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Anthrax Appraisal 5 Years Later: Top 10 Accomplishments and Remaining Challenges

By the Staff of the Center for Biosecurity, September 22, 2006

September 18 marked the 5-year anniversary of the mailing of the first letter laced with Bacillus anthracis in 2001. Bacillus anthracis was, and remains, the number 1 threat on most lists of bioterrorism agents, and it is the only agent for which vaccines and multiple treatments exist. This anniversary is a good time to take stock of the progress that has and has not been made in improving the capacity of the U.S. public health and medical systems to respond to bioterrorist attacks in general, and to respond to a future attack with anthrax, specifically. Overall, while much progress has been made, there is much left to do. 

Progress—Top 10 Accomplishments of the Past 5 Years

1. Antibiotic stockpile. The strategic national stockpile (SNS) now includes approximately 40 million 60-day courses of doxycycline and ciprofloxacin to be used for post exposure prophylaxis [1].

2. Vaccines stockpile. The Department of Health and Human Services (HHS) has purchased or contracted for 85 million doses of anthrax vaccine. Using a 3-dose regimen, this is enough to vaccinate 28 million people or about 10% of the country’s population. Five million doses of the already licensed anthrax vaccine, AVA [2, 3], have been delivered, and delivery of another 5 million is pending. The other 75 million doses, of a new second generation vaccine based on recombinant protective antigen (rPA) [4], will be delivered in 2009.

3. Immune globulin. In July 2006, the HHS announced that it will purchase 10,000 courses of treatment of anthrax immune globulin (AIG), with delivery set to begin in late 2007. AIG may serve as an adjunct therapy to antibiotics in severely ill persons, and may also be useful in the event of an attack employing anthrax bacteria resistant to antibiotics [5].

4. Antitoxin. In June 2006, the HHS announced that it contracted to purchase 20,000 courses of ABthraxTM, a monoclonal antibody to the protective antigen of B. anthracis, which works by preventing PA from binding to lethal and edema factors and forming toxins. It is believed that most of the morbidity and mortality of anthrax are exerted by the lethal and edema toxins. Once sufficient toxin is released, treating the infection with antibiotics alone may not prevent death. As with AIG, antitoxin may offer hope to patients who are in the later stages of the disease and may be useful to treat patients infected with antibiotic resistant organisms. Product delivery is expected to start in late 2007, with completion by 2009 [6].

5. Improved diagnostic tests. With greater speed and accuracy than was possible 5 years ago, B. anthracis can now be identified from clinical specimens once they submitted to the Laboratory Response Network (LRN). Today, LRN labs can perform rapid screening with PCR- or antigen detection-based assays directly on clinical specimens or on cultures, and can perform confirmatory testing that employs either lysis by gamma-phage or direct fluorescent antibody assay (DFA) [7]. Submission of specimens to the LRN, however, still requires the suspicion of anthrax.

6. BioShield legislation. On July 21, 2004, President Bush signed into law the Project BioShield Act of 2004 (BioShield 1), which is intended to accelerate the research, development, acquisition, and availability of effective medical countermeasures for biological, chemical, radiological, and nuclear agents. Under Bioshield 1, a 10-year, $5.6 billion, discretionary special reserve fund was authorized for the advanced development and purchase of priority medical countermeasures. In addition, BioShield 1 established the Emergency Use Authorization (EUA) process, which, following a Declaration of Emergency by the Secretary of HHS, can be used to provide access to certain medical countermeasures that are available but not yet approved for use by the U.S. Food and Drug Administration and for which no alternative exists. [8]

7. Federal funding of state and local preparedness. Approximately $4 billion has gone to state public health departments as part of the Centers for Disease Control (CDC) bioterrorism program. These funds have allowed heath departments to hire epidemiologists, train staff, develop labs, purchase information technology, conduct planning activities, and support the salaries of state bioterrorism coordinators. Another $2 billion has been spent to fund hospital preparedness through the Health Resource and Services Administration’s (HRSA) National Bioterrorism Hospital Preparedness Program (NBHPP) [9]. And The Department of Homeland Security (DHS) has also funneled billions of dollars to states and cities for first responder preparedness.

