine that is FDA-approved. It requires two shots one month apart, a large amount of antigen (90ug), and does not contain an adjuvant. It is not commercially available but a limited supply is in the federal Strategic National Stockpile (SNS). Clade 2 based H5N1 virus vaccines are also undergoing testing, however, and additional candidate vaccines are being studied using adjuvants and lower concentrations of H5N1 vaccine antigen.
29 September 2008
Daniel R. Lucey, MD, MPH
Acanthamoeba in vitro to co-culture the bacteria that cause tularemia: A model system in multiple laboratories in Europe and North America.
The following is a short list of publications that focus on the study of Acanthamoeba protozoan parasites cultured in vitro with bacteria such as those that cause tularemia.
Tularemia (Francisella tularensis)
- Gustafson K. 1989. Growth and survival of four strains of Francisella tularensis in a rich medium preconditioned with Acanthamoeba palestinensis. Canadian J of Microbiology 35: 1100-1104. (The sole author is from Umea, Sweden (Swedish National Defense Research Institute).
- Abd H, Johansson T, Golovliov I, Sandstrom G, Forsman. Survival and Growth of Francisella tularensis in Acanthamoeba castellanii. Applied and Environmental Microbiology 2003. 69:600-606. (The authors are from Umea, Sweden (Swedish Defense Research Agency and Dept of Clinical Microbiology Umea University), and Stockholm, Sweden (the Karolinska Institute and Huddinge Hospital).
- Hassett DJ, Limbach PA, Hennigan RF, Klose KE, Hancock REW, Platt MD, Hunt DF. Bacterial biofilms of importance to medicine and bioterrorism: proteomic techniques to identify novel vaccine components and drug targets. Expert Opinion Biol Ther 2003. 3(8): 1201-1207. (University of Cincinnati, Ohio).
- Lauriano CM, Barker JR, Yoon S-S, Nano FE, Arulanandam BP, Hassett DJ, Klose KE. MglA regulates transcription of virulence factors necessary for Francisella tularensisintraamoebae and intramacrophage survival. 2004. Proc Natl Acad Sci (PNAS) 101(12): 4246-4249. (The authors are from UTHSC, San Antonio, Texas, U.Cincinnati, Ohio, U. of Victoria, BC, Canada). Edited by Dr. Stanley Falkow, Stanford University, California, USA).
- Additional grants and abstracts on Acanthamoeba-Francisella, interactions involving labs in the USA and Sweden, can be found online.
A more general “mini-review” article that focuses on “Amoebae as Training Grounds for Intracellular Bacterial Pathogens”, but that focuses on Legionella bacteria instead of Francisella tularensis bacteria, was published in 2005: Molmeret M, Horn M, Wagner M, Santic M, Kwaik YA. Applied and Environ Microbiology 71:20-28. (Authors are from the U. of Louisville, Kentucky, the U. of Vienna, Austria, and the U. of Rijeka, Croatia).
Other labs have also published on Acanthamoeba as an in vitro model system using Legionella or Vibrio Cholerae. For example, in 2006 researchers from Fudan University, School of Public Health in Shanghai, China published a paper titled “Study of the growth of Vibrio cholerae O139 within Acanthamoeba polyphaga and its survival in the cysts in low temperature” in the journal “Zhonghua Liu Xing Bing Xue Za Zhi 27(4):339-342. The authors are Li O, Jiang OW, Chen HY, Shen J, Chen, Shao YO, Tan JD, Li ZH.
Although Francisella have not been found in nature to be present inside Acanthamoeba protozoan parasites, co-cultures of Francisella tularensis and Acanthamoeba have been established in vitro over the past 20 years, in multiple labs in Europe and North America.
2 October 2008
Daniel R. Lucey, MD, MPH
US to make antibiotics available for postal workers and household members as CRI preparedness for anthrax
On October 1st the US Department of Health and Human Services (HHS) announced that antibiotic kits could be made available to eligible postal letter carriers and members of their households for potential future use in the event of an anthrax emergency. These oral antibiotics would be used to protect the letter carriers who could be called upon to deliver additional antibiotics directly to the homes of person in the general population who may have been exposed to anthrax as part of one or more bioterrorist attacks.
Use of letter carriers to deliver antibiotics has been discussed as part of the US government’s “Cities Readiness Initiative (CRI) since its inception in 2004. The CRI has more than doubled in size since 2004 such that it now includes 72 major US cities/metropolitan areas. One of the primary goals of the CRI is to deliver appropriate antibiotics to the entire exposed population (e.g., to aerosolized anthrax spores) population “within 48 hours of the decision to do so”.
As the point of contact for the Washington, DC Department of Health at the beginning of the Cities Readiness Initiative in the spring of 2004, one can appreciate the major obstacles faced from the beginning when trying to implement a realistic feasible plan to distribute all needed antibiotics within 48 hours.
This long-discussed action of providing antibiotic kits for letter carriers and their household members is an important step forward in this regard. Even so, the road ahead is still long.
5 October 2008
Daniel R. Lucey, MD, MPH
22 U.S. contracts for “Covered Countermeasures” against anthrax listed in HHS PREP Act Declaration
On October 1, 2008 the U.S. Department of Health and Human Services (HHS) published on their website www.hhs.gov a “Declaration under the Public Readiness and Emergency Preparedness Act” (“PREP Act”) that was summarized as:
“Declaration pursuant to section 319F-3 of the Public Health Service Act (42 U.S.C. 247d-6d) to provide targeted liability protections for anthrax countermeasures based on a credible risk that the threat of exposure to Bacillus anthracis and the resulting disease constitutes a public health emergency”.
Importantly, this declaration does NOT mean that there is any known imminent threat of an anthrax attack.
Previously, Secretary Ridge made a determination on January 20, 2004 that “anthrax presents a material threat against the United States population sufficient to affect national security.” On September 22, 2006 Secretary of the U.S. Department of Homeland Security (DHS) Michael Chertoff “made a determination under the same provision that “multidrug resistant Bacillus anthracis presents such a threat” (cited in a footnote on page 1 of 2 in the September 23, 2008 memorandum pertaining to anthrax from Secretary Chertoff to HHS Secretary Michael Leavitt posted on the DHS website at: www.dhs.gov/xlibrary/assets/ofsec_signed_determination092308.pdf)
The HHS Declaration on October 1st that focuses on “targeted liability protections for anthrax countermeasures” specifically cites “Covered Countermeasures”. These include 22 specific contracts listed in Appendix 1 of the HHS document that can be found on the HHS website at: www.hhs.gov/disasters/emergency/manmadedisasters/bioterorism/prepact-081001.html
Each of these 22 U.S. government contracts listed in Appendix 1 include the “Covered Countermeasure and the “Manufacturer”. These countermeasures can be divided into three categories:
A. Anthrax antitoxin(s) (antibody)
B. Anthrax Vaccine
C. Antibiotics
For example, Anthrax antitoxin(s)-antibodies listed in Appendix 1 include: Anthrax Immune Globulin (AIG) made both by Cangene and Emergent Biosolutions, and manufacturer-specific Anthrax monoclonal antibody made by HGS, Elusys, Pharmathene.
Anthrax vaccine includes both the Biothrax (Anthrax Vaccine, Adsorbed, AVA) manufactured by Emergent Biodefense Operations and BioPort (Emergent Biosolutions), as well as a newer generation of anthrax vaccine “recombinant protective antigen (rPA)” by Avencia (Pharmathene).
Antibiotics include: doxycycline, levofloxacin, ciprofloxacin, penicillin, amoxicillin, rifampin, vancomycin, and clindamycin (made by multiple specific manufacturers listed in Appendix 1).
This is a noteworthy reference document that addresses a long-recognized issue regarding liability for anthrax countermeasures. The list of “Covered Countermeasures” in Appendix 1 is of value to emergency planners as well as potentially to individual clinicians who appreciate the threat of another anthrax attack, especially with a multidrug-resistant Bacillus anthracis.
8 October 2008
Daniel R. Lucey, MD, MPH
Pakistan 2007: Family cluster of 5 brothers with H5N1 Avian Flu infection includes the full clinical spectrum from fatalities to the (rare) asymptomatic household contact case
This week’s “Weekly Epidemiological Record” of the World Health Organization provides a detailed description of the investigation of a family cluster in Pakistan last October-November (2007) of H5N1 avian influenza infection (www.who.int/wer 3 October 2008; No. 40. p 359-364). Several of the salient features of this cluster include:
1. The index case was most likely infected during culling of H5N1-infected poultry (without PPE) in the “poultry-belt” of the North-West Frontier Province (NWFP) of Pakistan. He developed a fever on October 29, 2007. On 2 November he travelled by public transport the four hours to his family’s home in Peshawar, where 5 brothers and 2 sisters lived. WHO stated that he is “the first person to have documented influenza A (H5N1) disease following occupational exposure during poultry culling” (p. 363).
2. Four of his brothers (Cases 2-5) became ill with probable or lab-confirmed H5N1 infection. These cases included a 33 year-old brother who was asymptomatic, but had an H5-PCR+ throat swab and a positive H5 antibody test. This is a rarely-documented event, and the WHO report did not cite a single other example of asymptomatic seroconversion in household contacts of H5N1 patients, except during the 1997 Hong Kong H5N1 initial outbreak (J Infect Dis 1999; 180:1763-1770).
3. None of the four brothers had exposure to poultry. All had prolonged close contact with the index case and/or one another. Based on contact exposures between the brothers, and estimated incubation periods, the multiple investigator teams determined that human-to-human transmission occurred for “3 generations of transmission”, but it was “not sustained in the community” beyond this one family (p. 364).
4. The full clinical spectrum was seen in Cases 1-5, including:
a. Fatal infection: Case 2 and Case 3.
b. Recovery with intensive care (ICU) (for 9 days). Case 1 (index)
c. Recovery without intensive care: Case 4
(Oseltamivir (“Tamiflu” was begun one day after fever started).
d. Asymptomatic lab-confirmed infection.
