Mark G. Kortepeter

Basic Clinical and Laboratory Features of Filoviral Hemorrhagic Fever

The filoviruses Marburg and Ebola cause severe hemorrhagic fever (HF) in humans. Beginning with the 1967 Marburg outbreak, 30 epidemics, isolated cases, and accidental laboratory infections have been described in the medical literature. We reviewed those reports to determine the basic clinical and laboratory features of filoviral HF. The most detailed information was found in descriptions of patients treated in industrialized countries; except for the 2000 outbreak of Ebola Sudan HF in Uganda, reports of epidemics in central Africa provided little controlled or objective clinical data. Other than the case fatality rate, there were no clear differences in the features of the various filovirus infections. This compilation will be of value to medical workers responding to epidemics and to investigators attempting to develop animal models of filoviral HF. By identifying key unanswered questions and gaps in clinical data, it will help guide clinical research in future outbreaks.

Invasive mold infections following combat-related injuries.

BACKGROUND Major advances in combat casualty care have led to increased survival of patients with complex extremity trauma. Invasive fungal wound infections (IFIs) are an uncommon, but increasingly recognized, complication following trauma that require greater understanding of risk factors and clinical findings to reduce morbidity. METHODS The patient population includes US military personnel injured during combat from June 2009 through December 2010. Case definition required wound necrosis on successive debridements with IFI evidence by histopathology and/or microbiology (Candida spp excluded). Case finding and data collected through the Trauma Infectious Disease Outcomes Study utilized trauma registry, hospital records or operative reports, and pathologist review of histopathology specimens. RESULTS A total of 37 cases were identified: proven (angioinvasion, n=20), probable (nonvascular tissue invasion, n=4), and possible (positive fungal culture without histopathological evidence, n=13). In the last quarter surveyed, rates reached 3.5% of trauma admissions. Common findings include blast injury (100%) during foot patrol (92%) occurring in southern Afghanistan (94%) with lower extremity amputation (80%) and large volume blood transfusion (97.2%). Mold isolates were recovered in 83% of cases (order Mucorales, n=16; Aspergillus spp, n=16; Fusarium spp, n=9), commonly with multiple mold species among infected wounds (28%). Clinical outcomes included 3 related deaths (8.1%), frequent debridements (median, 11 cases), and amputation revisions (58%). CONCLUSIONS IFIs are an emerging trauma-related infection leading to significant morbidity. Early identification, using common characteristics of patient injury profile and tissue-based diagnosis, should be accompanied by aggressive surgical and antifungal therapy (liposomal amphotericin B and a broad-spectrum triazole pending mycology results) among patients with suspicious wounds.

Managing Potential Laboratory Exposure to Ebola Virus by Using a Patient Biocontainment Care Unit

One-sentence summary for table of contents: Recommendations are needed for management of potential laboratory exposure to a Biosafety Level 4 pathogen.

Innovative Surveillance Methods for Rapid Detection of Disease Outbreaks and Bioterrorism: Results of an Interagency Workshop on Health Indicator Surveillance

A system designed to rapidly identify an infectious disease outbreak or bioterrorism attack and provide important demographic and geographic information is lacking in most health departments nationwide. The Department of Defense Global Emerging Infections System sponsored a meeting and workshop in May 2000 in which participants discussed prototype systems and developed recommendations for new surveillance systems. The authors provide a summary of the groups findings, including expectations and recommendations for new surveillance systems. The consensus of the group was that a nationally led effort in developing health indicator surveillance methods is needed to promote effective, innovative systems.

Immunization against Potential Biological Warfare Agents

The intentional release of biological agents by belligerents or terrorists is a possibility that has recently attracted increased attention. Law enforcement agencies, military planners, public health officials, and clinicians are gaining an increasing awareness of this potential threat. From a military perspective, an important component of the protective pre-exposure armamentarium against this threat is immunization. In addition, certain vaccines are an accepted component of postexposure prophylaxis against potential bioterrorist threat agents. These vaccines might, therefore, be used to respond to a terrorist attack against civilians. We review the development of vaccines against 10 of the most credible biological threats.

Health Care Response to CCHF in US Soldier and Nosocomial Transmission to Health Care Providers, Germany, 2009

Early recognition and implementation of appropriate infection control measures were effective in preventing further transmission.

