Viral Hemorrhagic Fevers

Terrorism WHAT CLINICIANS and NEED TO Disaster KNOW

Sponsored for CME Credit by Rush University Medical Center

Release Date: April 1, 2005 Expiration Date: March 31, 2007 errorism WHAT T CLINICIANS and NEED TO Disaster KNOW

SERIES Uniformed Services University Guest Faculty EDITORS Health Sciences Ronald E. Goans, PhD, MD, MPH* Bethesda, Maryland Clinical Associate Professor Rush University Tulane University School of Public Health & David M. Benedek, MD, LTC, MC, USA Medical Center Tropical Medicine Associate Professor of Psychiatry Chicago, Illinois New Orleans, LA Stephanie R. Black, MD* Steven J. Durning, MD, Maj, USAF, MC* Sunita Hanjura, MD* Assistant Professor of Medicine Associate Professor of Medicine Rockville Internal Medicine Group Section of Infectious Diseases Rockville, MD Department of Internal Medicine Thomas A. Grieger, MD, CAPT, MC, USN* Associate Professor of Psychiatry Niranjan Kanesa-Thasan, MD, MTMH* Daniel Levin, MD* Associate Professor of Military & Director, Medical Affairs & Pharmacovigilance Assistant Professor Emergency Medicine Acambis General Psychiatry Residency Director Assistant Chair of Psychiatry for Graduate Cambridge, MA Department of Psychiatry & Continuing Education Jennifer C. Thompson, MD, MPH, FACP* Gillian S. Gibbs, MPH* Molly J. Hall, MD, Col, USAF, MC, FS* Chief, Department of Clinical Investigation Project Coordinator Assistant Chair & Associate Professor William Beaumont Army Medical Center Center of Excellence for Bioterrorism Department of Psychiatry El Paso, TX Preparedness Derrick Hamaoka, MD, Capt, USAF, MC, FS* Faculty Disclosure Policy Linnea S. Hauge, PhD* Director, Third Year Clerkship It is the policy of the Rush University Medical Educational Specialist Instructor of Psychiatry Department of General Surgery Center Office of Continuing Medical Paul A. Hemmer, MD, MPH, Lt Col, USAF, MC* Education to ensure that its CME activities Associate Professor of Medicine are independent, free of commercial bias AUTHORS and beyond the control of persons or organi- Rush University Benjamin W. Jordan, MD, CDR, MC, USNR, FS* zations with an economic interest in influ- Assistant Professor of Psychiatry encing the content of CME. Everyone who Medical Center is in a position to control the content of an Chicago, Illinois James M. Madsen, MD, MPH, COL, MC-FS, USA* educational activity must disclose all relevant Stephanie R. Black, MD* Associate Professor of Preventive Medicine financial relationships with any commercial Assistant Professor of Medicine and Biometrics interest (including but not limited to pharma- Section of Infectious Diseases Scientific Advisor, Chemical Casualty Care ceutical companies, biomedical device manu- Department of Internal Medicine Division, US Army Medical Research Institute facturers, or other corporations whose prod- of Clinical Defense (USAMRICD), APG-EA ucts or services are related to the subject Daniel Levin, MD* matter of the presentation topic) within the Assistant Professor Deborah Omori, MD, MPH, FACP, COL, MC, USA* Associate Professor of Medicine preceding 12 months If there are relation- General Psychiatry Residency Director ships that create a conflict of interest, these Department of Psychiatry Michael J. Roy, MD, MPH, FACP, LTC, MC* must be resolved by the CME Course Associate Professor of Medicine Director in consultation with the Office of Director, Division of Internal Medicine Continuing Medical Education prior to the participation of the faculty member in the Jamie Waselenko, MD, FACP** development or presentation of course Assistant Professor of Medicine content. Assistant Chief, Hematology/Oncology Walter Reed Army Medical Center Washington, DC * Faculty member has nothing to disclose. **Faculty disclosure: CBCE Speaker’s Core for SuperGen. Viral Hemorrhagic Fevers

CASE AUTHORS: Steven J. Durning, MD, Maj, USAF, MC Michael J. Roy, MD, MPH, FACP, LTC, MC

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CME credits are available free of charge through March 2007. DISCLAIMER This project was funded by the Metropolitan Chicago Healthcare Council (MCHC) through a grant from the Health Resources and Services Administration (HRSA). The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as representing the opinion of Rush University Medical Center, the Department of the Army, Department of the Navy, Department of the Air Force, Department of Defense, MCHC or HRSA.

