1642 PART 5 Infectious Diseases

is found and if laboratory monitoring of therapy is feasible; there is no

proven benefit of such therapy. The available evidence suggests that VHF

patients have decreased cardiac output and will respond poorly to fluid

loading, which is often practiced in the treatment of shock associated

with bacterial sepsis. Specific therapy is available for several of the VHFs.

Strict barrier nursing and other precautions against infection of medical

staff and visitors are indicated when VHFs are encountered, except when

the illness is due to dengue viruses 1–4, orthohantaviruses, Rift Valley

fever virus, or yellow fever virus.

Novel VHF-causing agents are still being discovered. Besides the

viruses listed below, the latest additions are the severe fever with

thrombocytopenia syndrome bandavirus (which is continuing to cause

VHF cases in China, Japan, the Republic of Korea, and Vietnam) and

possibly the tibrovirus Bas-Congo virus (which has been associated

with three cases of VHF in the Democratic Republic of the Congo).

However, Koch’s postulates have not yet been fulfilled to prove cause

and effect in the case of Bas-Congo virus.

Bunyavirals The most significant VHF-causing bunyavirals are

arenavirids (Junín, Lassa, and Machupo viruses), hantavirids, nairovirids

(Crimean-Congo hemorrhagic fever virus), and phenuivirids (Rift Valley fever and severe fever with thrombocytopenia syndrome viruses).

Other bunyavirals—e.g., the Garissa variant of Ngari virus and Ilesha

virus (both orthobunyaviruses) or Chapare, Guanarito, Lujo, and Sabiá

viruses (all mammarenaviruses)—have caused sporadic VHF outbreaks.

ARGENTINIAN AND BOLIVIAN HEMORRHAGIC FEVERS These severe

diseases (with lethality reaching 15–30%) are caused by Junín virus and

Machupo virus, respectively. Their clinical presentations are similar, but

their epidemiology differs because of the distribution and behavior of

the viruses’ rodent reservoirs. Argentinian hemorrhagic fever has thus

far been recorded only in rural areas of Argentina, whereas Bolivian

hemorrhagic fever seems to be confined to rural Bolivia. Infection with

the causative agents almost always results in disease, and all ages and

both sexes are affected. Person-to-person or nosocomial transmission

is rare but has occurred. The transmission of Argentinian hemorrhagic

fever from convalescing men to their wives suggests the need for counseling of patients with mammarenavirus hemorrhagic fever concerning

the avoidance of intimate contacts for several weeks after recovery. In

contrast to the pattern in Lassa fever (see below), thrombocytopenia—

often marked—is the rule, hemorrhage is common, and CNS dysfunction (e.g., marked confusion, tremors of the upper extremities and

tongue, and cerebellar signs) is much more common in disease caused

by Junín virus and Machupo virus. Some cases follow a predominantly

neurologic course, with a poor prognosis.

The clinical laboratory is helpful in diagnosis since thrombocytopenia, leukopenia, and proteinuria are typical findings. Argentinian hemorrhagic fever is readily treated with convalescent-phase plasma given

within the first 8 days of illness. In the absence of passive antibody therapy, IV ribavirin in the dose recommended for Lassa fever is likely to be

effective in all South American VHFs caused by mammarenaviruses. A

safe, effective, live attenuated vaccine exists for Argentinian hemorrhagic

fever. After vaccination of >250,000 high-risk people in the endemic

area, the incidence of this VHF decreased markedly. In experimental animals, this vaccine is cross-protective against Bolivian hemorrhagic fever.

LASSA FEVER Lassa virus is known to cause endemic and epidemic

disease in Nigeria, Sierra Leone, Guinea, and Liberia, although it is

probably more widely distributed in Western Africa. In countries

where Lassa virus is endemic, Lassa fever can be a prominent cause of

febrile disease. For example, in one hospital in Sierra Leone, laboratoryconfirmed Lassa fever is consistently responsible for one fifth of admissions to the medical wards. In Western Africa alone, probably tens of

thousands of Lassa virus infections occur annually. Lassa virus can be

transmitted by close person-to-person contact. The virus is often present in urine during convalescence and has been detected in seminal

fluid early in recovery. Nosocomial spread has occurred but is uncommon if proper sterile parenteral techniques are used. All ages and both

sexes are affected; the incidence of disease is highest in the dry season,

but transmission takes place year-round.