9 October 2008
Daniel R. Lucey, MD, MPH
12 Infectious Diseases Predicted to Spread (“Emerge”) due to Climate Change
On October 7th the Wildlife Conservation Society (WCS) posted a report listing a dozen infectious diseases of wildlife and humans that can be predicted to spread (“emerge”) beyond their current geographical locations due to climate change. The homepage of the WCS contains a link to this list of diseases termed “The Dirty Dozen”, and a color brochure summarizing these 12 diseases of both wildlife and humans (www.wcs.org). In alphabetical order, these 12 diseases are:
Avian Influenza: a group of viruses including H5N1, H7N7, H9N2, others.
Babesiosis: a parasite transmitted by certain species of ticks
Cholera: a bacterial disease spread via water
Ebola: a viral infection of gorillas, chimps, humans, (and perhaps bats)
Intestinal and external parasites: Many zoonotic (animal-human) species
Lyme Disease: a bacterial disease spread by ticks
Plague: a bacterial disease spread by rodent fleas (“bubonic” form)
“Red tides”: Coastal algal bloom toxins/freshwater Cyanobacteria
Rift Valley Fever (RVF): a viral disease spread by certain mosquitoes
Sleeping sickness: a parasite (trypansomes) spread by tsetse flies
Tuberculosis: a bacterial disease spread via air, or unpasteurized milk
Yellow Fever: a viral disease spread by certain species of mosquitoes
This report from the WCS was released in Barcelona, Spain. The following day (October 8) the World Health Organization and the Ministry of Health of Spain released a separate report outlining a 5-point research agenda on public health and climate change (www.who.int/mediacentre/news/releases/2008/pr36/en/print.html)
Such initiatives are valuable guideposts for potential near-term and long-term interventions in both the developing and the developed world. Increasingly in 2008 the global implications of infectious diseases, climate change, and financial markets are being better appreciated, and solutions proposed to current and future (predictable) problems.
October 13, 2008
Daniel R. Lucey, MD, MPH
A New Virus Found as the Cause of Death in 3 patients, including health care workers, in southern Africa.
On Monday, October 13, the World Health Organization (WHO) posted on their website a brief update regarding the three deaths of persons from Zambia and South Africa due to an undiagnosed infection. WHO reported that preliminary evidence from the renowned viral diagnostic laboratories in Johannesburg, and from the US CDC (Atlanta), shows that the cause is a “virus from the Arenaviridae family”.
WHO also reported today that a 4th patient has been diagnosed with this new arenavirus, based on PCR testing, symptoms, and contact exposure to one of the earlier known cases.This 4th patient is a health care worker (nurse), as were two of the earlier patients who had cared for the index patient.
Further characterization of this apparently novel virus is ongoing in labs in Johannesburg and Atlanta.
This family of viruses contains over 20 known members. They are single stranded RNA viruses. A variety of rodents are usually the viral reservoir. The viruses can be found in rodent (e.g., mouse) excreta, especially urine. With some areanviruses, aerosolization from the urine has been demonstrated.
Some of the best known examples of arenaviruses and their year/location of discovery are: Junin (1958/Argentina), Machupo (1963/Bolivia), Lassa (1969/Nigeria), Guanarito(1989/Venezuela) and Sabia (1990/Brazil). (Reference: CJ Peters, Principle and Practice of Infectious Diseases textbook 2005. Mandell, Bennett, and Dolin (eds). pages 2090-2098).
If confirmed, then this would be at least the second novel arenavirus reported this year, albeit on a different continent.
On February 6, 2008 the New England Journal of Medicine published a paper by Palacios and colleagues describing a novel arenavirus, similar to lymphocytic choriomeningitis virus (LCMV), that had infected a person from Australia while traveling in the Balkans (see also the accompanying editorial by Richard Whitley in the Feb 6, 2008 NEJM, and the Feb 12, 2008 “Newsletter” here at www.BePast.org).
Further information on this virus, how it is transmitted, its environmental reservoir, and what antiviral drug(s) it is susceptible to, if any (e.g., ribavirin), should be anticipated.
14 October 2008
Daniel R. Lucey, MD, MPH
South Africa reports frequent resistance to oseltamivir (Tamiflu) in Influenza A Viruses (H1N1) this winter, similar to Europe last winter
In the upcoming November 2008 issue of the Emerging Infectious Diseases journal posted on the US CDC website (www.cdc.gov) a paper is posted for early publication this month by Besselaar and colleagues from South Africa, and collaborators in the UK, titled “Widespread Oseltamivir Resistance in Influenza A viruses (H1N1), South Africa.
This paper is important because it demonstrates that the southern hemisphere is now seeing the same oseltamivir (Tamiflu) antiviral drug resistance in H1N1 influenza A viruses as was initially reported to variable degrees in European nations beginning last January (2008) in Norway.
So far, this oseltamivir resistance phenomenon remains unexplained, and is almost entirely seen in persons who have NOT taken the drug oseltamivir (Tamiflu). So far, this antiviral resistance to the only oral neuraminidase drug (oseltamivir, Tamiflu) is NOT being seen with H3N1 or H5N1 influenza A viruses.
This winter in South Africa saw the major influenza virus in circulation to be H1N1. Virus isolates were obtained from outpatients in South Africa by throat or nasopharyngeal swab between May and July (winter influenza season in this part of the southern hemisphere).
23/23 (100%) influenza A H1N1 virus isolates from May and June were tested in WHO Influenza Reference Labs in London and Melbourne and found to be “highly resistant to oseltamivir by the NA inhibition enzyme assay, with 50% inhibitory concentration values of 554nM to 1,485 nM”.
45/45 (100%) additional influenza A H1N1 virus isolates from July 2008 were tested by PCR in the National Institute for Communicable Diseases (NICD) in Sandringham, South Africa. They were also found to be resistant to oseltamivir at the 274 mutation site. Sequence analysis confirmed the H274Y mutation that confers oseltamivir resistance and established that the N1gene sequences were closely related to those in Europe at the beginning of 2008.
The authors reasoned that oseltamivir resistant H1N1 viruses had likely spread from Europe to South Africa, and then spread readily within the country. They conclude by noting that such drug-resistant viruses may appear soon in other nations in the southern hemisphere, and that influenza A H3N2 viruses remain susceptible to oseltamivir.
The mechanism whereby such drug-resistant influenza A (H1N1) viruses have developed, and acquired the ability to be transmitted efficiently and in a sustained manner from person-to-person, is important to define. Exposure to oseltamivir has been reported in only a very small fraction of patients with these oseltamivir-resistant viruses.
This resistance issue was mentioned briefly by Dr. Keiji Fukuda in the October 2, 2008 WHO virtual press conference on seasonal flu in the northern hemisphere posted on the WHO influenza website.
Understanding the mechanism of resistance is essential, in part to try to prevent such oseltamivir resistance from developing on the part of other influenza viruses such as influenza A (H3N2) and avian influenza A (H5N1).
In the majority of cases, the only oral anti-influenza drug that avian influenza A (H5N1) is susceptible to is oseltamivir. Hence, it is the primary anti-influenza drug stockpiled by WHO, USA, and multiple other nations for potential use if the H5N1 avian influenza virus changes such that it acquires the ability to spread in a sustained and efficient manner from person-to-person-to person.
15 October 2008
Daniel R. Lucey, MD, MPH
UN and World Bank Issue Global Progress Report on Avian Flu and Pandemic Preparedness: Specific Countries and Case Studies as Examples
On October 15th the UN System Influenza Coordinator and the World Bank posted online their 4th Global Progress Report on “Responses to Avian Influenza and State of Pandemic Readiness”
(http://un-influenza.org/files/ProgressReport2008.pdf). This 105-page pdf document discusses the latest work on the “continued threat of influenza pandemic”. The next three main sections of the report include specific nations and case studies as examples to illustrate the focus of that section. For example:
Section 2: International Financial and Technical Assistance
” 2.2: Yemen Country Case Study
Section 3: Capacity to Reduce the Threats of Avian Influenza to Animals and Humans.
” 3.2 Mongolia: Innovative Commitment by an At-Risk Country
“ 3.3 Lao PDR: Frontline early detection of infected backyard poultry by alert locals
” 3.5 Indonesia: Participatory Disease Surveillance and Response: Strengthening Veterinary and Empowering Communities
” 3.7 Egypt: Community-Based Education Campaigns—empowerment through education
” 3.10 China: Country Case Study
Section 4: Preparedness for Mitigating the Impacts of the next Influenza Pandemic
” 4.1 Cambodia: An example of sub-regional pandemic planning
” 4.2 Indonesia: One of the largest full-scale pandemic influenza exercises–planning process deemed just as important as the final simulation
” 4.6 Egypt: Country focus: Multi-Sector pandemic preparedness in Egypt
For example, in Egypt multi-sector pandemic preparedness includes (page 64, Box 4.6):
- Strategic level: “The Higher Ministerial Committee for crisis management was established and headed by the Prime Minister with the participation of the Ministries of Defense and Military Production, Interior Affairs, Information, Foreign Affairs and Health and Population.”
- Planning and preparation level: A national pandemic inter-ministerial committee was established and headed by the Minister of Health and Population. A broadly multidisciplinary sub-committee has organized pandemic simulation exercises. A simulation exercise was held at the national level at the Ministry of Health and Population.
- All 26 governates in Egypt have developed pandemic response and preparedness plans, under the aegis of the Information and Decision Support Centre (IDSC).
- The private sector received pandemic guidance on preparing Business Continuity Plans, again with assistance from the ISDC.
