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Viral Hemorrhagic Fevers

Chapter 13

VIRAL HEMORRHAGIC FEVERS

PETER B. JAHRLING, P h D * ; AILEEN M. MARTY, MD † ; and THOMAS W. GEISBERT, P h D ‡

INTRODUCTION

HISTORY AND EPIDEMIOLOGY

AGENT CHARACTERISTICS

CLINICAL MANIFESTATIONS

PATHOGENESIS

DIAGNOSIS

MEDICAL MANAGEMENT

PREVENTION AND CONTROL

SUMMARY

* Director, National Institute of Allergies and Infectious Diseases, Integrated Research Facility, National Institutes of Health, 6700A Rockledge Drive,

Bethesda, Maryland 20892; formerly, Senior Research Scientist, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort

Detrick, Maryland

† Senior National Security Advisor, Medical Instructor, Battelle Office of Homeland Security, Battelle Memorial Institute, Suite 601, 1550 Crystal Drive,

Arlington, Virginia 22202; formerly, Professor, Pathology and Emerging Infections, Uniformed Services University of the Health Sciences, 4301 Jones

Bridge Road, Bethesda, Maryland

‡ Chief, Department of Viral Pathology and Ultrastructure, US Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick,

Maryland 21702

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Medical Aspects of Biological Warfare

INTRODUCTION

Viral hemorrhagic fever (VHF) is an acute febrile

syndrome characterized by systemic involvement,

which includes generalized bleeding in severe infec-

tions. Patients with VHF manifest combinations of

malaise, prostration, generalized signs of increased

vascular permeability, and coagulation abnormalities.

Although the more severely ill patients manifest bleed-

ing, this does not result in a life-threatening loss of

blood volume. To a certain extent, however, it indicates

damage to the vascular endothelium and is an index

of disease severity in specific target organs. Much of

the disease appears to be caused by dysregulation of

the innate immune response, although replication of

these hemorrhagic fever (HF) viruses in target cells

and tissues can directly contribute to the pathological

manifestations of VHF. Factors that may contribute to

this subversion of the host immune response include

the rapid infection and impairment of dendritic cells,

a sudden and enigmatic death of lymphocytes, and the

release of a variety of mediators from virus-infected

cells that subsequently alter vascular function and

trigger the coagulation disorders that epitomize these

infections.

The viral agents causing severe HF, which are

taxonomically diverse, are all single-stranded RNA

viruses that can infect humans through contact with

contaminated animal reservoirs or arthropod vectors.

Under natural conditions, these viruses cause signifi-

cant infectious diseases, although their geographical

ranges may be tightly circumscribed. The relatively

recent advent of jet travel coupled with human de-

mographics increase the opportunity for humans to

contract these infections; from time to time, sporadic

cases of VHF are exported from endemic areas to new

areas. Clinical and epidemiological data on VHFs are

sparse; outbreaks are sporadic and unexpected, and

typically develop in geographical areas where cultural

customs and logistical barriers encumber systematic

investigations.

Because many VHFs spread easily in hospitals to

patients and staff alike, causing high morbidity and

mortality, they gained public notoriety in the past

decade from the enormous interest and fear gener-

ated by the news media. Ebola, an HF virus with a

high case-fatality rate (near 90% in some outbreaks),

dramatic clinical presentation, and lack of effective

specific treatment, was highly publicized when a new

Ebola species was isolated in a suburb of Washington,

DC, in 1989. 1 Progress in understanding the genesis of

the pathophysiological changes that make Ebola and

other HF viral infections of humans so devastating has

been slow, primarily because special containment is

required to safely work with most of these viruses.

Many of the VHF agents are highly infectious by

aerosol. Most VHF agents are also stable as respirable

aerosols, which means that they satisfy at least one

criterion for weaponization, and some have potential

as biological terrorism and warfare threats. Most of

these agents replicate in cell culture to concentrations

sufficiently high to create a small terrorist weapon, one

suitable for introducing lethal doses of virus into the

air intake of an airplane or office building. Some rep-

licate to higher concentrations, with obvious potential

ramifications. Because the VHF agents cause serious

diseases with high morbidity and mortality, their

existence as endemic disease threats and as potential

biological warfare weapons suggests a formidable

potential impact on public health.