Among the VHF agents, only mammarenaviruses are typically associated with a gradual onset of illness, which begins after an incubation

period of 5–16 days. Hemorrhage is seen in only ~15–30% of Lassa

fever patients; a maculopapular rash is often noted in light-skinned

patients. Effusions are common, and male-dominant pericarditis may

develop late in infection. Lethality among pregnant women is higher

than the usual 15–30% and is especially increased during the last

trimester. Fetal lethality reaches 90%. Excavation of the uterus may

increase survival rates of pregnant women, but data on Lassa fever and

pregnancy are still sparse. These figures suggest that interruption of the

pregnancy of women infected with Lassa virus should be considered.

White blood cell counts are normal or slightly elevated, and platelet

counts are normal or somewhat low. Deafness coincides with clinical

improvement in ~20% of patients and is permanent and bilateral in

some patients. Reinfection may occur but has not been associated with

severe disease.

High-level viremia or high serum AST activity statistically predicts

a fatal outcome. Data from randomized controlled trials is needed to

identify the optimal LASV-specific treatment to accompany aggressive supportive and critical care. Observational studies of Lassa fever

patients in the 1980's informed the current practice of treating patients

with ribavirin (intravenous route preferred). This antiviral nucleoside

analogue appears to be partially effective in reducing lethality from

that documented among retrospective controls. However, possible

side effects, such as reversible anemia (which usually does not require

transfusion), dependent hemolytic anemia, and bone marrow suppression, need to be kept in mind. Ribavirin should be given by slow

IV infusion in a dose of 32 mg/kg; this dose should be followed by

16 mg/kg every 6 h for 4 days and then by 8 mg/kg every 8 h for 6 days.

Inactivated Lassa virus vaccines failed in preclinical studies, but several

promising vaccine platforms are under experimental evaluation.

HEMORRHAGIC FEVER WITH RENAL SYNDROME HFRS is the most

significant VHF today, with >100,000 cases of severe disease in Asia

annually and thousands of mild infections in Europe. The disease

is widely distributed in Eurasia. The major causative viruses are

Puumala virus (Europe), Dobrava virus (the Balkans), and Hantaan

virus (Eastern Asia). Amur, gōu, Kurkino, Muju, Saaremaa, Sochi, and

Tula viruses also cause HFRS but much less frequently and in more

geographically confined areas that are determined by the distribution

of reservoir hosts. Seoul virus is an exception in that it is associated

with brown rats (Rattus norvegicus); therefore, the virus has a worldwide distribution because of the migration of these rodents on ships.

Despite the wide distribution of Seoul virus, only mild or moderate

HFRS occurs in Asia, and human disease has been difficult to identify in many areas of the world. Most cases of HFRS occur in rural

residents or vacationers; again, the exception is Seoul virus infection,

which may be acquired in an urban, rural, or laboratory setting. Classic

Hantaan virus infection in Korea and in rural China is most common

in the spring and fall and is related to rodent density and agricultural

practices. Human infection is acquired primarily through aerosols of

rodent urine, although virus is also present in rodent saliva and feces.

Patients with HFRS are not infectious.

Severe cases of HFRS evolve in four identifiable stages:

1. The febrile stage lasts 3 or 4 days and is identified by the abrupt

onset of fever, headache, severe myalgia, thirst, anorexia, and often

nausea and vomiting. Photophobia, retroorbital pain, and pain on

ocular movement are common, and the vision may become blurred

with ciliary body inflammation. Flushing over the face, the V area

of the neck, and the back is characteristic, as are pharyngeal injection, periorbital edema, and conjunctival suffusion. Petechiae often

develop in areas of pressure, the conjunctivae, and the axillae. Back

pain and tenderness to percussion at the costovertebral angle reflect

massive retroperitoneal edema. Laboratory evidence of mild to

moderate DIC is present. Other laboratory findings of HFRS include

proteinuria and active urinary sediment.