16 October 2008
Daniel R. Lucey, MD, MPH
N-95 Respirator fit-testing required for US postal carriers to receive a “Household Antibiotic Kit” (doxycycline) for use during an Anthrax attack
On October 3, 2008 a letter was sent from the Food and Drug Administration (FDA)/HHS Deputy Commissioner for Policy (Randall Lutter, Ph.D.) to the Director of the Biomedical Advanced Research and Development Authority (BARDA)/HHS (Robin Robinson, PhD) in response to BARDA’s request for the FDA “to issue an Emergency Use Authorization (EUA) for the pre-event provision and potential use of doxycycline hyclate tablet emergency kits for inhalational anthrax…specifically for eligible United States Postal Service (USPS) participants in the Cities Readiness Initiative (CRI)…and their household members.” The complete 17-page pdf can be accessed via the FDA website at:www.fda.gov/Cder/drugprepare/EUA_doxycycline.pdf A list of the CRI’s 72 cities and metropolitan areas in the 50 US states, as of April 2, 2008, is posted on the CDC website at: www.bt.cdc.gov/cri/facts.asp
A brief but critically important reference in the letter from the FDA to BARDA appears on page 9, and in a footnote (#20) on page 12, stating the requirement for successful N-95 respirator fit-testing in order for US Postal Service (USPS) postal carriers to be eligible to receive the Household Antibiotic Kit (HAK):
Page 9: “Policies and procedures must also include screening for fitness to receive OSHA-required personal protective equipment (PPE) (i.e., N-95 masks) and provision of PPE to eligible USPS participants. “
Page 12: “USPS postal carriers are not eligible to receive a doxycycline hyclate tablet emergency kit if they have not passed their N-95 mask fit test.”
The explicit rationale for successful N-95 fit-testing is not stated in this letter. Given that inhalational anthrax is NOT transmitted from person-to-person, however, the rationale is most likely due to concern that anthrax spores in the environment following an aerosolized release (attack) might put the postal carriers at risk of infection when they are delivering preventive antibiotics to persons in their homes.
If this is the actual rationale for use of N-95 respirators as part of the PPE to be worn by postal workers delivering antibiotics to the homes of persons who were possibly exposed to aerosolized anthrax spores as part of the Cities Readiness Initiative, then a key part of the associated risk communication will need to focus on explaining this rationale to the general public, who are unlikely to have N-95 respirators for their own use. Such risk communication could be a formidable challenge.
17 October 2008
Daniel R. Lucey, MD, MPH
Multiple Simulation Exercises for Pandemic Flu Provided from the Asia-Pacific Region
This month a very informative spectrum of national and regional pandemic flu preparedness exercises from over 15 nations in the Asia-Pacific region was published as a booklet and posted online at: www.un-influenza.org/files/asia_pacific/temp/unsic_pandemic_complete.pdf
Succinct, illustrated summaries of pandemic preparedness exercises are provided from nations including Australia, Brunei Darussalam, Cambodia, china, Fiji, Indonesia, Japan, Lao PDR, Malaysia, Myanmar, New Zealand, Philippines, Republic of Korea, Singapore, Thailand, and Vietnam.
For example, Japan reports that three national simulation exercises have occurred, in September 2006, February 2007, and November 2007. Discussion focuses on the third exercise, a full-scale functional exercise at the central and provincial level, including drills at Narita airport and Narita Red Cross Hospital. This exercise began at the Prime Minister’s Office. There were six evolving scenarios based on the WHO Pandemic Phases 3-6 (currently the world is at Phase 3).
The initial setting of the scenario began with a person suspected of having pandemic flu on board an aircraft coming into Narita airport in Tokyo from another country where the pandemic had already begun.
In response to the suspected case on this airplane, “….they tested the process and procedures for passenger separation on board; health check-ups by quarantine medical staff; patient transfer and isolation at Narita Red Cross hospital; and handling of close contacts, remaining passengers and baggage. The drills were accompanied by training on the appropriate use of PPE…” An 87-page pdf “After Action Report” on this exercise was posted online, in Japanese.
An online source for the complete, updated “Pandemic Influenza Preparedness Plan of the Japanese Government” can be found at: www.mhlw.go.jp/english/topics/influenza/index.html
This booklet is of significant value for its design of these national and regional exercises, and for the “lessons learned”. For example, the Indonesian government coordinated a very large outdoor live simulation pandemic flu exercise April 25-27 that included the international airport in Bali. This multisectorial exercise, the largest of its kind to date, is described and “lessons learned” provided in this booklet.
These two examples from Japan and Indonesia are illustrative of what is needed for multisectorial national pandemic flu preparedness training, as emphasized in the Foreward to the booklet by David Nbarro, Senior United Nations System Influenza Coordinator.
17 October 2008
Daniel R. Lucey, MD, MPH
Multiple Simulation Exercises for Pandemic Flu Provided from the Asia-Pacific Region
This month a very informative spectrum of national and regional pandemic flu preparedness exercises from over 15 nations in the Asia-Pacific region was published as a booklet and posted online at: www.un-influenza.org/files/asia_pacific/temp/unsic_pandemic_complete.pdf
Succinct, illustrated summaries of pandemic preparedness exercises are provided from nations including Australia, Brunei Darussalam, Cambodia, china, Fiji, Indonesia, Japan, Lao PDR, Malaysia, Myanmar, New Zealand, Philippines, Republic of Korea, Singapore, Thailand, and Vietnam.
For example, Japan reports that three national simulation exercises have occurred, in September 2006, February 2007, and November 2007. Discussion focuses on the third exercise, a full-scale functional exercise at the central and provincial level, including drills at Narita airport and Narita Red Cross Hospital. This exercise began at the Prime Minister’s Office. There were six evolving scenarios based on the WHO Pandemic Phases 3-6 (currently the world is at Phase 3).
The initial setting of the scenario began with a person suspected of having pandemic flu on board an aircraft coming into Narita airport in Tokyo from another country where the pandemic had already begun.
In response to the suspected case on this airplane, “….they tested the process and procedures for passenger separation on board; health check-ups by quarantine medical staff; patient transfer and isolation at Narita Red Cross hospital; and handling of close contacts, remaining passengers and baggage. The drills were accompanied by training on the appropriate use of PPE…” An 87-page pdf “After Action Report” on this exercise was posted online, in Japanese.
An online source for the complete, updated “Pandemic Influenza Preparedness Plan of the Japanese Government” can be found at: www.mhlw.go.jp/english/topics/influenza/index.html
This booklet is of significant value for its design of these national and regional exercises, and for the “lessons learned”. For example, the Indonesian government coordinated a very large outdoor live simulation pandemic flu exercise April 25-27 that included the international airport in Bali. This multisectorial exercise, the largest of its kind to date, is described and “lessons learned” provided in this booklet.
These two examples from Japan and Indonesia are illustrative of what is needed for multisectorial national pandemic flu preparedness training, as emphasized in the Foreward to the booklet by David Nbarro, Senior United Nations System Influenza Coordinator.
20 October 2008
Daniel R. Lucey, MD, MPH
APIC “Infection Preventionists” Support Requiring Flu Vaccine for Healthcare Workers
On October 9th the Association of Professionals in Infection Control and Epidemiology (APIC) “announced its support for requiring flu immunization for healthcare workers who have direct patient control as well as ancillary staff. APIC further recommended that healthcare facilities obtain informed statements acknowledging the risk to patients from employees who decline the vaccine for reasons other than medical”.
The 3-page APIC Position Paper can be found on the homepage of APIC at www.apic.org
APIC cites US survey data showing that only 42% of health care workers received the flu vaccine in 2005-06 (Fiore AE et al. MMWR 2008; 57 (RR7): 1-50). The CDC has recommended, but not required, annual flu vaccination since 1981, according to the APIC position paper.
This position paper also states that “multiple studies show that 70% or more of HCP (health care professionals) continue to work despite being ill with influenza, thus exposing patients to the virus”.
APIC cites work showing that ”at least two randomized controlled studies have demonstrated decreased mortality in patients cared for by HCP who receive the vaccine” (JAMA 2000; 284:1655-63).
These recommendations by APIC apply to “all medical and non-medical personnel in contact with patients” who work in “acute care hospitals, nursing homes, skilled nursing facilities, physician’s offices, urgent care centers, outpatient clinics, and to persons who provide home health care.”
Hopefully, there will be a clear-cut response to APIC’s recommendations (soon) on the part of hospital organizations, hospital finance administrators, ethicists, and most of all, health care workers to this proposal.
21 October 2008
Daniel R. Lucey, MD, MPH
Botulism Countermeasures Declaration under the PREP Act made by US Government
In an online document dated 17 October 2008, the US Department of Health and Human Services (HHS) posted a notice in the US Federal Register (FR) by the HHS Secretary Michael O. Leavitt of a “Public Readiness and Emergency Preparedness Act (PREP) Act Declaration Regarding Botulism Countermeasures.” Find this link at: http://www.hhs.gov/disasters/discussion/planners/prepact/index.html
This HHS website, dedicated to the Public Readiness and Emergency Preparedness (PREP) act states that:
“A PREP Act declaration is specifically for the purpose of providing immunity from tort liability, and is different from, and not dependent on, other emergency declarations.”
In addition, “The PREP Act authorizes the Secretary of the Department of Health and Human Services (“Secretary”) to issue a declaration (“PREP Act Declaration”) that provides immunity from tort liability (except for willful misconduct) for claims of loss caused, arising out of, relating to, or resulting from administration or use of countermeasures to diseases, threats and conditions determined by the Secretary to constitute a present, or credible risk of a future public health emergency to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of such countermeasures.”
The US Federal Register official notice of this Botulism Countermeasure PREP act Declaration by HHS Secretary Leavitt is dated October 17, 2008 (Volume 73, Number 202) pages 61864-61866.