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1 Viral Hemorrhagic Fevers

CASE AUTHORS: Steven J. Durning, MD, Maj, USAF, MC Michael J. Roy, MD, MPH, FACP, LTC, MC

INTENDED AUDIENCE Internal medicine, family medicine, and emergency medicine physicians, and other clinicians who will provide evaluation and care in the aftermath of a terrorist attack or other public health disaster

EDUCATIONAL OBJECTIVES Upon completion of this case, participants will be able to: • Describe the natural and intentional sources of transmission and spread of viral hemorrhagic fevers (VHF), including use as a biologic weapon. • Discuss the initial presentation and clinical manifestations of VHF, including methods for confirming this diagnosis. • Outline important strategies for infection control for healthcare workers caring for patients with cases of suspected VHF. • Describe processes for communication with public health authorities and media about VHF. • Describe the current recommended therapy for patients with VHF.

CASE HISTORY A 32-year-old newspaper reporter with no significant past medical history presents to your office complaining of a 2-day history of fevers, diffuse myalgias, and severe pharyngitis. He also complains of vomiting and bloody diarrhea that began this morn- ing. On physical examination, his vitals are T=102.8˚F, BP=100/80, HR=80, RR=15. He has marked edema of the posterior pharynx, as well as a nonpruritic maculopapular eruption over his chest and back. He has not had recent travel overseas, exposure to pets, or recent outdoor recreational activities. He received an influenza vaccination earlier this year. He states that two of his coworkers have been absent from work and had been referred by the Tribune’s health insurance provider to your office for evaluation. Two of your practice partners confirm that recently they each have seen a worker from the Tribune who presented with fevers, diffuse myalgias, and pharyngitis. One patient was a 40-year-old editor with a history of diabetes. Her most prominent findings on presentation were conjunctivitis, facial flushing, and new onset of nondependent edema. Initially, she was sent home with close follow-up. The other

2 patient was a 24-year-old photographer whose examination was remarkable for hypotension, relative bradycardia, somnolence, oropharyngeal bleeding, and petechiae over his chest and abdomen. He was transferred to a nearby hospital immediately. Like your patient, neither of these 2 people reported other sick contacts, overseas travel, exposure to unusual pets, or recent outdoor recreational activities. They also all reported receiving their annual influenza vaccination.

QUESTION 1 You are called to the emergency room to evaluate a patient with suspected Ebola virus infection. The presence of which of the following should raise concern regarding a potential bioterrorism-related outbreak? a. No history of travel to Africa b. News of an outbreak of pharyngitis among local children on a school trip c. Temporal cluster of patients presenting with fever and increased vascular permeability on examination d. Abrupt onset of fever and signs of increased vascular permeability on exam e. a and c only

Reminder: You can find the Answer Key & Discussion on page 9.

COMMENT: This case vividly illustrates the varying typical presentations of Ebola or Marburg hemorrhagic fever syndrome, two of the several etiologies of VHF.The VHF agents are a diverse group of RNA viruses that present with common clinical characteristics known as the VHF syndrome. The Ebola and Marburg viruses are specific etiologies of VHF in humans (see Table 1). VHF syndrome can manifest as an acute febrile illness similar to influenza (characterized by prominent nonspecific findings such as malaise, myalgias, and prostration), but patients with VHF are also at risk for virus-induced endothelial damage that increases vascular permeability. Early signs of this process may include conjunctival injection, flushing, and petechiae or ecchymoses; later signs of vascular permeability include hypotension, shock, or disseminated intravascular coagulation (DIC). VHF should be suspected in any patient presenting with a febrile illness accompanied by evidence of vascular involvement (ie, flushing, nondependent edema, hypotension, petechiae, and/or hemorrhagic diathesis), who has traveled to an area where a hemorrhagic fever virus is known to circulate (see Table 1) and/or where evidence suggests a possible bioterrorism-related outbreak. In this case, the near simultaneous presentation of 3 individuals who work in close proximity and lack other likely etiologies for their symptoms should immediately raise the possibility of a bioterrorism-induced outbreak. This concern should be further heightened given their work in the media environment, which was targeted in the anthrax attacks in the fall of 2001. The Filovirus hemorrhagic fevers, Marburg and Ebola, share similar pathologic and clinical features and have specific findings that facilitate their differentiation from other forms of VHF. Ebola virus, named after a small river in northwest Zaire, is morphologically similar to, but antigenically distinct from, Marburg virus, which is named after the city in Germany where it was first identified. These two viruses cause necrosis of parenchymal cells in the liver, spleen, lung, kidney, skin, testes and other organs. Highly suggestive findings of Filovirus hemorrhagic fever include severe posterior pharyngeal edema that can cause dysphagia or dyspnea, and an evanescent nonpruritic maculopapular rash that is fol- lowed by desquamation of the affected skin.2 Previous case reports and experiments in primates have shown that neutrophilia, lymphopenia, and abnormalities of platelet number (thrombocytopenia) and function often occur early in the illness.5,6 Evidence suggests that lymphopenia is due to early virus- induced apoptosis, while thrombocytopenia is often a manifestation of DIC that can occur with Ebola