8. Bioterrorism awareness and training. Bioterrorism is now acknowledged to be a major strategic national security threat at the highest levels of government, and bioterrorism education has been delivered throughout the response community, to clinical, public health, emergency management, fire, police, and EMS staff. In addition, there have been training drills at all levels focusing on anthrax specific issues. Nevertheless, much of the medical and public health communities remain skeptical about the threat of bioterrorism, and detailed and accurate knowledge of biological agents remains the domain of small, highly specialized groups.

9. Research and development. There has been a significant increase in basic science research and some applied research and development into biodefense in general and anthrax specifically, which has included studies of the microbiology of the organism, the pathogenesis of the disease, vaccines, antitoxins, diagnostics, sensing, and early detection technologies.

10. Communication and information sharing. By implementing the Health Alert Network (HAN), the Clinicians Outreach and Communication Activity (COCA), an emergency preparedness website, and other electronic systems over the past 5 years, the CDC has improved its systems for disseminating information to state health departments, on through to hospitals and individual clinicians. Many states have also improved their communication with the medical community. And several academic centers and other non-governmental organizations have created information sharing listservs and websites that aim to provide current information related to biodefense. The extent to which this information actually reaches the majority of clinicians in a timely fashion is unclear.

What Still Needs to Be Accomplished--The Top 10 Remaining Challenges

1. Improve distribution of the Strategic National Stockpile (SNS). Development of protocols for the request, receipt, breakdown, transport, and distribution of the SNS is the responsibility of each state, and capabilities vary widely. A 2005 report from Trust for America’s Health (TFAH) revealed that only 7 states and 2 cities were recognized by the CDC as adequately prepared to distribute contents of the SNS in the event of an emergency [10]. The SNS is not much good if it can’t be accessed when needed. States and major cities must make this a priority.  

2. Update prophylaxis strategies. In October 2001, the CDC recommended 60 days of ciprofloxacin or doxycycline as the preferred post exposure prophylaxis (PEP) regimens to prevent inhalational anthrax in adults or children [11]. In 2005, the CDC stated that 60 days of selected oral antibiotics in conjunction with a 3-dose regimen of anthrax vaccine (AVA) was the optimal regimen for the prevention of inhalational anthrax in exposed persons [12]. Doxycycline, like other tetracyclines, can cause staining and deformity of teeth in children and in newborns when given to pregnant women. Ciprofloxacin and other fluoroquinolones have caused permanent cartilage damage and arthropathy in immature animals [13]. In addition, both medications have unpleasant side effects, particularly gastrointestinal upset, that can make them difficult to tolerate for extended periods of time, so adherence tends to be poor.

An alternative PEP strategy that combines shorter courses of antibiotics with post exposure vaccination has been tested and proven effective in nonhuman primates [14]. Despite some limitations related to study design and reliance on data derived from an animal disease model, the results suggest that improvements in the current recommendations are possible. This research, with the promise it suggests for a new, safe and tolerable PEP regimen, should be actively pursued.

3. Assure vaccination delivery capability. Now that HHS is stockpiling vaccines, states and localities must demonstrate an ability to open and operate points of distribution (PODs) quickly enough to vaccinate their populations within a few days. This will require training of POD personnel, repeated drilling, and sharing of lessons learned. CDC guidance based on demonstrated best practices may be helpful.  

4. Revise treatment guidelines. The CDC treatment guidelines for patients with inhalational anthrax have not changed since October 2001 and do not yet incorporate the clinical insight gleaned from the 2001 experience of treating patients with anthrax. The guidelines should be revised to include specific combination antibiotic regimens and to address the roles of immune globulin, antitoxin, and pleural drainage [15].

5. Create a doctrine for use of anthrax countermeasures in the SNS. Federal policies related to the SNS remain unclear, such that states, cities, and hospitals have not been given information about how those federal agencies in charge of anthrax countermeasures will allow them to be used in the case of a mass anthrax attack. So we are lacking not just plans for distributing SNS supplies once they are delivered to states, but we also lacking policies that detail the conditions under which those supplies will be released. These policies must be either developed or made public not just so that states, cities and hospitals can plan, but also so that additional needs for the SNS can be determined.