Real-time Monitoring of Cardiovascular Function in Rhesus Macaques Infected With Zaire ebolavirus

Nine rhesus macaques were implanted with multisensor telemetry devices and internal jugular vein catheters before being infected with Zaire ebolavirus. All animals developed viremia, fever, a hemorrhagic rash, and typical changes of Ebola hemorrhagic fever in clinical laboratory tests. Three macaques unexpectedly survived this usually lethal disease, making it possible to compare physiological parameters in lethally challenged animals and survivors. After the onset of fever, lethal illness was characterized by a decline in mean arterial blood pressure, an increase in pulse and respiratory rate, lactic acidosis, and renal failure. Survivors showed less pronounced change in these parameters. Four macaques were randomized to receive supplemental volumes of intravenous normal saline when they became hypotensive. Although those animals had less severe renal compromise, no apparent survival benefit was observed. This is the first report of continuous physiologic monitoring in filovirus-infected nonhuman primates and the first to attempt cardiovascular support with intravenous fluids.

Necrotizing Scleritis, Conjunctivitis, and Other Pathologic Findings in the Left Eye and Brain of an Ebola Virus–Infected Rhesus Macaque (Macaca mulatta) With Apparent Recovery and a Delayed Time of Death

A 3.5-year-old adult female rhesus macaque (Macaca mulatta) manifested swelling of the left upper eyelid and conjunctiva and a decline in clinical condition 18 days following intramuscular challenge with Ebola virus (EBOV; Kikwit-1995), after apparent clinical recovery. Histologic lesions with strong EBOV antigen staining were noted in the left eye (scleritis, conjunctivitis, and peri-optic neuritis), brain (choriomeningoencephalitis), stomach, proximal duodenum, and pancreas. Spleen, liver, and adrenal glands, common targets for acute infection, appeared histologically normal with no evidence of EBOV immunoreactivity. These findings may provide important insight for understanding sequelae seen in West African survivors of Ebola virus disease.