HISTORY AND EPIDEMIOLOGY

Natural Disease

a patient’s history of being in a rural locale is an im-

portant factor to consider when reaching a diagnosis.

Human-to-human spread is possible for most of the HF

viruses. The majority of person-to-person spread has

been attributed to direct contact with infected blood

and body fluids. Airborne transmission of VHF agents

appears to be an infrequent event, but cannot categori-

cally be excluded as a mode of transmission.

Under natural conditions members of the Arena-

viridae , Bunyaviridae , Filoviridae , and Flaviviridae (Table

13-1) that cause VHF have specific geographic distribu-

tion and diverse modes of transmission. Although the

natural reservoir for Filoviridae remains unknown, as a

group, the HF viruses are linked to the ecology of their

vectors or reservoirs, whether rodents or arthropods.

These characteristics have great significance not only

in the natural transmission cycle for arenaviruses and

bunyaviruses (rodents to humans) and for flaviviruses

(arthropods), but also in the potential for nosocomial

transmission. Most reservoirs tend to be rural, and

Arenaviridae

The name arena is derived from the Latin words

“arenosus” (sandy) and “arena” (sand) in recogni-

tion of the sand-like ribosomal contents of virions in

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Viral Hemorrhagic Fevers

TABLE 13-1

VIRAL HEMORRHAGIC FEVERS OF HUMANS

Virus Family Virus

Disease

Natural Distribution

Source

Incubation (Days)

Genus

Arenaviridae

Arenavirus

Lassa

Lassa fever

West Africa

Rodent

5–16

Junin

Argentine HF

South America

Rodent

7–14

Machupo

Bolivian HF

South America

Rodent

9–15

Sabia

Brazilian HF

South America

Rodent

7–14

Guanarito

Venezuelan HF

South America

Rodent

7–14

Whitewater

Unnamed HF

North America

Rodent

Unknown

Arroyo

Bunyaviridae

Nairovirus

Crimean-Congo HF Crimean-Congo HF Africa, Central Asia, Eastern Tick

3–12

Europe, Middle East

Phlebovirus

Rift Valley fever

Africa, Saudi Arabia, Yemen Mosquito

2–6

Hantavirus

Agents of HFRS

HFRS

Asia, Balkans, Europe *

Rodent

9–35

Filoviridae

Ebolavirus †

Ebola

Ebola HF

Africa

Unknown

2–21

Marburgvirus Marburg

Marburg HF

Africa

Unknown

2–14

Flaviviridae

Flavivirus

Dengue

Dengue HF

Asia, Africa, Pacific, Americas Mosquito

Unknown

Yellow fever

Africa, tropical Americas

Mosquito

3–6

Omsk HF

Central Asia

Tick

2–9

Kyasanur forest

India

Tick

2–9

disease

HF: hemorrhagic fever; HFRS: hemorrhagic fever with renal syndrome

* The agents of hantavirus pulmonary syndrome were isolated in North America.

† There are four species of Ebola: Zaire, Sudan, Reston, and Ivory Coast.

thin section under the electron microscope. The fam-

ily Arenaviridae contains a single genus, Arenavirus .

However, the arenaviruses are divided into an Old

World group (eg, Lassa virus) and a New World group

(South American and North American HF viruses)

by phylogenetic analysis of RNA and serology. The

New World complex is further divided into three

major clades: A, B, and C. All of the viruses caus-

ing HF belong to clade B. 2 Arenaviruses survive in

nature by a lifelong association with specific rodent

reservoirs. Rodents spread the virus to humans, and

outbreaks can usually be related to some perturbation

in the ecosystem that brings humans in contact with

rodents or material contaminated by rodent products.