The Botulinum toxin covered countermeasures under this PREP Act Declaration are defined under section IX in this Federal Register document by Secretary Leavitt to include “any vaccine; antimicrobial/antibiotic, or other drug or antitoxin; or diagnostic or device to identify, prevent or treat botulinum toxin or adverse events from such countermeasures (1) licensed under section 351 of the public Health Service Act; (2) approved under section 505 or section 515 of Federal the Food, Drug, and Cosmetic Act (FDCA); (3) ….” The full Federal Register notice can be found online at: http://edocket.access.gpo.gov/2008/E8-24734.htm
Appendix I to this document lists five U.S. government Contracts as covered countermeasures for this PREP Act declaration:
| “Covered Countermeasure” | Manufacturer |
| Heptavalent antitoxin | Cangene |
| Heptavalent antitoxin | PerImmune |
| Heptavalent antitoxin, | Cangene |
| Monovalent E | |
| Monovalent E | Aventis Pasteur |
| Bivalent A and B | Aventis Pasteur |
Similar PREP Act Declarations were made for anthrax countermeasures on October 1, 2008, as well as on October 17, 2008 for smallpox countermeasures, pandemic influenza antivirals, and acute radiation syndrome countermeasures.
22 October 2008
Daniel R. Lucey, MD, MPH
Smallpox Countermeasures Declaration under the U.S. Public Readiness and Preparedness (PREP) Act
The US Department of Health and Human Services (HHS) posted a notice in the US Federal Register on October 17th by the HHS Secretary Michael O. Leavitt of a “Public Readiness and Emergency Preparedness Act (PREP) Act Declaration Regarding Smallpox Countermeasures.” See: http://www.hhs.gov/disasters/discussion/planners/prepact/index.html
Appendix I to this document includes the following six (6) specific U.S. government contracts as one part of this PREP Act declaration:
| “Covered Countermeasure” | Manufacturer |
| MVA (Modified Vaccinia Ankara) | Bavarian Nordic |
| WetVax | Aventis Pasteur |
| VIG (Vaccinia Immune Globulin) | Cangene |
| ACAM 2000 (Vaccine) | Acambis |
| ACAM 2000 warm-base | Acambis |
| Cidofovir (antiviral) | Gilead |
The Federal Register notice of this Smallpox Countermeasure PREP Act Declaration by HHS Secretary Leavitt can be found in Volume 73, Number 202, pages 61869-61871. The ”smallpox countermeasures” could include vaccines, antiviral or other drugs, diagnostics or devices to identify, prevent, or treat smallpox or orthopoxviruses or adverse events from such countermeasures that are licensed, approved or authorized for emergency use under specific Federal documents as listed in the full Federal Register notice at: http://edocket.access.gpo.gov/2008/E8-24734.htm
“The PREP Act authorizes the Secretary of the Department of Health and Human Services (“Secretary”) to issue a declaration (“PREP Act Declaration”) that provides immunity from tort liability (except for willful misconduct) for claims of loss caused, arising out of, relating to, or resulting from administration or use of countermeasures to diseases, threats and conditions determined by the Secretary to constitute a present, or credible risk of a future public health emergency to entities and individuals involved in the development, manufacture, testing, distribution, administration, and use of such countermeasures.”
Similar PREP Act Declarations were made for anthrax countermeasures on October 1, 2008, as well as on October 17, 2008 for Botulism countermeasures, pandemic influenza antivirals, and acute radiation syndrome countermeasures.
24 October 2008
Daniel R. Lucey, MD, MPH
H2 and H6 Influenza A as potential pandemic threats and their vaccines and other countermeasures added to prior U.S. PREP Act Declaration for H5, H7, and H9
On October 17th the U.S. Department of Health and Human Services (HHS) posted a document in the Federal Register related to pandemic influenza preparedness and the Public Readiness and Emergency Preparedness Act (PREP) Act.
This document was a notice of an amendment to pandemic influenza vaccines and other countermeasures against H5, H7, and H9 viruses that were already covered under a PREP Act Declaration in terms of tort liability protection as of February 1, 2007. Specifically, vaccines and related countermeasures against H2 and H6 influenza A were added as an amendment to the prior PREP Act Declaration for the following reasons:
“Whereas the H2 class of influenza viruses, which caused the human influenza pandemic of 1957 and reappeared recently in U.S. animals including swine, is viewed as a likely candidate to evolve into an influenza strain capable of causing a pandemic of human influenza;
Whereas the H6 class of influenza viruses, which appeared recently in animals including domestic fowl, is viewed as a likely candidate to evolve into an influenza strain capable of causing a pandemic of human influenza…”
The full notice in the Federal Register can be found in Volume 73, number 202, pages 61861-61864 and at: www.hhs.gov/disasters/discussion/planners/prepact/index.html
This Federal register document was signed by the Secretary of HHS, Michael O. Leavitt. The only “manufacturer” cited in appendix 1 to this document pertaining to U.S. government contracts for “covered countermeasures” against Influenza H2, H5, H6, H7, H9 was with St. Jude Children’s Research Hospital.
28 October, 2008
Daniel R. Lucey, MD, MPH
Global Spread of Oseltamivir (Tamiflu)-Resistant Human Influenza A (H1N1)
The World Health Organization (WHO) on 14 October updated on their influenza website the global tracking of “Influenza A (H1N1) virus resistance to oseltamivir—2008 influenza season”. The results show that such resistance is continuing to spread globally, including in the southern hemisphere during the recent flu season.
From the second quarter of 2008 until 13 October 2008 an illustrative selection of nations from the WHO report demonstrates:
| Country | Number (%) of resistant isolates |
| South Africa | 225/225 (100%) |
| Senegal | 10/10 (100%) |
| Ghana | 5/13 (38%) |
| Argentina | 15/33 (45%) |
| Chile | 10/79 (13%) |
| Uruguay | 13/16 (81%) |
| Australia | 47/59 (80%) |
| Philippines | 10/11 (91%) |
| Hong Kong SAR | 97/583 (17%) |
| Japan | 0/61 (0%) |
| Brazil | 0/12 (0%) |
| Thailand | 0/12 (0%) |
The neuraminidase mutation that has been found responsible for this oseltamivir resistance is the H274Y histamine to tyrosine mutation. Only rarely have any of the patients with this human H1N1 flu virus mutation been exposed to oseltamivir (Tamiflu). The reason for the occurrence of these oseltamivir-resistant viruses is still unknown.
Of note, however, these viruses are clearly transmitted from person-to-person. Previously, oseltamivir-resistant influenza viruses were generally thought to be “less-fit”, and thus unable to be transmitted readily from person-to-person in a sustained manner as is being seen now both in the southern and northern hemispheres during their respective influenza seasons in 2008.
These oseltamivir resistant viruses remain susceptible to the (inhaled) neuraminidase inhibitor drug “zanamivir” (Relenza).
The advent of the flu season in the northern hemisphere now can be predicted to bring with it increased resistance to oseltamivir among influenza A (H1N1) viruses. Whether this resistance pattern expands to include human influenza A (H3N2) or avian influenza A (H5N1) warrants close surveillance world-wide, including from nations near the equator that can have year-round influenza virus transmission.
5 November 2008
Daniel R. Lucey, MD, MPH
US Announces New Funding for Avian and Pandemic Flu at International Conference in Sharm el-Sheikh, Egypt
At the recent International Ministerial Conference on Avian and Pandemic Influenza held at Sharm el-Sheik, Egypt the US pledged an additional $320 million. This conference had representatives from over 100 nations and was organized by the Government of Egypt in cooperation with the International Partnership on Avian and Pandemic Influenza. The U.S. pledge was made by Under Secretary of State for Democracy and Global Affairs, Paula Dobriansky.
In a U.S. Department of State media note October 25th it was reported that U.S. support to international organizations and more than 90 nations for avian and pandemic influenza preparedness is now $949 million. The complete statement is posted at: http://www.state.gov/r/pa/prs/ps/2008/oct/111241.htm
U.S. funding is reported by the Department of State to go to support “stockpiles of non-pharmaceutical supplies such as personal protective equipment, laboratory and decontamination kits for outbreak surveillance, investigation, response, and containment; technical and humanitarian assistance and international coordination; wild bird surveillance; international research, including vaccine research; and global communications and outreach.”
10 November 2008
Daniel R. Lucey, MD, MPH
New Biodefense Book Includes Media, Legal, and Psychosocial Perspectives as well as Pathogens
Last month a valuable new 17-chapter book on biodefense issues was published titled “Beyond Anthrax: The Weaponization of Infectious Diseases”. The editors are Dr. Larry Lutwick and Suzanne Lutwick and the publisher is Springer/Humana Press. Updated chapters devoted to many of the CDC Category A and B threat agents are followed by excellent chapters on media, legal, psychosocial, and public health infrastructure perspectives.
For example, a chapter titled “The Role of the Media in Bioterrorism” by David Brown, a Science writer for the Washington Post, provides a detailed analysis using specific issues and quotations from the 2001 anthrax letter attacks. He begins by discussing two concepts: (1) the principle of parsimony (e.g., “Occam’s razor”) and (2) the bell-shaped curve. The Principle of Parsimony he defines first. “One should always choose the simplest explanation of a phenomenon, the one that requires the fewest leaps of logic” and “the principle that entities should not be multiplied needlessly; the simplest of two competing theories is to be preferred”.
Brown observes that “Bioterrorism dilutes the importance of parsimony. That’s because bioterrorism is an unnatural event even if its components—viruses, toxins, organs, medicines—are each natural and at some level behaving in familiar ways. Bioterrorism creates interactions that do not occur on their own. It produces conditions of unpredictable risk; it makes vulnerable people who aren’t normally vulnerable…”
He also describes the bell-shaped curve and notes that “bioterrorism tends to magnify the importance of the bell curve as an informative idea”. The bell-shaped curve depicts that: “Most outcomes are similar to one another. They inhabit the fat, or humped-up, part of the curve, and define the average. A small number, however, are quite different from the rest, either much less or much more by whatever metric is in use. Those outcomes inhabit the two thin ends, or tails, of the curve.” Such a bell-shaped curve could be applied to help explain how several persons may have been infected by the Bacillus anthracis bacteria sent through the mail system in 2001.