3 and Marburg hemorrhagic fever. Anemia may also be seen in the setting of DIC, however, the hemoglobin is usually normal on presentation; hemoglobin may alternatively be increased in the presence of concurrent dehydration. Elevated liver transaminase levels, with AST greater than ALT, are common.5 Proteinuria has also been reported with these agents and typically occurs early in the course of disease. Several subtypes of Ebola virus have been identified, and all but one have originated in Africa and been highly pathogenic to humans (case lethality rates up to 88%). Devastating outbreaks of Ebola were documented in central Africa in 1976. A U.S. Army SWAT team was called in to quell a 1989 outbreak in a laboratory in Reston, Virginia that was traced to monkeys imported from the Philippines for research purposes — an event that was described so compellingly by Richard Preston in his book, The Hot Zone.7 There have been numerous cases of Ebola in Gabon and the Republic of Congo in recent years, attributed to handling infected gorilla, chimpanzee, or duiker carcasses.8 The initial Marburg virus outbreak was traced to monkeys imported from Uganda. Marburg hemorrhagic fever has subse- quently been reported in South Africa and Kenya. The natural reservoirs of Ebola and Marburg viruses have not been determined.8 The differential diagnosis of VHF is quite extensive and includes other infections associated with fever, rash, and hemorrhage such as falciparum malaria, acute African trypanosomiasis, typhoid fever, lep- tospirosis, pneumonic plague, and bacterial septicemia.

You obtain the following lab results for your patient:

Complete blood count: WBC=2,000/mm3, hemoglobin=15.1gm/dL, platelets=100,000/mm3.

Serum chemistries: Sodium=141mEq/L, potassium=4.0mEq/L, chloride=100mEq/L, bicarbonate=20mEq/L, BUN=22mg/dL, creatinine=1.1mg/dL.

Liver panel: AST=80U/L, ALT=60U/L, albumin=4.1mg/dL, total bilirubin=1.5mg/dL Alkaline phosphatase=100U/L.

Urinalysis: 1+ protein with 0 RBCs, 0 WBCs, and no sediment findings.

Similar laboratory findings were present in his two coworkers, and the one who was sent to the hospital also had schistocytes on his peripheral blood smear, indicative of DIC.

QUESTION 2 Given these laboratory findings, what is the most appropriate next step? a. Send the patient home and advise him to drink plenty of fluids. b. Contact local public health officers due to concern for a potential bioterrorism-induced outbreak, and admit to hospital. c. Arrange for immediate air transport to a nearest tertiary care hospital and contact local public health officers. d. Administer an empiric course of doxycycline.

4 Table 1. Recognized Causes of VHF in Humans*

Virus Genera Disease Natural Distribution Vector/Exposure Incubation Period (days) Arenavirus Lassa fever Africa Rodent‡ 5-16 Argentine HF† South America Rodent 7-14 Bolivian HF South America Rodent 9-15 Brazilian HF South America Rodent 7-14 Venezuelen HF South America Rodent 7-14

Phlebovirus Rift Valley fever Africa Mosquito§ 2-5

Nairovirus Crimean-Congo HF Europe, Asia, Africa Tick 3-12

Hantavirus Hantavirus Renal Asia, Europe, likely Rodent 9-35 syndrome worldwide Hantavirus Pulmonary North & South Rodent 3-28 Syndrome America

Filovirus Marburg Africa Unknown¶ 3-16 Ebola Africa Unknown¶ 2-21 Exposure to Carcasses#

Flavivirus Yellow fever Africa, South America Mosquito 3-6 Dengue HF Asia, Americas, Mosquito Unknown Africa Kyasanur Forest disease India Tick 3-8 Omsk HF States of the Tick** 3-8 former Soviet Union

* Data from Jahrling 1, Isaacson2, Rigquelme3, and Peters4. † HF = Hemorrhagic Fever ‡ Nosocomial transmission is a less likely source of human infection than the listed vector. § Domestic animal slaughter is a less likely source of human infection than the listed vector.  Domestic animal slaughter and nosocomial transmission are less likely sources of human infection than the listed vector. ¶ Nosocomial transmission is uncommon. # Gorilla, chimpanzee, or duiker carcasses **Muskrat contaminated water is a less likely source of human infection than the listed vector.

The local health department instructs you to place the patient in isolation while wait- ing for a mobile laboratory that will be sent from the Centers for Disease Control and Prevention (CDC) to assist with handling of blood and body fluid specimens from the patient.

