Anthrax Crisis Standards of Care

On December 4, the Centers for Disease Control and Prevention (CDC) published Clinical Framework and Medical Countermeasure Use During an Anthrax Mass-Casualty Incident.  The framework provides updated recommendations for anthrax diagnosis and treatment, specifically addressing crisis standards of care.  During a mass-casualty incident involving the dissemination of B. anthracis, demand will quickly exceed available healthcare resources, and the shift to crisis standards of care represents a fundamental change in the way medical care is delivered.  In emergency situations with relatively limited resources, healthcare professionals will need to prioritize allocation of limited time, personnel, medications, medical supplies and equipment to those who stand to benefit most.

The new recommendations build upon the 2014 CDC guidelines for prevention and treatment of anthrax to address situations where increased demand for medical care will exceed available healthcare resources.  The crisis standards of care guidelines, compiled at a March 2014 meeting of 102 subject matter experts, represent evidence-based best practices to efficiently address anthrax mass-casualty scenarios.  The clinical framework addresses four specific decision points in the clinical care of anthrax cases that would likely be impacted by limited resources.

  • Due to the high incidence of meningitis in anthrax patients, the first decision point discusses “diagnostic evaluation of anthrax meningitis” in order to determine the appropriate approach to antimicrobial therapy.
  • The second decision point helps determine appropriate antimicrobial treatment options based on their availability.
  • Considering the significant pathologic effect of B. anthracis exotoxins, the third decision point addresses use of antitoxins as adjuncts to antimicrobial therapy.
  • The fourth decision point covers identifying and draining accumulated pleural, pericardial and peritoneal fluid, which is associated with improved outcomes.

The challenges associated with each decision point and the evidence supporting the associated crisis standards of care are discussed in depth.  In addition to the crisis standards of care, the report provides conventional and contingency standards of care for comparison.  The guidance also addresses the challenges posed by pregnant and lactating women and pediatric cases, determining that both of these types of cases should be considered as high a priority as non-pregnant adults while noting that they will likely require additional monitoring and specialized care.  Finally, the report identifies areas for future research, specifically assessment of potential clinical markers to better assess disease progression in anthrax cases to support clinical care decision-making.

These guidelines provide data-driven recommendations for the dire situation where demand for life-saving therapies exceeds supply.  In the absence of a situation requiring a move to contingency or crisis standards of care, all safe and effective therapies should be used in every patient who could potentially benefit from them, even if the prognosis is relatively poor.  In a situation in which limited supplies of certain medications such as toxin-directed antibodies are insufficient, however, these scarce resources should ideally be reserved for patients who will unequivocally benefit from them.  The guidelines delineate in which situations certain therapeutic actions are appropriate and provide the treating clinician with a framework with which to provide optimal care. 

The new CDC guidance is designed to be used in preparing response protocols for or in responding to the "exhaustion (or impending exhaustion) of the capability to provide conventional standards of care," but it "does not address primary triage decisions, anthrax post-exposure prophylaxis (PEP), hospital bed or workforce surge capacity, or the logistics of dispensing MCMs."  These recommendations highlight that resource deficiencies may not affect all aspects of clinical response simultaneously, so crisis standards of care may be applied to individual aspects of diagnosis and treatment as necessary.  The guidance also caveats that clinical protocols should shift back to conventional standards of care as soon as possible.  

In the event of a mass-casualty anthrax incident, the updated CDC guidance provides clinicians with a standardized methodology for optimizing limited resources to achieve the overall greatest impact on the affected population under sub-optimal conditions. 

On the Department of Defense’s Anthrax Shipments

This week, it was reported that a Department of Defense (DoD) facility has inadvertently shipped samples of live Bacillus anthracis, the causative agent of the disease anthrax. Subsequent updates have indicated that up to 18 domestic laboratories may have received the improperly inactivated samples, intended for use during diagnostic development, from a period between March 2014 and April 2015. Additionally, a sample was sent to Osan Air Base in South Korea, where 22 individuals were apparently exposed during an exercise. An effort to confirm additional at risk receiving facilities and personnel is currently being undertaken, and CDC has been alerted and is conducting an investigation.