Brown’s discussions are especially interesting when he describes “US Anthrax Attacks—The Media and HHS”, “US Anthrax Attacks—The Media and the CDC”, and “Getting It Right”.
11 Nov 2008
Daniel R. Lucey, MD, MPH
Sporadic Flu Activity Reported in DC and 15 states:
No Shortage of New Trivalent Flu Vaccine
The most recent CDC update on influenza (flu) activity in the USA for week 44, ending November 1 reports sporadic activity in Washington, DC, Puerto Rico and 15 states: Alaska, California, Colorado, Connecticut, Delaware, Hawaii, Idaho, Illinois, Indiana, Massachusetts, Nevada, New York, Pennsylvania, Texas, and Utah. So far, the proportion of outpatient visits due to Influenza-Like-Illness (ILI) remains below national and region-specific baseline levels.
The three components of this year’s annual flu vaccine are all different than last year’s flu vaccine, based on the best assessment of what strains of Influenza A (H1N1 and H3N2) and Influenza B are most likely to be circulating this year. The current 2008-2009 trivalent vaccine virus strains are:
—Influenza A/ Brisbane/59/2007 (H1N1)-like
—Influenza A/Brisbane/10/2007 (H3N2)-like
—Influenza B/Florida/4/2006-like antigens.
No shortage of influenza vaccine in this country is expected this year. This is true even though starting this 2008-2009 season all young persons ages 5-18 years have been added to the list of those recommended to receive the annual flu vaccine.
Now is a good time to receive the flu vaccine in order to develop protective immunity before influenza viruses become more widespread in the US and elsewhere in the northern hemisphere. The emergence of oseltamivir (Tamiflu)-resistant influenza A (H1N1) viruses will continue to be monitored closely in the USA after their appearance last January in Europe and during the flu season several months ago in the southern hemisphere e.g., in South Africa.
4 November 2008
Daniel R. Lucey, MD, MPH
The Jakarta Post Reports 17 Persons being tested for H5N1 Avian Flu in South Sulawesi Hospital
Today’s 14 November issue of The Jakarta Post reports that 17 persons, mostly children, have been admitted to Wahidin Sudirohusodo General Hospital in Makassar, South Sulawesi on Wednesday and Thursday this week (November 12-13) for a febrile influenza-like illness. This hospital is reported by the Jakarta Post as having 11 beds dedicated for the evaluation of patients with possible H5N1 avian influenza, as do multiple other hospitals in Indonesia.
Laboratory testing for H5N1 avian influenza is ongoing for these 17 patients. At least some of these persons had exposure to chickens that died between November 7-9. Preliminary tests on some of the dead poultry were consistent with avian influenza, according to the Head of the husbandry Division of the Makassar Marine and Agriculture Office.
Most human infections with this H5N1 avian flu virus have occurred in Java (particularly the western part of the island). Only a few human infections have occurred on the island of Sulawesi.
In May 2006 a cluster the (“Karo cluster”) of 8 family members with H5N1 avian influenza infection, and non-sustained person-to-person transmission, occurred in the northern part of Sumatra island.
The most recent update (October 2007—13 months ago) of the World Health Organizations’s draft interim protocol for the rapid response and containment of an avian influenza outbreak at its epicenter is posted on the WHO avian influenza website at: www.who.int/csr/disease/avian_influenza/guidelines/draftprotocol/en/index.html
In April 2008 Indonesia held the world’s largest live simulation of the emergence of a new human pandemic flu virus (epicenter) in collaboration with many Indonesian governmental organizations, NGOs, the WHO, US CDC, and other participants. It was held over the course of three days in Bali, Indonesia and included both village areas and the international airport. This exercise produced multiple “lessons learned” that could be integrated into Indonesia’s pandemic influenza planning as well shared with the WHO and other partners.
Official results of laboratory testing for H5N1 avian influenza in these patients is awaited from the Indonesian Ministry of Health.
14 November 2008
The Jakarta Post Reports 17 Persons being tested for H5N1 Avian Flu in South Sulawesi Hospital
Today’s 14 November issue of The Jakarta Post reports that 17 persons, mostly children, have been admitted to Wahidin Sudirohusodo General Hospital in Makassar, South Sulawesi on Wednesday and Thursday this week (November 12-13) for a febrile influenza-like illness. This hospital is reported by the Jakarta Post as having 11 beds dedicated for the evaluation of patients with possible H5N1 avian influenza, as do multiple other hospitals in Indonesia.
Laboratory testing for H5N1 avian influenza is ongoing for these 17 patients. At least some of these persons had exposure to chickens that died between November 7-9. Preliminary tests on some of the dead poultry were consistent with avian influenza, according to the Head of the husbandry Division of the Makassar Marine and Agriculture Office.
Most human infections with this H5N1 avian flu virus have occurred in Java (particularly the western part of the island). Only a few human infections have occurred on the island of Sulawesi.
In May 2006 a cluster the (“Karo cluster”) of 8 family members with H5N1 avian influenza infection, and non-sustained person-to-person transmission, occurred in the northern part of Sumatra island.
The most recent update (October 2007—13 months ago) of the World Health Organizations’s draft interim protocol for the rapid response and containment of an avian influenza outbreak at its epicenter is posted on the WHO avian influenza website at: www.who.int/csr/disease/avian_influenza/guidelines/draftprotocol/en/index.html
In April 2008 Indonesia held the world’s largest live simulation of the emergence of a new human pandemic flu virus (epicenter) in collaboration with many Indonesian governmental organizations, NGOs, the WHO, US CDC, and other participants. It was held over the course of three days in Bali, Indonesia and included both village areas and the international airport. This exercise produced multiple “lessons learned” that could be integrated into Indonesia’s pandemic influenza planning as well shared with the WHO and other partners.
Official results of laboratory testing for H5N1 avian influenza in these patients is awaited from the Indonesian Ministry of Health.
15 November 2008
Daniel R. Lucey, MD, MPH
H5N1 Avian Flu Lab Tests for 17 Persons in Sulawesi hospital awaited from Indonesian Ministry of Health
Today’s 15 November issue of The Jakarta Post reports that the 17 persons in respiratory isolation for suspected H5N1 avian flu in a regional hospital in Makassar, South Sulawesi, Indonesia are clinically stable and that family members are being restricted from visiting them pending their H5N1 virus lab tests.
A spokesman for the Wahidin Sudirohusodo regional hospital, Halik Saleh, is quoted by the Post as saying “Generally the patients are getting better” with all but one no longer having fever.
Initial tests for H5N1 avian influenza virus were reportedly positive both for some of the poultry that the 17 persons with an influenza-like illness had been exposed to as well as the patients themselves. All the poultry within a 1km radius of these animals has reportedly been culled.
Importantly, however, Halik Saleh states that: “The only results we will refer to in order to treat our patients will be those from the laboratory of the health ministry’s research and development center”. This national reference laboratory for H5N1 avian flu is the capital, Jakarta, on the island of Java.
In my opinion, the fact that none of the 17 persons with suspected (not proven) H5N1 avian flu infection are reported to have died, and that 16/17 no longer have fever is important information because the case fatality rate for H5N1 virus infection is ~80%. Therefore, with the caveat that the clinical course of any of the 17 persons could still worsen in the coming days, then the lack of fatalities so far suggested one of three possibilities:
1. Rapid treatment with anti-influenza medications (e.g., oseltamivir or “Tamiflu”) and excellent supportive care with fluids, oxygen and antibiotics for possible bacterial co-infections has prevented the overall typically fatal (80%) clinical course of lab-confirmed H5N1 virus infection in Indonesia from 2005-2008. Such a standard treatment protocol for suspected H5N1 avian flu infection has been in place across the country of Indonesia for some time. Many dozens of specific H5N1 avian flu referral hospitals have been established across the archipelago, including with patient isolation wards such as those at Wahidin Sudirohusodo regional hospital in South Sulawesi where these 17 persons are being treated.
2. Another possible explanation for the lack of fatalities (so far) is that none (or few) of these 17 persons, some of whom are children, do Not have H5N1 avian flu infection. Instead, they have another febrile illness due to either a different infection or a non-infectious cause.
3. A much less likely, and so far completely unprecedented possible explanation is that some or all of these 17 persons have infection with an H5N1 avian flu virus that has become weakened (attenuated in terms of its virulence) and thus is significantly less likely to cause life-threatening illness or death. To date, no such weakened H5N1 virus has been reported anywhere in the world; however, some persons have predicted that a future pandemic flu virus will have to become less deadly in order to be able to be transmitted in a sustained manner across human populations. In my opinion, we have NO reason to assume that is the case with these 17 persons in Sulawesi.
In my opinion, these 17 patients appear to be receiving excellent medical care at Wahidin Sudirohusodo regional hospital in south Sulawesi for suspected avian flu infection as witnessed by the fact that none have died and 16/17 no longer have fever. Use of hospital isolation rooms and restricting visitors is prudent and a standard precaution.
Indonesia has a very extensive clinical experience with the clinical management of suspected and proven H5N1 avian flu patients. Clinicians in Indonesia involved in the care of such patients continue to improve their clinical protocols to diagnose and treat H5N1 patients more rapidly in a multidisciplinary manner (antiviral drugs, oxygen, fluids, intensive care (ICU), ventilators if needed, and antibiotics for secondary bacterial infections), and thereby decrease the case fatality rate of 80% experienced to date in Indonesia
Hopefully, the results of H5N1 lab tests performed in the referral laboratory in Jakarta will be announced by the Ministry of Health very soon.