QUESTION 3 Which of the following is not an accepted means to confirm the diagnosis of Ebola or Marburg virus? a. Demonstrating IgM or a 4-fold rise in IgG antibodies titers for the virus b. Electron microscopy c. Viral isolation d. Reverse transcriptase polymerase chain reaction (RT-PCR) assay e. Toxin isolation

5 COMMENT: Biosafety Level 4 (BSL-4) is required for laboratory work with dangerous and exotic agents of VHF, such as Ebola, Marburg, Rift Valley Fever, and hantavirus, because these viruses pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease. Laboratory personnel should be verbally notified that VHF is a diagnostic consideration, and specimens should remain in the custody of a designated individual until testing is completed. Laboratory staff that work under this Biosafety Level have specific and thorough training in handling extremely hazardous infectious agents; they also understand the primary and secondary containment functions of the standard and special practices, the containment equipment, and the laboratory design characteristics. BSL-4 lab- oratories are typically located within a dedicated, specially structured building, or in the instance of a laboratory building that is used for other investigations, within a controlled area which is completely isolated from all other areas of the building. Entry into a BSL-4 area is through an airlock fitted with airtight doors. Personnel who enter a BSL-4 area wear a one-piece positive pressure suit that is venti- lated by a life-support system protected by HEPA filtration. A chemical shower is provided to decontam- inate the surface of the suit before the worker leaves the area. All suspected cases of infection with VHF should be reported immediately to local and state health departments and to the CDC. The CDC can be contacted 24 hours a day by calling the emergency response hotline at 770-488-7100. Specimens for virus-specific diagnostic testing should be sent to the CDC as rapidly as possible, following CDC instructions. Given the potential for spread with contact with blood, laboratory testing should be kept to the minimum required for the immediate care of the patient until a mobile CDC laboratory arrives. Further, all specimens submitted to the laboratory should be labeled as biohazardous material.

QUESTION 4 Given your high clinical suspicion of Filovirus hemorrhagic fever, you place the patient in isolation as instructed by the local public health official and the CDC. Which of the following isolation precautions should be instituted? a. Place the patient in a private room; universal precautions for hospital personnel b. Place the patient in a private room with negative pressure; barrier precautions for hospital personnel c. Place the patient in a private room with negative pressure; Biosafety Level 4 for hospital personnel d. Transfer the patient to the CDC mobile unit as soon as possible; Biosafety Level 4 for all contacts

COMMENT: As the Filovirus hemorrhagic fevers are lipid containing RNA viruses, they are readily inactivated by disinfectant solutions to include 0.5% sodium hypochlorite, glutaraldehyde, and phenolic disinfectants. Likewise, soaps and detergents also induce viral inactivation and thus should be used liberally. Further, patients with Filovirus hemorrhagic fever should use a chemical toilet, by autoclaving or treating with several ounces of bleach for more than 5 minutes,5 before flushing or disposing in a drain connected to a sanitary sewer. Disinfectant solution should also be copiously applied to the outer surface of airtight bags for all materials used by the patient (such as disposable linen and pajamas), disposable items worn by caretakers, and the outside and inside of containers in the patient’s room, such as disposable sharps containers. If available, an anteroom for putting on and removing protective clothing is useful.5

6 If an individual is exposed to potentially infected material (eg, through an injection or a cut on the hand) the individual should immediately wash the affected area of the skin, apply a disinfectant solu- INFECTION CONTROL tion, and notify the VHF patient’s physician. These individuals should be considered high-risk contacts PRECAUTIONS and placed on surveillance. WITH SYMPTOMATIC Spills of potentially contaminated fluids should be liberally covered with disinfectant and left to soak VHF PATIENTS for a minimum of 30 minutes.5 The contaminated area should then be wiped up with an absorbent • Patient placed in private negative material that is likewise soaked in disinfectant. pressure room (with an anteroom, if available) QUESTION 5 • Caretakers of patient use barrier Your patient expresses concern for his family. He has a 10-year-old son and his precautions: gloves, gowns, N-95 wife is 20 weeks pregnant. He reports that they are both feeling well, with no masks, eye protection, leg covers, symptoms of illness. What should you do regarding his family’s care? shoe covers a. Isolate both his wife and 10-year-old son • Disinfectant solution applied to outer surface of airtight bags for b. Isolate his wife all materials used by the patient, c. Conduct daily medical surveillance of family members without isolating them disposable items worn by caretak- d. Admit his wife and son to the hospital ers, and the outside and inside of containers in the patient’s room • Mark all patient blood and/or other body fluid specimens as COMMENT: The levels of contact risk are summarized in Table 2, and details on the definitions of biohazards contact risk are as follows: • Face shields or masks with eye 1. Casual contacts protection should be worn to Persons who have remote contact with the suspected case of VHF. Individuals in this category include prevent contact with blood, body people who sat next to the suspected case of VHF on the bus or metro, stayed in the same hotel as the fluids, or respiratory secretions suspected case, or shopped in the same mall as the suspected case. Since the agents of VHF are not that may be rendered airborne spread by such casual contact, no special surveillance is indicated. by coughing or sneezing 2. Close contacts Persons who have more than casual contact with the patient. Close contacts include persons living with the patient, those caring for the patient (eg, nurses, physicians), and/or those who have shook hands with or hugged the patient. State and local health departments should identify close contacts as soon as VHF is considered to be a likely diagnosis. Once the diagnosis of VHF is confirmed, close contacts should be placed under surveillance. This requires close contacts to record their temperature twice daily and report any temperature over 101˚F or any symptom of illness. Surveillance should be continued for 3 weeks after the person’s last contact with the index case. If a fever ≥101˚F and/or symptoms of illness develop, the patient should be immediately placed in isolation and treated as a VHF patient.5 3. High-risk contacts High-risk contacts are individuals who have had mucous membrane contact with the patient, such as kissing or sexual intercourse, or have had a needlestick or other penetrating injury involving contact with the patient’s blood and/or other body fluids. These patients should be placed under surveillance as soon as VHF is considered a likely diagnosis in the index case. Again, if a high-risk contact develops fever ≥101˚F and/or other symptoms of illness, the patient should be immediately placed in isolation and treated as a VHF patient.5