2. The hypotensive stage lasts from a few hours to 48 h and begins

with falling blood pressure and sometimes shock. The relative

bradycardia typical of the febrile phase is replaced by tachycardia.

1643CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

Kinin activation is marked. The rising hematocrit reflects increasing vascular leakage. Leukocytosis with a left shift develops, and

thrombocytopenia continues. Atypical lymphocytes—which, in fact,

are activated CD8+ and, to a lesser extent, CD4+ T cells—circulate.

Proteinuria is marked, and the urine’s specific gravity falls to 1.010.

Renal circulation is congested and compromised from local and

systemic circulatory changes resulting in necrosis of tubules, particularly at the corticomedullary junction, and oliguria.

3. During the oliguric stage, hemorrhagic tendencies continue, probably in large part because of uremic bleeding defects. Oliguria persists

for 3–10 days before the return of renal function marks the onset of

the polyuric stage.

4. The polyuric stage (diuresis and hyposthenuria) carries the danger of

dehydration and electrolyte abnormalities.

Mild cases of HFRS may be much less stereotypical. The presentation may include only fever, gastrointestinal abnormalities, and

transient oliguria followed by hyposthenuria. Infections with Puumala

virus, the most common cause of HFRS in Europe (nephropathia epidemica), result in a much-attenuated picture but the same general presentation. Bleeding manifestations are found in only 10% of patients,

hypotension rather than shock is usually documented, and oliguria

is present in only about half of patients. The dominant features may

be fever, abdominal pain, proteinuria, mild oliguria, and sometimes

blurred vision or glaucoma, followed by polyuria and hyposthenuria in

recovery. Lethality is <1%.

HFRS should be suspected in patients with rural exposure in an

endemic area. Prompt recognition of the disease permits rapid hospitalization and expectant management of shock and renal failure.

Useful clinical laboratory parameters include leukocytosis, which may

be leukemoid and is associated with a left shift; thrombocytopenia;

and proteinuria. HFRS is readily diagnosed by an IgM-capture ELISA

that is positive at admission or within 24–48 h thereafter. The isolation

of orthohantaviruses is difficult, but RT-PCR of a blood clot collected

early in the clinical course or of tissues obtained postmortem should

give positive results. Such testing is usually undertaken if definitive

identification of the infecting virus is required.

Mainstays of therapy are management of shock, reliance on vasopressors, modest crystalloid infusion, IV human serum albumin

administration, timely renal replacement therapy to prevent overhydration that may result in pulmonary edema, and control of hypertension that increases the possibility of intracranial hemorrhage. Use of IV

ribavirin has reduced lethality and morbidity in severe cases, provided

treatment is begun within the first 4 days of illness. Lethality may be

as high as 15% but, with proper therapy, lethality should be lower than

5%. Sequelae have not been definitively established.

CRIMEAN-CONGO HEMORRHAGIC FEVER (CCHF) This severe VHF

has a wide geographic distribution, potentially emerging wherever virus-bearing ticks occur. Because of the propensity of CCHF

virus-transmitting ticks to feed on domestic livestock and certain wild

mammals, veterinary serosurveys are the most effective mechanism

for the monitoring of virus circulation in a particular region. Human

infections are acquired via tick bites or during the crushing of infected

ticks. Domestic animals do not become ill but do develop viremia.

Thus, risk of acquiring CCHF occurs during sheep shearing, animal

slaughter, or contact with infected hides or carcasses from recently

slaughtered infected animals. Nosocomial epidemics are common and

are usually related to extensive blood exposure or needlesticks.

Although generally similar to other VHFs, CCHF causes extensive

liver damage, resulting in jaundice in some patients. Clinical laboratory

values indicate DIC, elevations in activities of AST and creatine phosphokinase, and elevated bilirubin concentrations. Generally, patients

who do not survive have more distinct changes in the concentrations

of these markers than do survivors, even in the early days of illness,

and also develop leukocytosis rather than leukopenia. In addition,

thrombocytopenia is more marked and develops earlier in patients

who do not survive than in survivors. The mainstay of treatment is

supportive care that may include support of organ dysfunction. The

benefit of IV ribavirin for treatment remains debated and unproven.