Caring for patients with Ebola: a challenge in any care facility

The largest outbreak of Ebola virus continues unabated in West Africa. With the recent death of a patient with Ebola virus disease at a hospital in Dallas, Texas, and the sobering reality that nosocomial spread has occurred in a U.S. facility, U.S. medical centers are coming to grips with the need to prepare for care of patients with this devastating disease. The Centers for Disease Control and Prevention has developed a hospital preparedness checklist, and the latest guidelines continue to express confidence that patients with Ebola can be cared for safely in a conventional medical facility by using barrier methods (standard, contact, and droplet precautions) as the primary means of protecting medical staff (1, 2). Recent experience with several Ebola-infected patients in the United States provides validation that such patients can be cared for safely in a facility that is adequately prepared. Since the first reported outbreaks of Marburg (1967) and Ebola (1976), there has been an evolution in our thinking about the optimal personal protective measures for medical staff caring for patients infected with these viruses. From 1972 to 2010, a high-level containment care (HLCC) unit at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), often called the slammer, was considered the gold standard for such care. The units engineering controls were modeled after a biosafety level4 (BSL-4) laboratory, with positive-pressure space suits, compressed in-line air, HEPA filtration, a decontamination shower, ultraviolet light pass boxes, an airlock, and antiseptic dunk tanks for movement of items in and out of the containment area. Toilet waste was discharged into the laboratory sewer system, and the facility possessed its own autoclave, operating room, and bedside laboratory. These built-in capabilities significantly reduced logistics challenges and provided reassurance that nosocomial spread could be reduced to near zero. Given the relatively high percentage of caregivers who have died of filoviral and other BSL-4 virus infections in the field, and the prior uncertainty in whether such high infection rates might be caused by droplet or airborne spread, utilization of such a containment facility seemed reasonable. Although used on occasion to quarantine field workers potentially exposed to highly hazardous viruses, the unit was used primarily for isolating individuals exposed to a BSL-4 virus in the laboratory. During the units 38 years of operation, 21 patients were quarantined after potential exposuresand none became ill (3). Over time, we learned that the spread of filoviruses occurs primarily by direct contact with blood and body fluids (1). Thus, it was determined that a patient care facility with the full panoply of BSL-4 laboratorylike features was no longer needed. The facility was decommissioned and refurbished as a training facility for scientists working in the institutes containment laboratories. If the USAMRIID HLCC is no longer needed because patients with filoviruses may be managed safely using barrier methods, one might ask whether any HLCC or biocontainment patient facilities are needed at all (4). Currently, 4 such facilities exist in the United States, operating at a higher level of containment (and possessing more sophisticated engineering controls) than a conventional hospital isolation room but lacking some BSL-4 features present in the USAMRIID HLCC: Emory University Hospital, Atlanta, Georgia; University of Nebraska Medical Center, Omaha, Nebraska; Saint Patricks Hospital, Missoula, Montana; and the National Institutes of Health Clinical Center, Bethesda, Maryland. All except the University of Nebraska serve as referral centers for laboratories that work with BSL-4 viruses. Although patients infected with such diseases as Lassa and Marburg have been safely managed in conventional settings, the serious nature of filoviral and arenaviral infections, their rarity and unfamiliarity to clinicians in developed settings, the lack of effective treatments and vaccines, their propensity to infect health care staff, and the infection control challenges they present argue for, in our opinion, specialized containment and treatment facilities. As many medical centers are no doubt learning in their preparation drills, caring for patients with filovirus and arenavirus infections in a conventional setting presents enormous challenges (5), many of which can be mitigated through the use of specialized facilities with highly trained staff practiced in the nuanced art of safely delivering HLCC. However, even in such facilities, it is impossible to completely engineer out human error, eliminate the risk for sharps or needlestick injury, or prevent inadvertent contact contamination. Care for such patients in a conventional setting, therefore, is more than checklists and standard operating procedures. The training, policies, procedures, and logistics necessary for the provision of such care are significant, cannot be assumed, are optimally in place well in advance of actual need, and must be continually reinforced through repetitious training. Every piece of the care continuum must be well-choreographed with significant attention to detail. At a minimum, preparations must be made for patient entry and movement pathways, optimal patient location and access control, safe donning and doffing of personal protective equipment (PPE), handling and testing laboratory specimens, disposal of significant volumes of waste, safe and unexpected cleanup of spills and bodily waste, and minimizing use of sharps. Donning and doffing PPE need to be regimented and monitored, with plans in place for peer policing. Lapses inevitably occur in infection control routines in conventional medical settings, but once a patient enters the facility, there is no margin for error. Significant risk for infection control errors occurs especially during doffing potentially contaminated PPE (6). While the physical features of high-containment isolation units like that previously housed at USAMRIID (3) are formidable, low-tech measures, such as checklists and the use of doffing partners, may be as important to optimizing the safety of health care workers, whether in an HLCC unit or in a conventional facility. Owing to the very limited number of existing HLCC beds and the fact that patients with highly contagious diseases can present unannounced, conventional facilities may be required to triage these patients and even provide definitive care, despite the enormous challenges they would inevitably face. Immediate and thorough preparation is thus imperative. Despite this necessary reliance on conventional facilities, we recognize the challenges inherent in maintaining a high nationwide state of readiness over the long term. Hence, we envision the need for a network of strategically located regional referral centers serving designated catchment areas tied to BSL-4 laboratories or airport quarantine stations. As such, transport of patients to these referral centers would constitute the preferred clinical option (4). These units would be associated with major medical centers and provide day-to-day routine care, but they would have the capability for rapid conversion to an HLCC unit without adversely affecting their primary activities. These could serve as national resources, coordinated through the Department of Health and Human Services and Centers for Disease Control and Prevention, with certification (much like trauma centers) to provide a higher level of care. As such, their focus would be on continuous preparation for the next emerging outbreak.

Management guidelines for laboratory exposures to agents of bioterrorism.

Over the past several years, funding for biodefense research has increased dramatically, leading to the possibility of increased laboratory-acquired infections with potential bioterrorism agents. The Special Immunizations Program at United States Army Medical Research Institute of Infectious Diseases reviewed its policy and management of potential occupational exposures (1989–2002) to assess guidelines for determining the risk of exposure and disease and to determine criteria for initiating postexposure prophylaxis (PEP). Initiating antibiotic PEP was based primarily on exposure risk but was also influenced by vaccination status and agent virulence. PEP was given to nearly all moderate- and high-risk bacterial exposures, regardless of vaccination status, to most unvaccinated and subsets of vaccinated minimal-risk exposures, but generally not to negligible-risk exposures. Algorithms for evaluating and managing potential exposures are presented to provide guidance to other agencies as they begin to work with these agents.