7 Table 2. Risk Categories for Contacts of Patients With VHF* MANAGING PUBLIC FEAR Risk Category Description Surveillance† Casual contacts Remote contact with index case, VHF not spread by casual contact, It is important to clearly convey risk eg, stayed in same hotel no special surveillance required categories to the lay press once an outbreak is identified due to the Close contacts More than casual contact, eg, living Place under surveillance once index heightened concern and possible with contact caretaker, shook hands case is confirmed fear that can be connected with the with contact identification of VHF. It is also important to discuss these categories to High-risk contacts Mucous membrane contact, eg, kissing, Place under surveillance as soon as educate the public regarding risk and or penetrating injury involving contract consider diagnosis of VHF in index case to prevent rumors. The media can with index case’s blood (needlestick) also be used to provide emergency *CDC Update: Management of patients with suspected viral hemorrhagic fever—United States5 information about personal protec- †Surveillance should be continued for 3 weeks after the person’s last contact with the index case. If a fever > tion or evacuation. Ongoing com- 101˚F and/or symptoms of illness develop, the patient should be immediately placed in isolation and treated as a munication with the media is neces- VHF patient. sary. Establishing and maintaining good relations with the media and identifying internal media liaisons should be part of hospital and public QUESTION 6 health center disaster preparedness The CDC mobile laboratory calls you because they have confirmed a diagnosis plans. of Ebola virus. Which of the following statements best describes the current therapy for Ebola virus? a. Supportive care only b. Supportive care + ribavirin c. Supportive care + immunoglobulin d. Supportive care + vaccine

COMMENT: Treatment of Ebola virus is supportive, as there is currently no definitive treatment for Ebola virus. Aspirin and other antiplatelet agents or anti-clotting factor drugs should be avoided, as they may potentiate hemorrhage. Secondary bacterial infections are relatively common and should be aggressively sought and treated. Intravenous lines, catheters, and other invasive techniques should be avoided unless clearly indicated given the concern of diffuse hemorrhage. The diffuse nature of vascular involvement often leads to multi-system organ failure. The management of bleeding in VHF patients is controversial. Uncontrolled observations support administration of fresh frozen plasma, clotting factor concentrates, and platelets. Corticosteroids may be helpful, but remain an untested modality for treating shock due to Ebola virus.1 Patients with hypotension and shock, due to advanced capillary leak syndrome, often respond poorly to fluid resusci- tation and develop pulmonary edema. Judicious use of saline solution and consideration of dopamine may be helpful for persistent hypotension. Alpha-adrenergic agents have not been shown to be helpful except in rare cases when emergent intervention to treat refractory hypotension is needed. Ribavirin is ineffective against the Filoviruses. Immunoglobulin therapy for experimental animals infected with Ebola virus has been disappointing. In a small, uncontrolled trial, transfusion of blood from patients convalescing from Ebola virus infection resulted in a markedly lower case fatality rate (13%) among 8 transfused patients in comparison with the overall case fatality rate of 80% during a 1995 epidemic; however these patients were transfused late in the course of their illness, when they may well have survived without the transfusion.

8 There are no current vaccines available against Ebola virus, however two recent vaccine candidates raise great hope. The first is a DNA-based vaccine, and the second is a harmless Ebola virus-like particle (VLP); they have been shown to evoke good humoral and cellular response, and are now in Phase 3 human studies.9,10 Yellow fever virus is the only VHF for which vaccine is available. Yellow fever is endemic in Africa and South America and vaccination should be considered before traveling to these regions. A vaccine has been licensed in the Republic of Korea for Korean Hemorrhagic Fever, and investigational vaccines are being studied for other VHF. CASE CONCLUSION The 3 patients described in this case scenario survived with aggressive supportive care. They had no physical long-term sequelae due to their illness.