17 November 2008
Daniel R. Lucey, MD, MPH
US FDA to open first China offices this week in Beijing, Guangzhou, and Shanghai; EU also signs agreement with China on consumer safety.
On Thursday, 13 November, the US Government’s Department of Health and Human Services (HHS) posted a news release (www.hhs.gov/news) announcing that HHS Secretary Mike Leavitt and Food and Drug Agency (FDA) Commissioner Andrew von Eschenbach, M.D. will go to China to open the FDA offices in Beijing, Guangzhou, and Shanghai.
Two bilateral conferences on global food safety are scheduled in Beijing for November 18-19. Topics on the agenda include fresh produce-related foodborne disease outbreaks in the USA, and melamine contamination of dairy products in China. The Minister of Health in China, Chen Zhu, will meet with Leavitt and von Eschenbach to “discuss policy and governance reforms aimed at improving the safety of food and other consumer products in China and the United States” on November 18.
After opening the Beijing office, Secretary Leavitt and Dr. von Eschenbach will travel over the next two days to Guangzhou, the capital of Guangdong province in SE China, and to Shanghai on the east coast, to open FDA offices there in collaboration with their Chinese counterparts.
In a related development, the China Daily newspaper reported the arrival of the US delegation this week in Beijing. In addition, the China Daily reported that the European Union (EU) and China signed an agreement on November 17 to enhance cooperation on consumer safety. As part of this accord information exchange will be expedited on potentially “tainted food and other dangerous goods”.
20 November 2008
Daniel R. Lucey, MD, MPH
South Sulawesi Creates a Bird Flu Commission as Indonesian Ministry of Health Reports H5N1 virus tests are negative for 17 suspected cases in Sulawesi
A brief article in the November 20 Jakarta Post quoted a spokesperson for the Ministry of Health in Indonesia saying that tests in the central reference lab in Jakarta for H5N1 avian influenza are negative for all 17 persons suspected to have this viral infection in South Sulawesi. The patients, many of whom were children, had reportedly been exposed to chickens that had died, at least some of whom were thought to have had H5N1 infection. Chickens in this neighborhood were subsequently culled, as illustrated in a photo and report in an earlier article in the Jakarta Post.
Clinically, none of these 17 persons had died, and overall they were reported in the Post to be improving. Thus, as mentioned several days ago on this website, clinically it was unlikely that infection with the established Indonesian Claude 2.1 strain of H5N1 virus had occurred in these 17 persons, given that the case fatality rate to date has been 80% in Indonesia since the initial human infections in July 2005.
One day earlier, in the November 19 issue of The Jakarta Post online (www.thejakartapost.com) another article (by Andi Hajramurni) reported the creation of a 51-member “Bird Flu Control and Handling Commission” in South Sulawesi by the Governor Syahrul Yasin Limpo. Recognition was given to the established presence of the H5N1 avian influenza virus in South Sulawesi poultry.
This Post article reported that in order to minimize risk of human H5N1 infections in South Sulawesi, “new measures stipulate that once a bird flu case is detected, all poultry in the affected area must be culled and the area sealed off. Any residents showing symptoms of the disease must be taken to the nearest community health center (Puskesmas) and treated at a designated hospital”.
This new Bird Flu Commission and explicit clinical evaluation measures should prove helpful in the months (and perhaps years) ahead. It is likely that there will be further suspected human H5N1 virus infections in South Sulawesi, due to exposure to infected poultry, even though to date there have not been a large number of human infections in South Sulawesi, unlike in western Java 2005-2008 or the Karo cluster in northern Sumatra in May 2006.
25 November 2008
Daniel R. Lucey, MD, MPH
“Emerging Infections: a perpetual challenge” described as an Historical Review by NIH authors
This month’s issue of the Lancet Infectious Diseases journal (2008; 8:710-719) contains an insightful “historical review” on “Emerging” Infectious Diseases over the centuries and into the modern era.
The authors, David Morens, Gregory Folkers, and Anthony Fauci discuss ten (10) examples of emerging infectious diseases, beginning with the Plague of Athens 430-426 BCE, as described by the renowned historian Thucydides, and ending with the HIV/AIDS pandemic of our 20th-21st century.
In between they discuss the “Black Death” (yersinia pestis) of the 1340’s, “French pox” due to syphilis (temporally linked to the return of Christopher Columbus to Europe), Smallpox (“hueyzahuatl”) among the Aztecs 1520-1521, European cattle epizootics (including anthrax, FMD, and the rinderpest virus), “The American Plague” (Yellow Fever) of 1793-1798, the 2nd Cholera pandemic as seen in France (Paris) in 1832, the devastating outbreak in the Fiji islands of Measles virus (“virgin soil epidemic” of immunologically-susceptible hosts), and the 1918-19 H1N1 influenza pandemic.
The authors list 13 determinants or factors involved in infectious disease emergence. These include, for example: war and famine, international trade and commerce, poverty and social inequality, climate and weather, economic development and land use as well as microbial adaptation and change, human susceptibility to infection, and human demographics and behavior.
They conclude that “Well-understood determinants of modern disease emergence, typically acting in concert, have been associated throughout recorded history with the emergence of major diseases…That most of the historical emerging diseases we examined were associated with unique patterns of common determinants suggests to us that an increasingly complex modern world will probably provide increasing opportunities for disease emergence…emerging infections remain among the principal challenges to human survival.”
The perspective of this excellent historical review supports the importance of studying the “Past as Prologue’ in order to understand prior emerging infectious diseases and their context, and thus to better predict and prepare for the ever-emerging infections in our future.
26 November 2008
Daniel R. Lucey, MD, MPH
Bird Flu simulation involving 300 people held in South Sulawesi, Indonesia following recent hospitalization of 17 persons for suspected bird flu
The November 24 edition of the Jakarta Post reported that Makassar, South Sulawesi, Indonesia carried out a bird flu outbreak simulation on November 22 that involved 300 people from multiple organizations. This newspaper article, written by Andi Hajramurni, closed with the statement: “Meanwhile, seven of the 17 bird flu suspected patients in Wahidin Sudirohusodo general hospital in Makassar who have been declared bird flu free have been sent home, while the rest were still at the hospital, for further treatment.”
The simulation of an outbreak of H5N1 avian influenza among people included participants from the “Health Agency, the Food Self-Reliance and Marine Agency, the Education Agency, the Communication Agency, the National Police, the Indonesian Army and the public service center.” Such a multidisciplinary approach to a influenza outbreak in humans and poultry was also taken in the longer, 3-day simulation pandemic flu epicenter exercise in Bali, Indonesia last April 25-27 of this year.
In this November 22 simulation, the region “was declared a pandemic-affected area and had to be closed or isolated. Only the authorities, who wore protective suits…were permitted to enter the affected area.” They also “prepared an emergency post, shelters, and a communal kitchen in the sterile zone for evacuees.”
Such a simulation exercise, being organized so rapidly after the hospitalization of 17 persons for suspected H5N1 avian influenza (“bird flu”) in Makassar, South Sulawesi is admirable. Such a training exercise can be particularly helpful in terms of risk communication messaging, and multi-sectorial community preparedness and response should an outbreak of avian/pandemic flu occur, whether in Sulawesi or any of the thousands of other islands in the Indonesian Archipelago.
29 November 2008
Daniel R. Lucey, MD, MPH
New Subtype of Ebola Virus (#5) reported from 2007 Uganda Outbreak: Estimated 36% Fatality Rate
This month’s issue of the online journal PLoS Pathogens (www.plospathogens.org) contains the initial report by Towner and colleagues from Uganda, the US CDC and Columbia (NYC) University Mailman School of Public Health of a distinct 5th subtype of Ebola virus. The proposed name, Bundibugyo ebolavirus, is based on the region in which it was discovered in western Uganda during an outbreak of an unknown disease 12 months ago, in November 2007.
The authors report that the case fatality rate of ~ 36% due to this species of ebolavirus was less than that seen with most outbreaks of Zaire ebolavirus (~ 80-90%) or Sudan ebolavirus (50-55%). They also stated, however, that the outbreak that occurred between late November 2007 and late December 2007 “resulted in 149 suspected cases and 37 deaths”.
The other two species of Ebola virus are Ebola Reston (Virginia) that did not cause any human illness, and Ebola Cote d’Ivoire (Ivory Coast) that caused one non-fatal human case in a veterinarian that occurred while carrying out an autopsy on an infected chimpanzee found in the Tai Forest in 1994.
This new Ebola virus species differs by more than 30% at the genome level from the other four known species. The genetically closest of the other four subtypes is Ebola Cote d’Ivoire. This genomic difference resulted in initial specimens from the patients in 2007 being “negative when initially tested with highly sensitive real-time RT-PCR assays specific for known Zaire and Sudan ebola viruses and marburgviruses.” A newly designed real-time PCR assay, as well as antigen capture, IgM, and IgG tests were transferred to the Uganda Virus Research Institute during the outbreak one year ago to facilitate outbreak control.
Current filovirus vaccine approaches include a multistrain vaccine that includes both Ebola Zaire and Sudan. Thus, the antigenic and immunogenic characteristics of this new subtype from Bundibugyo, Uganda will need to be assessed in future Ebola vaccine development.
9 December 2008
Daniel R. Lucey, MD, MPH
DHS Recommends Manhattan, Kansas as site for Proposed National Bio and Agro-Defense Facility (NBAF)
On Friday, December 5 the Department of Homeland Security (DHS) released a press statement that followed a similar one December 4 from Kansas State University, both of which announced that Manhattan, Kansas has been recommended as the site for the National Bio and Agro-Defense Facility (NABF). A formal “Record of Decision” will be published in one month, on January 12, 2009 that will officially designate a site on which to build the NABF.
