Viral Hemorrhagic Fevers The Viral Hemorrhagic Fevers are a group of illnesses which are a diverse group of RNA viruses that present with common clinical characteristics known as the viral hemorrhagic fever syndrome. These illnesses range from a mild flu-like illness to endothelial damage resulting in increased vascular permeability and bleeding complications. This picture is an Electron micrograph of the Filovirus, Ebola

Objectives Describe the natural geographic distribution of VHF and scenarios suggestive of bioterrorism Describe the clinical manifestations of VHF in general List exposure classification of contact for cases of VHF Describe infection control precautions for personnel caring for patients with VHF List therapeutic options for patients with VHF

Case Presentation 38 yo business man returned from West Africa via London, ill for 3 days new onset fever chills severe sore throat diarrhea back pain PE: T103.6 BP 90/60, alert Skin with diffuse ecchymosis and a maculopapular rash on the extremities Case presentation of an actual VHF presentation Sept. 2004 in New Jersey in a businessman originally from Liberia who had resided in the US for 5 years. During the 4 months prior to his hospitalization, the patient had been in West Africa where he commuted between Liberia and Sierra Lione, where he owned some farms. In August, a month prior to presentation, he developed symptoms as described above. He traveled via London back to Newark, NJ where he took a train to Trenton, NJ and sought medical care. MMWR 2004;53(38):891-897

Differential Diagnosis Fever in a traveler Malaria Typhoid fever Other Differential Diagnoses Meningococcemia Rickettsial infection Leptospirosis Acute leukemia Idiopathic or thrombotic thrombocytopenic purpura

Hospital Course Hospital Day #4 Despite empiric antibiotics including antimalarials, pt develops acute respiratory distress syndrome (ARDS) Required intubation

Differential Diagnosis Fever in a traveler Malaria Typhoid fever Yellow fever Lassa fever Now you expand your DDx in a traveler to include the viral hemorrhagic fevers in Africa, particularly West Africa.

Hospital Course Hospital Day #4 Hospital Day #5 Despite empiric antibiotics including antimalarials, pt develops ARDS Required intubation Hospital Day #5 Local and state health departments notified Investigational new drug (IND) protocol to administer IV ribavirin Patient died before administration of any drug

Diagnosis Clinical and post-mortem specimens sent to CDC Lassa virus confirmed Serum antigen detection Immunohistochemical staining liver tissue Virus isolation in cell culture RT-PCR sequencing of virus

FAMILY/GEOGRAPHY AGENT CASE-FATALITY Filoviridae Sub-saharan Africa Ebola Marburg 50-75% 25% Arenaviridae West Africa (Lassa) South America, California (Whitewater) Old World: Lassa New World: Junin, Machupo, Guanarito Sabia, Whitewater arroyo Lassa:1-2% (up to 25% in hospitalized pts) 30% for New World Bunyaviridae Egypt, Yemen SW US (Hantavirus) Phlebovirus: Rift Valley Nairovirus: Crimean Congo Hantavirus: Sin Nombre Rift Valley: <1% overall 50% in hemorrhagic Flaviviridae Central Asia Yellow fever Dengue Omsk Kyasanur Yellow Fever: 5-7% overall The Viral Hemorrhagic Fevers are comprised of a number of different diseases. All are single-stranded RNA viruses and enter the bloodstream through various routes (i.e. tick, mosquito, rodent bite vectors, mucous membrane exposure. Endothelial infection occurs which leads to thrombocytopenia and endothelial dysfunction which may result in disseminated intravascular coagulation (Ebola, Marburg, Rift Valley Fever, Crimean Congo Fever) and cytokine storm (Ebola and Marburg). Vascular permeability and disregulation can occur, leading to periorbital edema, hemoconcentration and flushing, respectively. Animal models of Ebola pathogenesis suggest that the virus leads to immunosuppression and apoptosis (self-destruction) of T-lymphocytes and natural killer cells. In this table the major families of VHF are listed along with the endemic region, the specific agents and average case fatality rates for the diseases listed. For more information see the Center for Infectious Disease Reasearch and Policy and Infectious Disease Society of America (CIDRAP/IDSA) summary document on VHF which can be found on the websites: www.idsasociety.org or www.cidrap.umn.edu/index.html www.cidrap.umn.edu/index.html accessed 2/4/05

Epidemiology Incubation period Endemic regions 2 days to 3 weeks for most VHF Lassa fever: 21 days Endemic regions Sub-saharan Africa Lassa fever causes 100-300,000 infections and 5,000 deaths each year 20 imported cases reported worldwide Human to human transmission has occured South America Pictured is the Mastomys rodent, the natural host of Lassa fever virus.