ANSWER KEY & DISCUSSION QUESTION 1 You are called to the emergency room to evaluate a patient with suspected Ebola virus infection. The presence of which of the following should raise concern regarding a potential bioterrorism-related outbreak? a. No history of travel to Africa b. News of an outbreak of pharyngitis among local children on a school trip c. Cluster of patients presenting with fever and increased vascular permeability on examination d. Abrupt onset of fever and signs of increased vascular permeability on exam e. a and c only

ANSWER: The correct answer is e. Given the fact that this patient has not traveled to a region where the Ebola virus is endemic, and that there is a cluster of people presenting with similar symptoms, the possibility of a bioterrorism attack should be considered and the local health department should be notified immediately according to your emergency preparedness and disaster plan.

QUESTION 2 Given these laboratory findings, what is the most appropriate next step? a. Send the patient home and advise him to drink plenty of fluids b. Contact local public health officers due to concern for a potential bioterrorism-induced outbreak, and admit to hospital c. Arrange for immediate air transport to a nearest tertiary care hospital and contact local public health officers d. Administer an empiric course of doxycycline

ANSWER: The correct answer is b. As previously discussed, this patient’s presentation is consistent with VHF syndrome. You also have reasonable evidence that 2 close contacts may have the same illness. Given that this patient and his coworkers have neither a history of travel to an area endemic for VHF or exposure to exotic animals, you should be very concerned that this may represent the deliberate dissemination of VHF. Given the prominent rash and pharyngeal findings on physical examination, you should be particularly concerned about an Ebola or Marburg virus or Lassa fever outbreak. Therefore, you should contact local public health officials immediately.

9 VHF agents are characteristically stable viruses that are highly infectious fine-particle aerosols. Sending the patient home may lead to further spread of VHF to close contacts. Unnecessary transport should be avoided in patients where the diagnosis of VHF is suspected. In particular, air transport should be avoided since changes in ambient pressure with flight can further damage fragile capillary beds, result- ing in pulmonary hemorrhage. Doxycycline is not effective therapy for VHF and may exacerbate the alterations in liver function tests.

ANSWER: The correct answer is e. Scientists have not developed an assay to detect toxin proteins in Ebola or Marburg virus infections to date. Choices a-d are all acceptable means for making a diagnosis of Marburg or Ebola virus, and each of these tests will discriminate between the two Filovirus hemorrhagic fevers. Appropriate precautions should be observed in collection, handling, shipping, and processing of blood and/or other body fluid diagnostic samples. Due to the potential risks associated with handling these infectious materials, laboratory testing should be the minimum necessary for diagnostic evaluation and patient care. Clinical laboratory specimens should be placed in plastic bags that are sealed, and then transported in clearly labeled (as biohazardous material) durable, leakproof containers directly to the specimen handling area of the laboratory. Care should be taken not to contami- nate the external surfaces of the container.5 Viral isolation should not be attempted without maximum Biosafety Level (BSL-4) containment. RT-PCR identification of VHF agents may grow in use due to the need of maximum biosafety with viral isolation, time lag with IgM assay (need acute and convalescent sera) and equipment, as well as technical expertise needed with electron microscopy.

QUESTION 4 Given your high clinical suspicion of Filovirus hemorrhagic fever, you place the patient in isolation as instructed by the local public health official and the CDC. Which of the following isolation precautions should be instituted? a. Place the patient in a private room; universal precautions for hospital personnel. b. Place the patient in a private room with negative pressure; barrier precautions for hospital personnel. c. Place the patient in a private room with negative pressure; Biosafety Level 4 for hospital personnel. d. Transfer the patient to the CDC mobile unit as soon as possible; Biosafety Level 4 for all contacts.

ANSWER: The correct answer is b. The patient was vomiting. Patients with symptoms such as prominent cough, vomiting, diarrhea, as well as hemorrhage, should be placed in a negative-pressure room, given the potential for aerosolization of the virus and possibility of infecting other individuals. This being said, the available evidence indicates that the majority of reported nosocomial VHF cases, including Filovirus hemorrhagic fever, have been acquired by inoculation with virus-contaminated instruments or by direct contact with blood or body fluids from infected patients.

In addition to isolation in a negative pressure room, the caretakers of symptomatic patients should use barrier precautions to prevent skin or mucous membrane exposure to blood, other body fluids, or secretions. All persons entering a VHF patient’s room should wear gloves and gowns to prevent contact with surfaces that may be contaminated. Further, face shields or masks with eye protection should be worn to prevent contact with blood, body fluids, or respiratory secretions that may be rendered airborne by coughing or sneezing. Leg and shoe covers should also be worn to minimize the risk of transmission outside of the room. Patients with suspected VHF who do not have a prominent cough, vomiting, diarrhea, or hemorrhage can be placed in a private room with institution of universal precautions.5 Individuals attempting virus isolation or cultivation must institute Biosafety Level 4 (BSL-4) precautions. Specimens in clinical labo- ratories should be handled in a class II biological safety cabinet following BSL-3 practices. Routine procedures can be used for automated analyzers and should be disinfected per manufacturer's recom- mendations. Serum used in laboratory tests should be pre-treated, though 100% inactivation of virus should not be assumed.5 QUESTION 5 Your patient expresses concern for his family. He has a 10-year-old son and his wife is 20 weeks pregnant. He reports that they are both feeling well with no symptoms of illness. What should you do regarding his family’s care? a. Isolate both his wife and 10-year-old son b. Isolate his wife c. Conduct daily medical surveillance of family members without isolating them d. Admit his wife and son to the hospital