The DHS statement noted that the NABF is intended to replace the Plum Island Animal Disease Center near Long Island, New York. Construction of the NABF is anticipated to start in 2010. This Plum Island facility is the only one in the U.S. currently working on the live virus that causes Foot-and-Mouth disease in animals. Once this new NBAF laboratory facility becomes operational in 2015, then the long-standing and illustrious Plum Island facility will be closed. This DHS press release also noted that “there is currently no laboratory facility in the U.S. with capabilities for Biosafety Level 4 (BSL-4) research on livestock”.
DHS defines laboratories with BSL-4 as: “Facilities appropriate for handling exotic pathogens that pose a high risk of life-threatening disease in animals and humans through the aerosol route and for which there is no known vaccine or therapy. BSL-4 facilities have complex, specialized ventilation requirements and waste management systems to prevent release of viable agents to the environment”. (Ref: Chapter one, page 2 of the DHS June 2008 NBAF Draft Environmental Impact Statement).
Authority for establishment of the NBAF is linked to Homeland Security Presidential Directive (HSPD) 9 “Defense of United States Agriculture and Food”. The purpose of HSPD 9, cited on January 30, 2004 is as follows: “This directive establishes a national policy to defend the agriculture and food system against terrorist attacks, major disasters, and other emergencies”.
Extensive discussion and comments have occurred prior to this DHS recommendation of Manhattan, Kansas as the site of the NBAF. There were five other sites in the USA that were under consideration for this site including locations in: Georgia, North Carolina, Mississippi, Texas, and Plum Island itself.
11 December 2008
Daniel R. Lucey, MD, MPH
ASM Biodefense and Emerging Diseases Conference February 2009 to include “The Science behind the “Anthrax Letter” Attack Investigation”
The 7th annual American Society of Microbiology (ASM) Biodefense and Emerging Diseases Research Meeting will be held February 22-25, 2009 in Baltimore, Maryland. This state-of-the art conference will include sessions on “Threat Reduction/Counter-Proliferation Policy and Science, Antimicrobial Resistance, Reversing Pathogenesis, Aerosol Biology, Select Agent Process, and Synthetic Genomes. A detailed description of the preliminary program is posted on the ASM Biodefense website: www.asmbiodefense.org
Other topics include a plenary session on “The Science behind the “Anthrax Letter” Attack Investigation”. The two moderators for this session will be Paul Keim, Ph.D. from Northern Arizona University, and Jason.D. Bannan, Ph.D. from the Chemical-Biological Sciences Unit, FBI, Quantico, Virginia. This session will be on Tuesday morning, February 24th.
The six presentations scheduled for this session are:
- The B.anthracis Ames Strain and the Development of an Investigative Strain Repository. Paul Keim, Ph.D: Northern Arizona Univ, Flagstaff, AZ.
- The Silicon Content in B. anthracis Spores is in the Spore Coat, not Exogenously Applied. Joseph R. Michael; Sandia Natl. Lab., Albuquerque, New Mexico.
- Comparative Genome analysis to Identify Minor B. anthracis Mutant Components in the Anthrax-Letter Spores. Jacques Ravel, Ph.D. Microbial Genomics, the Inst. For Genomic Res., Rockville, Maryland.
- A1 and A3 Assay Development. Thomas R. Reynolds, BS; Commonwealth Biotechnologies, Inc., Richmond, Virginia.
- Morph D assay Development. Valorie T. Ryan, Ph.D. Florida Division, Midwest Res. Int., Palm Bay, Florida.
- FBIR Process, Validations and Synopsis of the Results. Jason D. Bannan, Ph.D. Chemical-Biological Sciences Unit, FBI, Quantico, Virginia.
The Institute of Medicine (IOM) is participating in a review of the information pertaining to the 2001 anthrax attacks, pursuant to the recent announcement by the FBI that they had identified one perpetrator.
Before the IOM completes its report, however, this February 2009 ASM conference session on the “Science behind the …Investigation” should prove to be very helpful in understanding this case from 2001, and potentially understanding any future anthrax attack cases as well.
12 December 2008
Daniel R. Lucey, MD, MPH
H5N1 Avian Flu Virus Infects New Patients in Cambodia and Indonesia
This week the World Health Organization (WHO) announced three patients with lab-confirmed H5N1 avian influenza virus infection, the first confirmed human infections since September.
Today the WHO reported a 19 year-old man in Cambodia’s Kandal province, south of Phnom Penh, hospitalized with H5N1 virus infection. He initially developed symptoms on November 28th and sought medical attention two days later. All seven previous patients in Cambodia with lab-proven H5N1 virus infection have died. The source of his infection is still under investigation given that there were no known ongoing poultry outbreaks of H5N1 virus.
On December 9, the WHO reported that the Ministry of Health in Indonesia reported lab-confirmed H5N1 infections during November in two children. Both were linked to exposure to avian exposures. A 9 year-old girl from Riau Province was hospitalized November 12th, five days after symptoms began. Fortunately, with excellent treatment she was able to recover and left the hospital November 27th. The overall case mortality rate of H5N1 in Indonesia since the initial human cases in the summer of 2005 has been approximately 81% (113 deaths/139 patients).
A 2 year-old girl from East Jakarta was hospitalized 26 November, eight days after symptoms began due to H5N1 virus infection. Presumably her illness was already advanced by that time because she died three days later on November 29th.
In separate reports, H5N1 virus has been reported as the cause of new poultry outbreaks in Hong Kong and India’s Assam state this week. To date, no associated human infections have been found.
As the winter approaches in the northern hemisphere outbreaks of H5N1 virus in animals and limited numbers of human infections are predictably likely, as during the past five years. Continued surveillance for ongoing genetic and antigenic variation in the H5N1 virus is essential to help select the best avian H5 vaccines (as is under investigation now in Hong Kong) and also to continue developing new H5N1 vaccines for humans.
18 December 2008
Daniel R. Lucey, MD, MPH
Fatal case of H5N1 Avian flu reported from Egypt, and Outbreaks in Animals Occur in Multiple Nations
The World Health Organization (WHO) reported on 16 December that a 16 year-old female from Upper Egypt (Assuit Governate) died on December 15th. Her symptoms began on December 8. She was admitted to a district hospital December 11th and transferred to Assuit University Hospital on December 13th. No mention was made of when antiviral therapy was begun, but clearly this was a rapidly progressive clinical course, as is so often the case with this fulminant viral infection in the 15 nations that have reported human cases to the WHO.
The case fatality rate remains extremely high world-wide (247 deaths/391 cases = 61%), including in Egypt (23 deaths/51 cases = 45%).
The epidemiological link (“Epi-Link”) was contact with ill poultry, presumably infected with H5N1 virus. Identification of the patient’s H5N1 virus infection was made at the Egyptian Public Health Laboratory and later at the NAMRU-3 lab in Cairo.
As previously noted, each year as the weather turns colder, there are increasing outbreaks in animals of H5N1 avian flu virus. China recently reported an outbreak on two poultry farms in Jiangsu province. In Hong Kong recent outbreaks have further stimulated discussion regarding whether animal vaccines against H5N1, including the currently used H5N1 avian vaccine, should be changed due to potential significant antigenic change in the circulating virus.
Animal outbreaks of H5N1 avian flu virus in Cambodia and India have also recently been noted. In Taiwan an outbreak of bird flu is being reported as not due to H5N1, but to another avian flu virus (possibly H5N2).
Results of antiviral testing of recent human infections with H5N1 virus from Egypt, Indonesia, and Cambodia are awaited. If the virus becomes susceptible again in the majority of cases to the older anti-influenza drugs, rimantidine and amantidine, then presumptive combination therapy with BOTH rimantidine and the current standard monodrug therapy “oseltamivir” (or “Tamiflu”, a neuraminidase inhibitor) would seem reasonable to study in an international clinical study, given the extraordinarily high case fatality rate and high viral loads that have been reported with this virus.
19 December 2008
Daniel R. Lucey, MD, MPH
Drum Maker in England with Inhalational Anthrax illustrates the Challenge of Curing Patients in the Late-Fulminant Stage
The December 18th issue of the journal “Eurosurveillance” contains a “rapid communication” titled “Investigation and control measures following a case of inhalational anthrax in East London in a Drum Maker and Drummer, October 2008”. This 3-page paper, submitted December 12, is posted at: www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19076
This brief report reemphasizes the rapid progression of inhalational anthrax and the difficult challenge of curing a patient once they have passed from the “intermediate-progressive” clinical stage to the “late-fulminant” stage (ref 1-2).
In this case the patient was treated in the late-fulminant stage with anthrax immune globulin (AIG) flown in from the US CDC as well as three antibiotics to which this Bacillus anthracis was (apparently) susceptible.
This patient was the first case of inhalational anthrax to be reported in more than 30 years in England and Wales. Thus, clinical experience was very limited. The rapid clinical course was described as:
October 21, 2008: Patient presents to a London hospital “with a two day history of fever, night sweats and rigors”. “The patient commenced on oral and intravenous antibiotics immediately after admission.” “The admission chest x-ray showed some basal shadowing and a widened mediastinum”.
October 22: Admission blood cultures had become positive and Gram-positive rods were seen on microscopy.
October 23: Patient “rapidly deteriorated during early hours” and was transferred to the intensive care unit “with respiratory failure”. The Bacillus anthracis isolate from the blood cultures “produced pure growth on media plates”.
October 24 (Friday): “Multiple organ failure developed”. A PRELIMINARY diagnosis of B. anthracis was made. Antibiotics were changed from the initial (unspecified) regimen to rifampicin, ciprofloxacin, and clindamycin. The B. anthracis culture was “couriered to the Health Protection Agency’s (HPA) laboratory for Novel and Dangerous Pathogens (NADP) in Porton Down, where the identity of the organism was confirmed on the same day as B. anthracis.
October 25 (Saturday): “Further molecular and microbiological investigations on the next day confirmed the identification of the organism and drug sensitivities.”
