Viral hemorrhagic fevers (VHFs) refer to a group of illnesses caused by several distinct families of viruses (Table 50-1
). As noted by the U.S. Centers for Disease Control and Prevention (CDC), the term “viral hemorrhagic fever” is used to describe a severe multisystem syndrome, in which characteristically the overall vascular system is damaged, and the body’s ability to regulate itself is impaired.1
The syndrome is often accompanied by hemorrhage; however, the bleeding is itself rarely life threatening. While some types of hemorrhagic fever viruses can cause relatively mild illnesses, many of these viruses cause severe, life-threatening disease. VHFs are caused by viruses of four distinct families: Arenaviridae
, and Flaviviridae
All of these families share a number of characteristics: (1) they are all enveloped RNA viruses; (2) their natural reservoir is an animal or insect host; (3) each virus is geographically restricted to the areas where their host species lives; (4) human are not the natural reservoir for any of these viruses. Humans are infected when they come into contact with infected hosts. However, for some VHFs, person-to-person transmission may occur (Table 50-2
); (5) human cases or outbreaks of hemorrhagic fevers caused by these viruses occur sporadically and irregularly. These timing, location, and size of these outbreaks cannot be easily predicted; and (6) with a few exceptions discussed later in this chapter, these VHRs cannot be prevented by a vaccine, and there are no proven effective therapies.
All healthcare personnel (HCP) who provide direct patient care should know the clinical presentations of VHF, and all healthcare facilities should have preparedness plans in place for safely treating such patients for several reasons. First, many VHFs have a substantial mortality (Table 50-2
). Second, a number of VHFs have personto-person transmission that places other patients, visitors, and HCP at risk for acquisition of infection3,4,5
). Third, special isolation precautions including use of enhanced personal protective equipment (PPE) is required to protect HCP.3,4,5,6
Fourth, diagnostic testing for many of the VHF pathogens requires management in a Biosafety Lab (BSL) using BSL-3 or BSL-4 safety precautions7
). Hospital or commercial laboratories should always be notified PRIOR to sending any body fluids including specimens for diagnosis of a VHF because of the hazard of transport and risks to the laboratory personnel. Fifth, some VHFs are considered potential bioterrorism agents/diseases by the CDC including Filoviruses (ie, Ebola and Marburg), and
Arenaviruses (ie, Lassa and Machupo).8
These viruses are classified by the CDC as category A biothreats because of the following: (1) they can be easily disseminated or transported from person-to-person; (2) they result in high mortality rates and have the potential for major public health impact; and (3) they might cause public panic and social disruption. HCP providing direct patient care should be familiar with the signs and symptoms of the category A biothreats,9,10
including the pertinent VHFs.11,12
Hospital epidemiologists and infection preventionists should be familiar
with epidemiological clues that might signal a biologic attack12,13,14
TABLE 50-1 Hemorrhagic Fever Viruses
Rift Valley fever virus (BSL-3)
Crimean-Congo hemorrhagic fever (CCHF) virus (BSL-4)
Hantaviruses (diseases; hemorrhagic fever with renal syndrome; hantavirus pulmonary syndrome) (BSL-3)
Adapted from Biosafety in Microbiology and Biomedical Laboratories. 5th ed. HHS Publication No. (CDC) 21-1112; 2009.
TABLE 50-2 Clinical Characteristics of Hemorrhagic Fever Viruses With Person-To-Person Transmission
Key clinical features
Incubation period (d)
Illness typically progresses from “dry” symptoms (fever, aches, pain, fatigue) to “wet” symptoms (diarrhea, vomiting). Late symptoms include hemorrhage, bruising and bleeding
Africa (West, Central)
8-10 (range, 2-21)
Supportive, specific therapyregeneron, mAb114 (investigational)
Most patients have mild symptoms (80%). Disease may progress to hemorrhage (gums, eyes, nose); respiratory distress; vomiting; facial swelling; pain in chest, back, and abdomen; and shock
Africa (West, Central)
Sudden onset of fever, chills, headache, and myalgias. Around 5th day after onset, development of a maculopapular rash (most prominent on trunk) then nausea, vomiting, sore throat, abdominal pain, and diarrhea. Disease may progress to liver failure, massive hemorrhage, multiorgan dysfunction, hemorrhage, and shock
3-7 (range, 2-14)
Crimean-Congo fever virus
Sudden onset with headache, high fever, pain (back, joint, abdominal), and vomiting. Also flushed face, pharyngitis, petechiae on palate. Disease may progress to bruising, bleeding, and hemorrhage
Eastern Europe, Asia, Africa, Middle East
Depends on exposure mechanismb
˜30% (for hospitalized cases, 9%-50%)
Supportive, ribavirin (controversial)
New World Arenavirusesc
Gradual onset of fever, myalgias, nausea, abdominal pain, conjunctivitis, flushing of face and trunk and generalized lymphadenopathy. May progress with petechiae, hemorrhage, and central nervous system dysfunction
a Species causing human disease; Zaire, Sudan, Taï Forest, and Bundibugyo viruses.
b Following infection by a tick bite, the incubation period is usually 1-3 days (maximum, 9). The incubation period following contact with infected blood or tissues is usually 5-6 days (maximum, 13).
c Viruses with person-to-person spread: Machupo, Junin, Lujo.