ANSWER: The correct answer is c. A contact is an individual who has been exposed to an infected person or to an infected person’s secretions, excretions, or tissue within 3 weeks (conservative incubation period) of the patient’s onset of illness. Contacts can be divided into 3 levels of risk: casual contacts, close contacts, and high-risk contacts. The patient’s wife and son are high-risk contacts. The patient’s wife and son should be placed under surveillance, given the clinical suspicion of VHF.

QUESTION 6 The CDC mobile laboratory calls you because they have confirmed a diagnosis of Ebola virus. Which of the following statements best describes the current therapy for Ebola virus? a. Supportive care only b. Supportive care + ribavirin c. Supportive care + immunoglobulin d. Supportive care + vaccine

ANSWER: The correct answer is a. The only current treatment of Ebola is supportive care. Aspirin and other antiplatelet agents or anti-clotting factor drugs should be avoided, as they may potentiate hemorrhage. Secondary bacterial infections are relatively common and should be aggressively sought and treated. Intravenous lines, catheters, and other invasive techniques should be avoided unless clearly indicated given the concern of diffuse hemorrhage. The diffuse nature of vascular involvement often leads to multi-system organ failure. Ribavirin is ineffective against the Filoviruses. Immunoglobulin therapy for experimental animals infected with Ebola virus has been disappointing. There are no current vaccines for Ebola virus.

11 REFERENCES 1. Jahrling PB. Viral Hemorrhagic Fevers. In: Sidell FR, Takafuji ET, Franz DR, eds. Textbook of Military Medicine: Medical Aspects of Chemical and Biologic Warfare. Washington, DC: Borden Institute; 1997:592-601. 2. Isaacson M. Viral Hemorrhagic Fever hazards for travelers in Africa. CID. 2001;33:1701-1712. 3. Riquelme R, Riquelme M, Torres A, et al. Hantavirus Pulmonary Syndrome, Southern Chile. EID. 2003:1438-1443. 4. Peters CJ. California Encephalitis, Hantavirus Pulmonary Syndrome, and Bunyavirid Hemorrhagic Fevers. In Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. Edinburgh, UK: Churchill Livingstone; 2000:1850-1855. 5. CDC Update: Management of patients with suspected viral hemorrhagic fever— United States. MMWR. 1995;44:475-479. 6. Fisher-Hoch SP, Platt GS, Neild GH, et al. Pathophysiology of shock and hemorrhage in a fulminating viral infection (Ebola). J Infect Dis. 1985;152:887-894. 7. Preston R. The Hot Zone: A Terrifying True Story. New York, NY: Random House; 1995. 8. Leroy EM, Rouquet P, Formenty P, et al. Multiple Ebola Virus transmission events and rapid decline of central African wildlife. Science. 2003;303:387-397. 9. Balter M. On the trail of Ebola and Marburg Viruses. Science. 2003;290:923-925. 10. Vastag B. Ebola vaccines tested in humans, monkeys. JAMA. 2004;291:549-550.

SUGGESTED READING 1. CDC Update: Outbreak of Ebola Hemorrhagic Fever—Uganda, August 2000- January 2001. MMWR. 2001;50:73-76. 2. CDC Update: Filovirus infection associated with contact with nonhuman primates or their tissues. MMWR. 1990;39:404-405. 3. Geisbert TW, Marty A, Jahrling B. Viral Hemorrhagic Fevers. In: Roy MJ, ed. Physician’s Guide to Terrorist Attack. Totowa, NJ: Humana Press; 2003:221-242. 4. Dieter Klenk H, Feldman H. Symposium on Marburg and Ebola Viruses. Virus Res. 2001;80:117-123. 5. Thacker PD. An Ebola epidemic simmers in Africa. JAMA. 2003;290:317-319.