October 27: Anthrax Immune Globulin (AIG) administered to the patient after having been flown in from the US CDC (requested rapidly on October 24th).
November 2: The patient died.
November 5: A post mortem examination was carried out. Preliminary results confirm death due to “pulmonary anthrax”. The body is “buried in a sealed coffin according to the family’s wishes”.
Epidemiological investigation revealed that of the samples taken from the patient’s studio flat (apartment) only “one drum and two pieces of leftover animal skins proved to be contaminated with B. anthracis.”
The rapid progression of inhalational anthrax is illustrated despite the superb treatment given by the Health Care Providers in London, including Anthrax Immune Globulin and 3 potent antibiotics (ciprofloxacin, rifampicin, and clindamycin) to which the B. anthracis isolate was (apparently) sensitive. In addition, to emphasize, this was the first patient with inhalational anthrax reported in 30 years in England, making the clinicians’ rapid therapy even more remarkable.
Several clinical observations from this brief report include:
- When the patient initially presented he had only experienced non-specific symptoms of fever, night sweats, and rigors for two days (Oct 19-21).
- Yet, the patient was already in the 2nd clinical stage of symptomatic inhalational anthrax, the “intermediate-progressive” stage based on either one of his inclusion criteria of bacteremia and a widened mediastinum on chest x-ray (no comment is made on whether a chest CT scan, ideally without contrast to show the hemorrhagic nature of the mediastinal lymphadenopathy, was performed).
- Characteristically, the blood cultures turned positive within the day after they were drawn (October 21 to October 22). One of the multiple clinical lessons learned from the US experience in 2001 was that all patients’ positive blood cultures showed B. anthracis in < 24 hours. Hence, the essential point of obtaining blood cultures, BEFORE antibiotics are given, in any patient suspected of having inhalational anthrax. Even seven years to the month after the October 2001 clinical presentation of the initial US patients, blood cultures remain the single best clinical test for individual patients suspected of having inhalational anthrax.
- By the 4th day after symptoms began (October 19-October 23) the patient progressed to the 3rd clinical stage, the “late-fulminant” stage, when “respiratory failure” occurred. None of the 5 patients in 2001 survived who, before appropriate antibiotics, reached this late-fulminant stage, defined as including any one of three inclusion criteria: 1) respiratory failure, 2) meningitis, or 3) shock.
- The time required to determine antibiotic susceptibilities ranged from when the blood cultures were drawn on admission October 21 until October 25 (a Saturday). This typical time frame will prove critical in any efforts to dispense mass antibiotics to large numbers of people after an aerosol attack in a major city or metropolitan area. Current public domain US plans under the “Cities Readiness Initiative (CRI), for such a catastrophic bioterrorism scenario call for prophylactic antibiotics to be given within 48 hours in order to minimize the number of symptomatic patients. Thus, it is plausible that the oral antibiotics given under this plan may prove inappropriate if a multidrug resistant (“MDR”) isolate of B. anthracis is used in such an attack, if it takes four (4) days (e.g., Oct 21-25) to determine antibiotic sensitivities.
- Giving anthrax immune globulin (AIG), as has been done previously this decade for one patient in 2006 in the USA, does not guarantee survival, especially when the patient has already been in the late-fulminanat stage for four days (October 23-27).
Several additional clinical facts may become available in a more detailed report, hopefully, such as:
- Were the typical bloody pleural effusions present, and if so, how early were they drained? Did they reaccumulate if thoracenteses rather than chest tubes were used for drainage? In this writer’s opinion, expressed repeatedly at the CDC conference on anthrax in March 2006, drainage of pleural fluid is essential to successful treatment of inhalational anthrax.
- Was meningeal, GI, or pericardial anthrax present?
- What were the anthrax toxin levels present in the serum (or pleural fluid) at different points between October 21 and November 2nd? (Such information was published by the CDC anthrax lab and co-authors for the US patient in 2006 before and after AIG treatment).
- Did the anthrax toxin levels decrease after clindamycin was started on October 24th, and before anthrax immune globulin was administered on October 27th? The hypothesis that clindamycin will “turn-off” anthrax toxin production has yet to be demonstrated in vivo.
References:
- Lucey DR. “Anthrax” in the Bioterrorism section of Principles and Practice of Infectious Disease. (published Oct 22, 2004.) Editors: Mandell, Bennett, Dolin. 6thEdition. Chapter 324. p. 3618-24.
- Lucey DR. Anthrax. 23rd edition (2007) of Cecil’s Textbook of Medicine. Chapter 317. p. 2197-2200.
29 December 2008
Daniel R. Lucey, MD, MPH
64/65 (99%) of Human Influenza A (H1N1) isolates tested in the USA are resistant to (oral) oseltamivir (Tamiflu).
The US CDC reported in their latest weekly update on human influenza virus surveillance in the USA (Week 51: December 14-20, 2008) that a striking resistance pattern is emerging for human influenza A (H1N1). So far this flu season (October 1- December 20, 2008) 64 of 65 virus isolates of human influenza A (H1N1) are resistant to the only oral neuraminidase inhibitor of influenza viruses “oseltamivir” (Tamiflu). The CDC report from last week (Week 50) showed that 49/50 isolates were resistant to oseltamivir.
Fortunately, none of these 65 influenza A (H1N1) isolates were resistant to the inhaled neuraminidase inhibitor drug “zanamivir” (Relenza). In addition, 50 of these virus isolates have also been tested and none have been found to be resistant to the older anti-influenza oral adamantine class of drugs “rimantidine” and “amantadine”.
Unfortunately, however, as in the past few years, human Influenza A (H3N2) viruses have been resistant to these older adamantine drugs “rimantidine” and “amantadine” and most rapid influenza tests do not distinguish between human influenza (H1N1 and H3N2) viruses. Thus, unless health care personnel know that there is a very strong predominance of either Influenza A H1N1 or H3N2 in the specific area where an individual patient is likely to have been infected with their specific influenza virus, then it is very difficult to know whether treatment with the older adamantine antiviral drugs “rimantidine” and “amantadine” will be effective.
As a result of the above evolving situation, the CDC issued a “Health Advisory” on December 19th that provided new interim recommendations for the “selection of antiviral treatment using laboratory test results and viral surveillance data”. A useful table is provided that contains four columns:
1): Rapid antigen or other laboratory test results
2) Predominant virus(es) in the community
3) Preferred medication
4) Alternative (combination treatment).
Readers interested in this table summarizing these CDC recommendations can find it at: www.cdc.gov/flu/professionals/antivirals/antiviraltable.htm
An illustrative example taken from this table that emphasizes the need to know from local health departments what influenza viruses are circulating in the community, and the evolving information regarding oseltamvir (Tamiflu) resistance on the part of human influenza A (H1N1) viruses is:
If a rapid influenza test comes back “positive for influenza A”, AND the predominant virus in the community is H1N1 or B, then the preferred medication is “Zanamivir” (Relenza) (an inhaled drug that requires a unique inhaler). The alternative treatment is “oseltamivir + rimantidine” (i.e., because oseltamivir will treat the influenza virus if it is either Influenza A (H3N2) or Influenza B, whereas the rimantidine will treat the virus if it is influenza A (H1N1)).
In sum, the antiviral management of human influenza has now become significantly more complex. One must anticipate that this complexity could in the future become more generally applicable to avian influenza viruses that infect humans.
31 December 2008
Daniel R. Lucey, MD, MPH
FDA Approves Change in Anthrax Vaccine to IM Administration and one less dose PRE-exposure
The US Food and Drug Administration (FDA) announced earlier this month approval of a change in the schedule and route of administration for the already-licensed Anthrax Vaccine (“BioThrax”). Instead of subcutaneous (SQ) administration, the vaccine is now licensed to be given pre-exposure to Bacillus anthracis by the intramuscular (IM) route. Fewer local reactions to the vaccine when given IM were found in a study comparing the SQ and IM routes. The FDA approval letter, dated December 11, is posted on their website at: www.fda.gov/cber/approvltr/biothrax121108L.htm
In addition, the FDA this month also approved giving one fewer dose than previously licensed, and thus five doses instead of six over 18 months. Specifically, the dose at 2 weeks can now be omitted for pre-exposure (not post-exposure) immunization. The newly-licensed schedule is for doses to be given at 0 and 4 weeks, then at 6, 12, and 18 months. (Previously the schedule was for doses to be given at 0, 2, and 4 weeks, and then at 6, 12, and 18 months).
The complete 18-page pdf document describing the updated, revised package insert for the vaccine is posted on the FDA website at:
www.fda.gov/cber/label/biothraxLB.pdf
Of note, this revised vaccine package insert applies to pre-exposure immunization and does not explicitly address post-exposure immunization, except to state that: “The safety and efficacy of BioThrax in a post-exposure setting have not been established” (page 1 of 18).
With regard to safety, the revised package insert states on page 7 of 18 that: “the anlaysis of injection site (local) reactions demonstrated that administration of the vaccine by the IM route, as compared to the SQ route, resulted in a statistically significant reduction in reactogenicity (i.e. cutaneous adverse reactions). Injection site adverse reactions, including warmth, tenderness, itching, erythema, induration, edema, and nodules, consistently occurred at lower frequencies and for shorter duration in participants given BioThrax by the IM route. Route of administration did not statistically significantly influence the occurrence or duration of systemic adverse reactions, with the exception of muscle ache (increased occurrence only).”
The above safety findings, as well as those of immunogenicity, were based on a CDC sponsored, double-blind, prospective randomized, placebo-controlled clinical trial between 2002 and 2008 that is described in detail in this 18-page revised package insert for the anthrax vaccine.
Explicit commentary from the US Department of Health and Human Services (that includes the FDA and CDC) regarding whether this vaccine can be given IM, and at 0, 2, and 4 weeks for POST-exposure prophylaxis against aerosolized spores, is awaited.