This episode comes nearly a year after two separate biosafety lapses at the CDC.  In the first, an improperly inactivated sample of B. anthracis was removed from a high containment laboratory, exposing 67 individuals. In the second, CDC scientists sent a sample of low pathogenic avian influenza H9N2 to a USDA laboratory. This would have been fine, except that it was subsequently discovered that the sample was contaminated with highly pathogenic avian influenza H5N1. See this Science article for good recap of both lapses. This latest incident appears to couple problems with ineffective inactivation with the transport of select agents.

It’s important to note that no infections have been reported as a result of these miscues, and the risk to public health is deemed to be very low at this time. Fortunately, anthrax does not spread by person to person transmission. If a more transmissible pathogen had been involved, the risk to public health would have been increased. A total of 26 individuals have started courses of post-exposure prophylaxis, including all 22 individuals exposed in South Korea. The Center’s Dr. Amesh Adalja has explained why he believes there will not be any infections resulting from this lapse at Tracking Zebra.

Another important point to keep in mind is that, while B. anthracis is a Category A bioterror agent, and regulated under the Federal government’s Biological Select Agent and Toxins program, we have no indication that the agent that was shipped was in any way weaponized. In both cases involving B. anthracis, scientists were engaged in biodefense research. The United States does not operate an offensive biological weapons program, and has not since the Nixon administration. The same cannot be said for every nation on earth. You may well have noticed that a South Korean facility was included in the list of receiving facilities, and might wonder why that might be. The threat posed to our South Korean allies by a suspected North Korean biological weapons program is the most likely explanation.

How could this happen? Before considering systems and scientists, let’s think about the agent in question. In the past, B. anthracis has been considered a candidate for weaponization in part because of its toughness. This ability to persist is due to the spore that covers the exterior of the bacterium, and allows it to survive for long periods in conditions that would have killed other microbes.

That said, a review of the inactivation technology and associated protocols used to render the bacteria inactive at the facility in question is clearly needed. The other alternative is that there was some degree of operator error. While we wait for the facts to emerge, we can be thankful that no one has become ill or died due to these events. Prompt corrective action is needed to ensure that this vital research is conducted in a safe and secure manner.  

Revisiting the Anthrax Attacks 13 years later

It’s been over 13 years since the anthrax attacks of 2001 during which 22 people were infected with the anthrax bacilli (Bacillus anthracis) via mailed letters with 5 succumbing to their illness. This attack was instrumental in fostering government and hospital preparedness for bioterrorist attacks. After a massive investigative effort that basically created the field of microbial forensics, the FBI declared their case to be closed after they identified anthrax expert Dr. Bruce Ivins as the perpetrator. This conclusion was supported by the findings of specific genetic mutations in the anthrax bacilli found in the letters and also in a flask (RMR-1029) managed by Dr. Ivins. However, no charges, trial, or conviction occurred because Dr. Ivins committed suicide.

The FBI’s case against Dr. Ivins, because it relied heavily on sophisticated science, was the subject of a National Academy of Sciences (NAS) review. That review cast doubt on some of the FBI’s scientific findings that formed one of the pillars of their conclusion regarding Dr. Ivins. Aspects of the NAS report which I found particularly compelling include the following finding: “the scientific link between the letter material and flask number RMR-1029 is not as conclusive as stated” and their overarching conclusion that “it is not possible to reach a definitive conclusion about the origins of the B.anthracis in the mailings based on the available scientific evidence alone.”

Now, a new GAO report shares the concerns of the NAS.  Specifically the GAO found that “the FBI's research did not provide a full understanding of the methods and conditions that give rise to genetic mutations used to differentiate between samples of B. anthracis,” “did not institute rigorous controls over the sampling procedures it used to build the repository of B. anthracis samples,” and  “did not include measures of uncertainty to strengthen the interpretation of the scientific evidence.”

The issuance of the GAO report will hopefully provide impetus to implement the final recommendations of the NAS that “a review should be conducted of the classified materials that are relevant…including the material pertaining to the overseas environmental sample collections, “ that “other tools, methods, and approaches available” be used in microbial forensic investigations, and that emphasis be placed on communicating “the goals of forensic science and realistic expectations and limitations regarding its use in the investigation of a biological attack.”