TABLE 50-3 Epidemiologic Clues That May Indicate an Intentional Release of a Biothreat Agent
A single case of infection caused by an uncommon agent with biothreat potential without an adequate epidemiologic explanation (eg, Ebola, Lassa, anthrax, plague)
A rapidly increasing disease incidence
Higher morbidity and mortality in association of a common disease or syndrome
Unusual disease presentations (eg, inhalation anthrax or pneumonic plague)
Unusual clustering of disease for the geographic area
Disease occurrence outside of the normal transmission season
Atypical disease transmission through aerosols, water, or food
Simultaneous outbreaks of different infectious diseases
Disease outbreak in humans after recognition of disease in animals
Unexplained number dead animals or birds
Disease requiring for transmission a vector previously not seen in the area
Rapid emergence of genetically identical pathogens from different geographic areas
Large numbers of unexplained patient deaths
Adapted from Christian MD. Biowarfare and bioterrorism. Crit Care Clin. 2013;29:717-756; Treadwell TA, Koo D, Kuker K, Khan AS. Epidemiologic clues to bioterrorism. Public Health Rep. 2003;118: 92-98; Radosavljevic V, Belojevic G. Unusual epidemic events: a new method of early orientation and differentiation between natural and deliberate epidemics. Public Health. 2012;126:77-81.
This chapter will focus on VHFs with person-to-person transmission that includes the Filoviruses (Ebola, Marburg), Bunyaviruses (Crimean-Congo), Old World Arenaviruses (Lassa, Lujo), and New World Arenaviruses (Machupo, Junin) (Table 50-2
). Person-to-person transmission of these and management of outbreaks is described later in this chapter. Detailed information on the microbiology, history, epidemiology, clinical characteristics, diagnosis, and treatment of discussed VHFs is available in from the CDC,1
World Health Organization (WHO)15
and general review articles on VHFs,9,11,12,16,17,18,19
and on specific VHFs from the CDC, WHO, and in review articles for Ebola20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38
; Crimean Congo19,46,47,48,49,50,51,52,53,54
; Old World Arenaviruses, Lassa21,55,56,57,58,59,60,61,62,63,64,65,66,67
; and New World Arenaviruses, Machupo19,52,71,72,73,74
Assessing and managing the threat of a VHF requires an understanding of the biology of the pathogen, its epidemiology, the clinical manifestations of infection, the methods of diagnosis, and therapies (if available). All healthcare facilities should have a highly communicable disease management plan (Table 50-4
). A detailed discussion of each of these components is beyond the scope of this chapter. Detailed information is best found, especially early in an epidemic, on the Web pages of local and state health departments, the CDC, and the WHO. General recommendations have been provided by infection control experts.3,4,5
There are two areas that place a healthcare facility and the personnel at substantial risk for disease acquisition and transmission. First, inadequate screening procedures when patients enter a healthcare facility can potentially allow transmission from an ill patient to HCP, other patients, or visitors. Second, inadequate supplies of PPE or inadequate training of HCP in proper donning and doffing procedures can increase the risk of exposure for HCP. General infectious disease issues include knowledge of the pathogen and hosts (if relevant), epidemiology (ie, locations of endemicity), and clinical characteristics (signs, symptoms, morbidity, mortality, diagnostic methods, and therapy). Other specific issues for infection prevention include transmission routes, incubation period, infectivity (ie, communicability), duration of infectivity, risk factors for acquisition, diagnostic methods, environmental survival, germicide susceptibility for both antiseptics and disinfectants, preexposure prophylaxis (availability, efficacy, and safety), postexposure prophylaxis (availability, efficacy, and safety), and recommended waste disposal.
HISTORY AND MICROBIOLOGY
Filoviruses: Ebola and Marburg
Ebola and Marburg are caused by a nonsegmented, singlestrand negative RNA virus of the family Filoviridae. There are 6 identified Ebola virus species, 4 of which are known to cause disease in humans: Ebola, Sudan, Tai Forest (formerly Cote d’Ivoire), and Bundibugyo. Reston virus has caused disease in nonhuman primates and pigs but not in humans. Unlike Ebola, there is only a single Marburg virus species. The natural reservoir hosts of Ebola and Marburg viruses are now believed to be fruit bats in Africa.