12 EVALUATION FORM TERRORISM AND DISASTER: WHAT CLINICIANS NEED TO KNOW Viral Hemorrhagic Fevers (VHF)

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Instructions for Physicians Receiving Credit The questions that follow may be used to obtain continuing medical education credit. To obtain 1 hour of Category 1 credit towards the AMA Physician’s Recognition Award, read this case study, which will take one hour of your time, circle the correct answer to each of the CME questions, complete the evaluation form, and return both the CME question page and the evaluation form via mail or fax to: Rush University Medical Center Office of Continuing Medical Education 600 South Paulina Street, Suite 433 AAF Chicago, Illinois 60612 Fax: (312) 942-2000

Case Study Evaluation Please rate this case study according to the following scale: 1=Very Poor 2=Poor 3=Fair 4=Good 5=Very Good 6=Excellent 1. Accredited CME activities must be “free of commercial bias for or against any product.” In this regard, 1 2 3 4 5 6 how would you rate this activity? If you perceived any bias, please provide specific comments below. oooooo ______

2. How well did the case study satisfy your purpose for reading it? oooooo 3. To what extent were the stated objectives of the case study achieved? oooooo 4. In general, was the case study well organized and presented? oooooo 5. To what extent has this CME activity improved your preparedness to recognize and care for victims of a oooooo terrorism attack or other public health disaster? 6. What was your overall rating of this case study? oooooo 7. I would recommend this case study to a colleague. o Yes o No 8. Based upon your review of this case, what specific action(s) could you take to enhance disaster Please estimate the probability that you will act on this item preparedness in your workplace? (0-100% where 100% = certainty) A. ______A. ______

B. ______B. ______C. ______C. ______oPlease check this box if you prefer not to be contacted for follow-up about the impact of this activity on your clinical practice.

13 QUESTIONS FOR CONTINUING MEDICAL EDUCATION

1. A technician sustains a needlestick injury from a syringe containing the blood of a patient with suspected Ebola virus hemorrhagic fever. Given this information, what is the most appropriate next step? a. Place the laboratory technician into isolation b. Place the laboratory technician under surveillance c. Admit the laboratory technician to a private room with negative pressure d. Administer ribavirin therapy and place the patient into isolation

2. Which of the following is not an etiologic agent of VHF? a. Ebola virus b. Hantavirus c. Dengue d. Omsk virus e. SARS

3. A patient is admitted to your service with VHF syndrome. Which of the following statements best describes the current therapy for VHF? a. Supportive care only b. Supportive care + immunoglobulin c. Supportive care + vaccine d. Supportive care + corticosteroids e. Supportive care + platelet transfusion

4. You admit a patient with suspected Marburg virus hemorrhagic fever. Which of the following statements best describes the role of communication with the press? a. Educate public on risk of disease transmission b. Prevent rumors c. Provide information on evacuation d. All of the above e. a and c only

5. An approved vaccine is available for which of the following causes of VHF? a. Dengue b. Ebola c. Yellow fever d. Hantavirus e. Lassa fever

14 NOTES

15 NOTES

16 errorism WHAT T CLINICIANS and NEED TO Disaster KNOW

Rush University Medical Center Authored by experts in the field, INTERDISCIPLINARY faculty, in collaboration with faculty each self-paced case includes a The interdisciplinary cases address from the Uniformed Services thorough case history, questions to basic medical management,general University of the Health Sciences test your knowledge, a resource list disaster planning, communicating (USUHS) authored a case series of additional readings and relevant with the media and concerned to provide continuing medical websites. One-hour CME and public, and psychosocial case education (CME) for terrorism CEU credit is available for each management. preparedness and other public case, following the successful com- • Inhalational Anthrax health emergencies. pletion of the CME questions • Pulmonary Toxicants included with each case. The CME • SARS A series of 14 case studies was devel- and CEU credit is available free of • Smallpox oped to provide innovative learning charge through March 2007. • Viral Encephalitis opportunities for health professionals The cases in the series include: to problem-solve issues related to For more information or to order terrorism or other public health MEDICINE your free copy of any of the cases emergencies. Due to the complicat- The medicine cases address recognition in this series, please contact: ed and volatile nature of a terrorist of the agent, diagnosis, treatment, and event, the case studies were designed Office of Continuing medical case management. to expand outside the clinician- Medical Education • Pneumonic Plague patient interaction and involve: Rush University Medical Center • Radiation Attack Suite 433 AAF • deploying outside resources • Sarin Chicago, Illinois 60612 • notifying appropriate officials • Smallpox Telephone: (312) 942-7119 • coordinating a response team • Staphylococcal Enterotoxin B Facsimile: (312) 942-2000 • dealing with media and • Viral Hemorrhagic Fevers E-mail: [email protected] concerned public • initiating emergency/disaster plans PSYCHIATRY The psychiatry cases address issues Each case provides the CME user of disaster psychiatry. with decision-making challenges • Emergency Mental Health within his or her discipline, along After a Suicide Bombing with scenarios that address broader • Psychiatric Sequelae in a interdisciplinary issues. This inter- Survivor of 9/11 disciplinary approach is particularly • Psychosocial Management important in disaster preparedness, of a Radiation Attack when health professionals will likely be called on to work outside their day-to-day experiences.