Arenaviruses initiate infection in the nasopharyngeal

mucosa.

Lassa fever made a dramatic appearance in 1969

when an American nurse working at a modest mis-

sion station in Lassa, a small town in northeastern

Nigeria, became ill and started a chain of nosocomial

infections that extended from healthcare workers in

Africa to laboratory workers in the United States.

Lassa virus produces Lassa fever, a major febrile dis-

ease of West Africa that causes 10% to 15% of adult

febrile admissions to the hospital and perhaps 40%

of nonsurgical deaths. 3 Lassa virus infects 100,000 to

300,000 people annually in West Africa, kills 5,000 to

10,000, and leaves approximately 30,000 deaf. 3,4 Lassa

fever causes high mortality in pregnant women and

is also a pediatric disease. Most Lassa virus infections

are traceable to contact with the carrier rodent, the rat

( Mastomys natalensis) , but nosocomial transmission

is also possible. Lassa fever has periodically been

imported to Europe, the United States, Canada, and

Japan by travelers from West Africa. 5 Since 2000 at

least five fatal Lassa fever cases have occurred in the

United Kingdom, Germany, the Netherlands, and the

United States. 6,7

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Medical Aspects of Biological Warfare

Argentine HF (AHF) was described in 1943, and

Junin virus was first isolated from one of its victims in

1958. Junin virus, which is carried by field voles such

as Calomys musculinus and Calomys laucha , is primarily

associated with agricultural activities in the pampas of

Argentina, where there have been 300 to 600 cases per

year since 1955. 8 Transmission is airborne from fomites,

contaminated food or water, or abrasions to the skin.

Direct person-to-person transmission is rare.

In 1959 physicians at the Beni department of Bolivia

noted a sporadic hemorrhagic illness in patients from

rural areas, which soon became known as Bolivian

HF. In 1963 Machupo virus was isolated from patients

with Bolivian HF, and shortly thereafter voles ( Calo-

mys callosus) were identified as the rodent reservoir. 9

Machupo virus produced several outbreaks of disease

in the 1960s, but more recently Bolivian HF has mani-

fested only sporadically; there was a cluster of cases in

1994. Transmission is through contaminated food and

water and direct contact through breaks in the skin;

there is only rare documentation of human-to-human

transmission.

In 1989 an outbreak of VHF involving several

hundred patients in the municipality of Guanarito,

Portuguesa state, Venezuela, led to the isolation of

Guanarito virus and identification of its probable ani-

mal reservoir, the cotton rat ( Sigmodon hispidus ). 10 Sabia

virus caused a fatal VHF infection in Brazil in 1990, 11

a severe laboratory infection in Brazil in 1992, and

another laboratory-acquired infection in the United

States in 1994. The most recently recognized arenavi-

rus linked to VHF is Whitewater Arroyo virus, which

apparently caused three fatal cases of HF in California

between 1999 and 2000. 12

1950–1951, an epizootic of RVF in Kenya resulted in

the death of about 100,000 sheep. An RVF epizootic can

lead to an epidemic among humans who are exposed

to diseased animals. Risk factors for human infection

include contact with infected blood, especially in

slaughterhouses, and handling of contaminated meat

during food preparation. Exposure to aerosols of RVF

virus is a potential source of infection for laboratory

workers. In 2000 RVF spread for the first time beyond

the African continent to Saudi Arabia and Yemen, af-

fecting both livestock and humans. 15

Crimean-Congo HF (CCHF) is a zoonotic disease

transmitted not only through the bite of at least 29 spe-

cies of ticks, of which Hyalomma marginatum is the most

important, but also by exposure to infected animals or

their carcasses, contact with blood and bodily secre-

tions of infected persons, and by aerosol. The agent

of CCHF is a Nairovirus . Although descriptions of this

illness can be traced to antiquity, this disease was first

recognized in 1944–1945 when a large outbreak oc-

curred in the Steppe region of western Crimea among

Soviet troops and peasants helping with the harvest.