The first Filovirus was recognized in 1967 when a number of laboratory workers in Germany, who were handling tissues from green monkeys, developed hemorrhagic fever. A total of 31 cases and 7 deaths were associated with these outbreaks. The virus was named after Marburg, Germany, the site of one of the outbreaks. Since then a few sporadic cases and two large outbreaks of Marburg HF have been reported (Democratic Republic of Congo in 1999 and Angola in 2005). Outbreaks and sporadic cases have been reported in Angola, Democratic Republic of the Congo, Kenya, South Africa (in a person with recent travel history to Zimbabwe), and Uganda. The WHO reported that between 2011 and 2017, there were 4 outbreaks of Marburg.15
Languon and Quaye have provided details on all 14 outbreaks of Marburg reported before 2019.75
Ebola virus was first described in 1976 near the Ebola River in what is now the Democratic Republic of Congo. Since then multiple outbreaks have occurred in West and Central Africa, including the Democratic Republic of the Congo, Uganda, Sudan, and Gabon. The 2014 outbreak of Zaire ebolavirus led to 28 610 cases and 11 308 deaths (39%). Single cases caused by laboratory accidents have also been reported from Russia and England. The WHO reported that between 2011 and 2017, there were 22 outbreaks of Ebola.15
Languon and Quaye have provided details on all 37 outbreaks of Ebola reported before 2019.75
TABLE 50-4 Preparedness for Managing a Highly Communicable Disease Spread by Contact With Body Fluids
Have a comprehensive facility plan for managing a highly communicable infectious disease transmitted by direct or indirect contact with body fluids (eg, Ebola).
Nestle the plan for managing a patient with a known or possible highly communicable disease spread by contact within the plan for managing emerging infectious diseases, which in turn should be nestled within the general disaster plan.
Incorporate the incident command structure in the plan.
Periodically train key personnel on the plan.
The plan should include care of single patient (eg, traveler) and managing large number of patients (eg, biothreat release).
Purchase and have immediately available appropriate personal protective equipment (PPE) to allow safe care of patients (ie, when caring for patients with a high communicable disease transmitted by the direct or indirect transmission there should be NO exposed skin).
Incorporate communications with local and state health department officials.
Screening and signage (when appropriate based on the threat of a highly communicable disease)
Place signs at every entrance to the hospital and clinics that include the following: epidemiologic clues to possible disease exposure (ie, travel locations), signs and symptoms of infection, and who to notify if the patient or visitor has both exposure, and appropriate signs or symptoms.
Include messaging about the signs and symptoms of the concerning disease in all telephone contacts with patients (eg, reminders about appointments) and who to contact prior to arrival at the healthcare facility.
Screen all patients immediately at the time of all healthcare visits.
Include screening in the electronic medical record (also have alerts in the medical record that require screening).
Place an appropriate isolation sign on the door of all patients being isolated because of the possibility of a highly communicate disease.
Emphasize the need for proper hand hygiene.
All messaging should be in appropriate languages for the region.
Train frontline person in all clinics and the emergency department in appropriate use of personal protective equipment.
Have appropriate personal protective equipment available.
Have a designated location in the emergency department and all clinics in which to immediately place the patient (a private room; ideally with access to a sink and toilet, and if possible, one that meets standards for a disease transmitted by the airborne route (ie, negative pressure, out-exhausted air, >12 air exchanges per hour).
Have a well-defined process for alerting key healthcare facility officials about the presence of a patient with a possible highly communicative disease (eg, disaster manager, infection preventionist).
Avoid blood tests or other procedures that may place the laboratory staff or other healthcare personnel at risk.
Have a well-defined and safe method for transporting a patient either to a properly equipped emergency department or hospital facility able to safely care for a patient.
Have a well-defined plan for the inpatient location that will provide care to a patient with a highly communicative disease (or a plan for transporting such a patient to facility that can provide such care).
In the inpatient care unit, designate areas that are hot (ie, potentially contaminated) and cold (ie, areas that are not contaminated).
Have a well-trained medical care team. For highly communicable diseases (eg, Lassa, Ebola), ideally provide three-step training: (1) basic individual training on personal protective equipment donning and doffing (and including how to manage contamination of the environment from a spill and breach of the personal protective equipment. Such training should be individualized to the specialty of the healthcare providers [ie, physician, nurse, respiratory therapist]); (2) team training using mannequins; and (3) team training in the designated containment unit.
Train team personnel on donning and doffing using an explicit written list of all donning and doffing steps.
Screen and exclude healthcare personnel unable to wear the proper personal protective equipment. Consider excluding from the care team personnel at high risk for disease acquisition or more severe illness, such as persons with nonintact skin, pregnancy, and immunocompromised persons. Consider excluding trainees from providing care.