6. Develop rapid diagnostics. Although the LRN has better diagnostic testing tools now, specimens must still be sent off to these labs, which are limited in number. The process, therefore, usually takes a day or more, and is dependent on clinical suspicion of anthrax. We still need rapid and inexpensive tests that can be performed at every hospital—at the point of care. Time is of the essence when treating inhalational anthrax and in detecting a bioterrorist attack. A wait of a day or more for test results could be a wait too long, resulting in unnecessary loss of life.

7. Enact the pending Biodefense and Pandemic Vaccine legislation. Two bills are currently moving through the House and Senate (H.R. 5533 and S. 2564) that would institute a number of needed reforms to the BioShield process. These reforms would enhance the tools available to HHS to develop and purchase   critically needed medicines and vaccines. Most importantly, these bills would create the Biomedical Advanced Research and Development Authority (BARDA) within HHS to manage the development and procurement of new countermeasures. With the coming elections, and the end of the current Congressional session looming, time is running out for passing these critical reforms into law. 

8. Increase health care system capacity to deal with mass casualties. Patients with inhalational anthrax usually require enormous medical resources, including intensive care and ventilatory support [16]. At baseline, intensive care units typically run at full capacity, and on any given day, most ventilators are in use. Thus, the healthcare system’s ability to quickly absorb a large number of critically ill patients is limited, at best. This is as true for a widespread attack with anthrax as it is for an attack with other biological agents, or for a naturally occurring outbreak of a contagious infectious disease, such as pandemic influenza. While HRSA has spent approximately $2 billion on the NBHPP, hospitals’ capacity has not improved significantly over the past 5 years. A national strategy to vastly improve inpatient surge capacity must be implemented.

9. Promote clinical education. While most physicians have heard of anthrax, knowledge is spotty at best, and misconceptions abound. While anecdotal, a recent experience is illustrative: During an internal medicine review course at a leading academic medical center, physicians in attendance were asked to suggest the next most appropriate step in the evaluation of a patient with suspected inhalational anthrax based on signs, symptoms, and epidemiological risk factors:

  • Only 27% of respondents indicated that they would obtain blood cultures, perform a chest CT scan, and admit the patient for intravenous antibiotics, which are essential in treating the disease.
  •  In contrast, 60% indicated that, to screen for exposure to inhalational anthrax, they would perform a nasal culture, an unreliable test that is not recommended. 

Respondents were then asked what they would do if the patient, now with confirmed inhalational anthrax, had coughed on them during the examination:

  • 69% indicated that they would start ciprofloxacin prophylaxis, because they believed anthrax to be contagious. 
  • Only 16% said they would do nothing, which is the correct answer because anthrax cannot be transmitted from person to person. 

This experience suggests that physicians’ knowledge of anthrax is not very deep. We need a national effort, led by medical schools, hospitals, and professional organizations to increase knowledge and awareness throughout the healthcare community so as to increase the number of clinicians who are able to accurately diagnose a suspect case of illness caused by a biological weapon.

10. Develop a health information highway. We need a new network of systems to support a rapid, coordinated, and efficient response to any bioterrorism attack. This network must push information to clinicians about how to find, diagnose, and treat; it must support the electronic exchange of information about patients, which means it has to support use of portable electronic health records (EHRs) and it must support real-time collaborative clinical research, which is needed during a fast spreading disease outbreak to determine which treatments actually are effective. This is especially true if the outbreak is caused by a new pathogen or by one that is genetically modified.   

Conclusion

While a great deal of money has been spent, and much has been accomplished over the past 5 years, preparedness for an anthrax attack remains very much a work in progress. Were another attack with B. anthracis to occur today, even one relatively modest in size, it is unlikely that all of the essential elements of effective medical response--vaccine, prophylactic antibiotics, and intensive care--would be available in sufficient quantity and time to avert illness and death on a large scale. Having some elements in place without others gains us very little. In the end, there is only one measure of success that matters: Can effective countermeasures and care be provided when and where they are needed?

Clearly, there is much left to do. While the federal government is responsible for some of the steps that remain to be taken, much of what remains to be done is the responsibly of state and local governments, hospitals, health departments, and medical schools.