In 1956 a similar illness was identified in a febrile

child from what was then the Belgian Congo (now the

Democratic Republic of the Congo), but it was not until

1969 that researchers realized that the pathogen caus-

ing Crimean HF was the same as that responsible for

the illness in the Congo. The linkage of the two place

names resulted in the current name for the disease

and the virus. CCHF is endemic in many countries in

Africa, Europe, and Asia; it causes sporadic, yet par-

ticularly severe, VHF in endemic areas. 16 CCHF is often

associated with small, hospital-centered outbreaks,

owing to the profuse hemorrhage and highly infective

nature of this virus in humans exposed by aerosol. An

HF outbreak on the Pakistani-Afghan border during

the 2001–2002 US campaign against terrorists is sus-

pected to have been caused by the CCHF virus, and

various media outlets have reported that CCHF was

confirmed by a laboratory in South Africa.

Hantaviruses, unlike other bunyaviruses, are not

transmitted by infected arthropods; rather, contact with

infected rodents and their excreta leads to most human

infections. However, person-to-person transmission

was described during a recent outbreak of hantavirus

pulmonary syndrome (HPS) in southwest Argentina, 17

and researchers have also documented transmission by

aerosol. 18 Of the more than 20 known types of hantavi-

ruses, at least nine (Hantaan, Seoul, Puumala, Dobrava,

Sin Nombre, New York, Black Creek Canal, Andes, and

Bayou) hantaviruses can cause significant clinical ill-

ness. Each virus has its own rodent vector, geographic

distribution, and clinical expression. The poor sanitary

conditions of combat promote exposure to rodents. A

Bunyaviridae

Of the five genera that comprise the family Bunya-

viridae , three genera contain viruses that cause HF: (1)

Phlebovirus (eg, Rift Valley fever virus); (2) Nairovirus

(eg, Crimean-Congo HF virus); and (3) Hantavirus (eg,

Hantaan virus). Bunyaviridae is transmitted by arthro-

pods (primarily mosquitoes, ticks, and phlebotomine

flies), or, as is the case for hantaviruses, by contact with

rodents or rodent products. Transmission by aerosol

is also documented.

The phlebovirus Rift Valley fever (RVF) virus,

which causes RVF, is a significant human pathogen.

Outbreaks of this major African disease often reflect

unusual increases in mosquito populations. 13 RVF

virus, which primarily affects domestic livestock,

can cause epizootic disease in domestic animals. RVF

was first described in 1931 as an enzootic hepatitis

among sheep, cattle, and humans in Kenya. 14 During

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Viral Hemorrhagic Fevers

review of illness during the US Civil War, World War I,

and World War II suggests that outbreaks of hantaviral

infections occurred among troops. Hantaviral disease

was described in Manchuria along the Amur River,

and later among United Nations troops during the

Korean War, where it became known as Korean HF. 19

The prototype virus from this group, Hantaan, which

causes Korean HF with renal syndrome (HFRS), was

isolated in 1977. The reservoir host for Hantaan virus

is the striped field mouse ( Apodemus agrarius) .

Hantaan virus is still active in Korea, Japan, and

China. Seoul virus, which is carried mainly by the

house rat ( Rattus norvegicus) , causes a milder form of

HFRS and may be distributed worldwide. Other han-

taviruses associated with HFRS include the Puumala

virus, which is associated with bank voles ( Clethriono-

mys glareolus ). An epidemic in 1993 in the Four Corners

region of the United States led to the identification of

a new hantavirus (Sin Nombre virus), and eventually

to identification of several related viruses (Black Creek

Canal, New York, Andes, and Bayou); all of these have

been associated with HPS. 20,21 The classical features of

the syndrome of acute febrile illness associated with

prominent cardiopulmonary compromise have been

extended to clinical variants, including disease with

frank hemorrhage. 21

fatal cases among residents and travelers in southeast

Africa. In 1998–2000, an outbreak of Marburg HF in

Durba, Democratic Republic of the Congo, was linked

to individuals working in a gold mine. 23 In 2004–2005

there was a Marburg virus outbreak in Angola that

caused over 200 deaths (90% mortality). 24

Ebola viruses, taxonomically related to Marburg

viruses, were first recognized during near-simultane-

ous explosive outbreaks in 1976 in small communities

in the former Zaire (now the Democratic Republic

of the Congo) 25 and Sudan. 26 Reuse of unsterilized

needles and syringes and nosocomial contacts caused

significant secondary transmission. These independent

outbreaks involved serologically distinct viral species.