Store an adequate supply of personal protective equipment.
Provide dedicated point of care laboratory equipment.
Develop a method to safely dispose of solid and liquid wastes.
Restrict visitors and maintain a log of all visitors.
Maintain a log of all healthcare personnel providing care.
Ideally, healthcare personnel providing care should be dedicated with care of the patient(s) with the potentially highly communicable disease (ie, not rotate during other shifts to provide care of other patients).
Ideally, provide quarters for healthcare providers providing care to sleep/eat on site when not providing care.
Develop a plan for managing healthcare personnel with unprotected exposure to the infectious agent (eg, needlestick).
Assure that care team members receive proper rest.
Adapted from Weber DJ, et al. Emerging infectious diseases: focus on infection control issues for novel coronaviruses (Severe Acute Respiratory Syndrome-CoV and Middle East Respiratory Syndrome-CoV), hemorrhagic fever viruses (Lassa and Ebola), and highly pathogenic avian influenza viruses, A(H5N1) and A(H7N9). Am J Infect Control. 2016;44:e91-e100, Table 4.
Bunyaviruses: Crimean-Congo Fever
Congo-Crimean fever is a member of the Nairovirus genus within the family Bunyaviridea
is an enveloped negativestranded RNA virus. It was first described in Soviet soldiers in the Crimea in 1944. In 1956, the virus was isolated from an ill child in the Congo and was named Congo virus. When the causative agents were shown to be identical, the disease was renamed Crimean-Congo fever. The WHO reported 49 outbreaks between 2011 and 2017.15
Arenaviruses: Lassa, Lujo, Muchupo, Junin
Although first described in the 1050s, the virus causing Lassa fever was not identified until 1969 and is named after the town in Nigeria where the virus was first isolated. Lassa fever is endemic in parts of West Africa including Benin, Ghana, Guinea, Liberia, Mali, Sierra Leone, Togo, and Nigeria. Neighboring countries are also at risk, as the animal vector for Lassa virus, the “multimammate rat” (Mastomys natalensis
) is distributed throughout the region. The WHO reported 23 outbreaks between 2011 and 2017.15
The viruses and diseases caused by selected Arenaviruses and year discovered are as follows: Junin (Argentine hemorrhagic fever), 1958; Machupo (Bolivian hemorrhagic fever), 1963; and Lujo (Lujo hemorrhagic fever), 2004.
Filoviruses: Ebola and Marburg
Ebola virus disease is most commonly reported from sub-Saharan Africa, near tropical rainforests. It is thought that fruit bats of the Pteropodidae family are natural Ebola virus hosts. Ebola is introduced into the human population through close contact with the blood, secretions, organs, or other bodily fluids of infected animals such as fruit bats, chimpanzees, gorillas, monkeys, forest antelope, or porcupines found ill or dead or in the rainforest. Person-toperson transmission then occurs through direct or indirect (via contaminated surfaces or objects) contact of body fluids (urine, saliva, sweat, feces, vomitus, breast milk, and semen) with a person’s mucous membrane (eye, noses, or mouth) or nonintact skin. Importantly, the virus has been reported to persist in certain body fluids (eg, semen, breast milk) for a prolonged period of time; sexual transmission has been reported. There is no evidence for transmission via food or insects. The incubation period is 2-21 days. Case fatality rates have varied from 25% to 90% (average, 50%) in past outbreaks.
The reservoir host of Marburg virus is the African fruit bat, Rousettus aegyptiacus. Fruit bats infected with Marburg virus do not to show obvious signs of illness. Primates (including humans) can become infected with Marburg virus and may develop serious disease with high mortality. Further study is needed to determine if other species may also host the virus. While it is not entirely known how Marburg virus is acquired from bats, the most likely routes of infection are unprotected contact with infected bat feces or aerosols. Once a human is infected, person-to-person transmission occurs via direct contact to droplets of body fluids from infected persons (eg, burial ceremonies) or via indirect contact with equipment or other objects (eg, bedding, clothes) contaminated with infectious blood or tissues. Infection via the respiratory route has not been reported. Transmission via infected semen has been documented up to 7 weeks after clinical recovery. In women who have been infected while breast-feeding, the virus may persist in breast milk. Human infection has occurred via handling infected primates or their fluids or contact with infected cell cultures. Healthcare-associated infection has been reported via contaminated injection equipment or through needlestick injuries is associated with more severe disease, rapid deterioration, and, possibly, a higher fatality rate. Transmission via insects has not been reported. The incubation period averages about 1 week (range, 2-21 days). Case fatality rates have ranged from 25% to 90% in outbreaks and depend on the viral strain and patient care management.
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