We know what to do, and we have the tools we need to topple anthrax from its position as the number 1 threat among known bioweapons. Let’s not allow another 5 years to pass without doing just that.  After all, history teaches that much can be accomplished in 5 years--it was less than 5 years from Pearl Harbor to the end of WWII.     

References

  1. Testimony of Gerald Parker, Principal Deputy to the Assistant Secretary, Office of Public Health Emergency Preparedness, U.S. Department of HHS on Anthrax Preparedness: HHS Progress before the Committee on Government Reform, Subcommittee on national Security, Emerging Threats and International Relations, U.S. House of Representatives. May 9, 2006. Available at http://www.hhs.gov/asl/testify/t060509a.html. Accessed September 15, 2006.

  2. HHS Awards BioShield Contract for AVA Anthrax Vaccine. HHS news release.  May 6, 2005. Available at http://www.hhs.gov/news/press/2005pres/20050506.html. Accessed September 15, 2006.

  3. HHS Buys Additional AVA Anthrax Vaccine. HHS news release. May 5, 2006.Avilable at http://www.hhs.gov/news/press/2006pres/20060505a.html. Accessed September 15, 2006.

  4. HHS Buys New Anthrax Vaccine for Stockpile. HHS news release. Nov. 4, 2004. Available at http://www.hhs.gov/news/press/2004pres/20041104a.html. Accessed September 15, 2006.

  5. HHS to Acquire Anthrax Immune Globulin for Stockpile. HHS press release. July 28, 2006.avialable at http://www.hhs.gov/news/press/2006pres/20060728.html. Accessed September 15, 2006.

  6. U.S. Government Agrees To Purchase Abthrax™ from Human Genome Sciences for the Strategic National Stockpile. HGS press release. June 20, 2006.Avialabe at http://www.hgsi.com/news/press/06-06-20_ABthrax.htm. Accessed September 15, 2006.

  7. CDC. Anthrax: diagnosis and Evaluation. Available at http://www.bt.cdc.gov/agent/anthrax/diagnosis/. Accessed September 15, 2006.

  8. Meadows M. Project BioShield: Protecting Americans from Terrorism. FDA Consumer magazine. November-December 2004. Available at http://www.fda.gov/fdac/features/2004/604_terror.html. Accessed September 18, 2006.

  9. Lam C, Franco C, Schuler A. Billions for Biodefense: Federal Agency Biodefense Funding, FY2006-FY2007 Biosecurity and Bioterrorism. 2006;4(2). Available at http://www.liebertonline.com/doi/pdf/10.1089/bsp.2006.4.113.  Accessed September 18, 2006.

  10. Ready or Not? Protecting the Public's Health from Disease, Disasters, and Bioterrorism, 2005. Trust for America’s Health. 2006. Available at http://healthyamericans.org/reports/bioterror05/. Accessed September 15, 2006.

  11. Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax. MMWR. November 02, 2001 / 50(43);941-8. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5043a1.htm, accessed September 15, 2006

  12. CDC. Anthrax Q & A: Preventive Therapy. Available at http://www.bt.cdc.gov/agent/anthrax/faq/preventive.asp. Accessed September 15, 2006.

  13. Post exposure anthrax prophylaxis. The Medical Letter on Drugs and Therapeutics. 2001;44. Available at http://www.medletter.com/freedocs/postexpanthrax.pdf #search=%22medical%20letter%20anthrax%20post%20exposure%22.  Accessed September 15, 2006.

  14. Vietri NJ et al. Short-course postexposure antibiotic prophylaxis combined with vaccination protects against experimental inhalational anthrax. PNAS, May 16, 2006; 103(20): 7813-6.

  15. Lucey DR. An Improved Clinical Staging System for Inhalational Anthrax. Clinicians Biosecurity Network. November 8, 2005. Available at http://www.upmc-cbn.org/secure/report_archive/2005/
    11_November_2005/cbnTOPICS_110805.html
    .  Accessed September 15, 2006.

  16. Holty JE, et al. Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005. Annals of Internal Medicine 2006;144:270-280.