Why do VHFs make good Bioweapons? Disseminate through aerosols Low infectious dose High morbidity and mortality Cause fear and panic in the public No effective vaccine Available and can be produced in large quantity Research on weaponization has been conducted

Clinical Presentation Initial: High grade fever, headache, myalgias, fatigue, abdominal pain Advanced disease: Bleeding Maculopapular rash Exudative Pharyngitis (Lassa) Meningoencephalitis Jaundice

Eccyhmosis encompassing left upper extremity one week after onset of Crimean-Congo Hemorrhagic Fever. D. Pigott, Associate Professor Dept. of Emergency Medicine, University of Alabama, Birmingham

Patients with Korean Hemorrhagic Fever caused by the Hantaan virus with the typical “sunburn flush” of the cheeks, chin, and base of the neck. Photograph courtesy of John Huggins, PhD. in article on emedicine by David C. Pigott, MD.

Morbiliform exanthem of Dengue fever with islands of sparing characteristic. Photo from Duane Gubler, PhD.

Ecchymoses complicating a case of Dengue hemorrhagic fever Ecchymoses complicating a case of Dengue hemorrhagic fever. Photo from Duane Gubler, PhD.

Transmission Direct contact with blood/body fluids/cadavers Aerosol spray (droplet v. airborne) Sexual transmission Percutaneous Bite of infected tick or mosquito Person to person transmission is greatest in the late stages of the illness when the patient has vomiting, diarrhea, and severe hemorrhage. VHF infection has not been reported in people whose contact with an infected patient occurred only during the incubation period (i.e. before the patient became febrile; the incubation period ranges from 2 days to 3 weeks). MMWR 1995;44(25):475-479.

Infection Control Lassa Fever in New Jersey Investigation: 5 high risk contacts (wife, kids, visitor) 183 low risk contacts 9 other family members 139 HCW at hospital: 42 labworkers, 32 RN, 11 MD 16 labworkers in Virginia and California 19 passengers on flight from London to Newark No additional cases occurred

Infection Control Risk Category Description Surveillance Casual Contacts Remote contact with index case (eg, stayed in same hotel) VHF not spread by casual contact, no special surveillance Close Contacts More than casual (eg, living with contact, caretaker, shook hands with contact) Place under surveillance once index case confirmed High-Risk Contacts Mucous membrane contact (eg, kissing, or penetrating injury involving contact with index case’s blood such as needlestick) Place under surveillance as soon as consider diagnosis of VHF in index case Surveillance should be continued for 3 weeks after the person’s last contact with the index case. If a fever > than 101°F and/or symptoms develop, the patient should be immediately placed in isolation and treated as a VHF patient. CDC Update: management of patients with suspected VHF-United States MMWR 1995;44:475-79

VHF Personal Protective Equipment Airborne and Contact isolation for patients with respiratory symptoms N-95 or PAPR mask Negative pressure isolation Gloves Gown Fitted eye protection and shoe covers if going to be exposed to splash body fluids Droplet and Contact isolation for patients without respiratory symptoms Surgical mask Environmental surfaces Cleaned with hospital approved disinfectant Linen incinerated, autoclaved, double-bagged for wash Isolation precautions will depend on the degree of illness and volume and location of blood loss. If a patient has respiratory symptoms with cough or aerosol generating procedures such as med nebs, or bronchoscopy are planned then use of airborne in addition to contact precautions are warranted. However, if a patient is not coughing than droplet and contact precautions are sufficient. PAPR is powered air-purifying respirator.

Treatment Supportive care: Fluid and electrolyte management Hemodynamic monitoring Ventilation and/or dialysis support Steroids for adrenal crisis Anticoagulants, IM injections, ASA, NSAIDS are contraindicated Treat secondary bacterial infections

Treatment Manage severe bleeding complications Cryoprecipitate (concentrated clotting factors) Platelets Fresh Frozen Plasma Heparin for DIC Ribavirin in vitro activity vs. Lassa fever New World Hemorrhagic fevers Rift Valley Fever No evidence to support use in Filovirus or Flavivirus infections

Vaccination Argentine and Bolivian HF Yellow Fever PASSIVE IMMUNIZATION Treat with convalescent serum containing neutralizing antibody or immune globulin Yellow Fever ACTIVE IMMUNIZATION Travelers to Africa and South America Several vaccines are under investigational new drugs including vaccine for Rift Valley Fever, Argentine HF, Dengue P. Jahrling, Chapter 29, Medical Aspects of Clinical and Biological Warfare; p591-602

This completes the current presentation. End presentation and distribute activity survey.