The Ebola-Zaire outbreak involved 318 cases and 280

deaths (88% mortality), and the Ebola-Sudan outbreak

involved 280 cases and 148 deaths (53% mortality).

Since 1976 Ebola virus has appeared sporadically in

Africa, causing several small- to mid-size outbreaks

between 1976 and 1979. In 1995 a large epidemic of

Ebola-Zaire HF involving 315 cases occurred, with an

81% case fatality rate, in Kikwit, a community in the

former Zaire. 27 Meanwhile, between 1994 and 1996, the

Ebola-Zaire virus caused smaller outbreaks in Gabon. 28

In 2000 Gulu, Uganda, suffered a large epidemic of

VHF attributed to the Sudan species of Ebola virus. 29

More recently, Gabon and the Republic of Congo suf-

fered small VHF outbreaks attributed to Ebola-Zaire

virus. The most recent outbreaks in Gabon and the

Republic of Congo also involved a catastrophic decline

in populations of great apes, which may have a role in

transmission to humans. 30,31

In 1989 a third species of Ebola virus appeared in

Reston, Virginia, in association with an outbreak of

VHF among cynomolgus monkeys ( Macaca fascicularis )

imported to the United States from the Philippine

Islands. 1 Hundreds of monkeys were infected (with

high mortality) in this episode, but no human cases

occurred, although four animal caretakers seroconver-

ted without overt disease. Epizootics in cynomolgus

monkeys recurred at other facilities in the United States

and Europe through 1992 and again in 1996. The lack

of human disease in these episodes suggests that the

Reston species of Ebola may be less pathogenic to hu-

mans, although the pathogenic potential in humans is

unknown. A fourth species of Ebola virus, Ivory Coast,

was identified in Côte d’Ivoire in 1994; this species was

associated with chimpanzees, and only one nonfatal

human infection was identified. 32

Little is known about the natural history of filovi-

ruses. Surveys in Central Africa of a variety of species

of animals and arthropods have yet to conclusively

identify a reservoir host. Laboratory studies have

shown that fruit and insectivorous bats can support

Filoviridae

Marburg virus and Ebola virus, the causative agents

of Marburg and Ebola HF, respectively, represent the

two genera that comprise the family Filoviridae . The

Marburgvirus genus contains a single species: Lake

Victoria marburgvirus . The Ebolavirus genus is divided

into four distinct species: (1) Ivory Coast ebolavirus , (2)

Reston ebolavirus , (3) Sudan ebolavirus , and (4) Zaire

ebolavirus . By electron microscopy, filoviruses have

a highly unusual filamentous appearance. The term

filovirus was derived from “filo,” which is Latin for

thread. Marburg virus was first recognized in 1967

when three simultaneous outbreaks of a lethal VHF

epidemic occurred at Marburg and Frankfurt, Ger-

many, and Belgrade, Yugoslavia, among laboratory

workers exposed to the blood and tissues of African

green monkeys ( Chlorocebus aethiops ) imported from

Uganda. Secondary transmission to medical person-

nel and family members was also documented. 22 A

clinician recognized the initial outbreak in Marburg. 22

Thirty-one patients became infected, and seven died.

The 23% human mortality and bizarre morphology of

the newly discovered virus had a great psychological

impact and led to new quarantine procedures for im-

ported animals. During the next two decades, Marburg

virus was associated with sporadic, isolated, usually

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