Clinical experience and retrospective comparison of patients with ominous clinical laboratory values support a contention that ribavirin may

be efficacious, but a randomized clinical trial was not supportive of a

benefit in lowering lethality rates. No human or veterinary vaccines are

recommended.

RIFT VALLEY FEVER The natural range of Rift Valley fever virus was

previously confined to sub-Saharan Africa, with circulation of the

virus markedly enhanced by substantial rainfall. The El Niño Southern Oscillation phenomenon of 1997 facilitated subsequent spread

of Rift Valley fever to the Arabian Peninsula, with epidemic disease

in 2000. The virus has also been found in Madagascar and Egypt,

where it caused major epidemics in 1977–1979, 1993, and thereafter.

Rift Valley fever virus is maintained in nature by transovarial transmission in floodwater Aedes mosquitoes and presumably also has a

vertebrate amplifier. Increased transmission during particularly heavy

rains leads to epizootics characterized by high-level viremia in cattle,

goats, or sheep. Numerous types of mosquitoes feed on these animals

and become infected, thereby increasing the possibility of human

infections. Remote sensing via satellite can detect the ecologic changes

associated with high rainfall that predict the likelihood of Rift Valley

fever virus transmission. High-resolution satellites can also detect the

special depressions in floodwaters from which the mosquitoes emerge.

The virus can be transmitted by contact with blood or aerosols from

domestic animals. Therefore, transmission risk is high during birthing,

and both abortuses and placentas need to be handled with caution.

Risk is also high during animal slaughter but decreases thereafter as

anaerobic glycolysis in postmortem tissues results in an acidic environment that rapidly inactivates bunyavirals in carcasses. Neither

person-to-person nor nosocomial transmission of Rift Valley fever has

been documented.

Rift Valley fever virus is unusual in that it causes several clinical

syndromes. Most infections are manifested as the fever-myalgia syndrome. A small proportion of infections result in VHF with especially

prominent liver involvement or encephalitis. Renal failure and DIC are

also common features. Perhaps 10% of otherwise mild infections lead

to retinal vasculitis, and some patients have permanently impaired

vision. Funduscopic examination reveals edema, hemorrhages, and

infarction of the retina as well as optic nerve degeneration. In a small

proportion of patients (<1 in 200), retinal vasculitis is followed by viral

encephalitis.

No proven therapy exists for Rift Valley fever. Both retinal disease

and encephalitis occur after the acute febrile syndrome has resolved

and serum neutralizing antibody has developed—but the immunopathophysiology is uncertain. Epidemic disease is best prevented by

vaccination of livestock. The ability of this virus to propagate after

introduction into Egypt suggests that other potentially receptive areas,

including the United States, should develop response plans. Rift Valley

fever, like Venezuelan equine encephalitis, is likely to be controlled

only with adequate stocks of an effective live attenuated vaccine, but

global stocks are unavailable. A formalin-inactivated vaccine confers immunity in humans; however, quantities are limited, and three

injections are required. This vaccine is recommended for potentially

exposed laboratory workers and for veterinarians working in subSaharan Africa. A new live attenuated vaccine, MP-12, is being tested

in humans (phase 2 trials have been completed). The vaccine is safe

and licensed for use in sheep and cattle. In addition, several vaccines

are being developed specifically for use in animals.

SEVERE FEVER WITH THROMBOCYTOPENIA SYNDROME This tickborne disease is caused by severe fever with thrombocytopenia syndrome bandavirus. Numerous human infections have been reported

during the past few years from China, and several cases have also been

detected in Japan, the Republic of Korea, and Vietnam. The clinical

presentation ranges from mild nonspecific fever to severe VHF with

high (>12%) lethality.

Flaviviruses The most significant flaviviruses that cause VHF are

the mosquito-borne dengue viruses 1–4 and yellow fever virus. These

viruses are widely distributed and cause tens to hundreds of thousands

1644 PART 5 Infectious Diseases

of infections each year. Alkhurma hemorrhagic fever virus (isolated

infections every year), Kyasanur Forest disease virus (~10,000 cases

over 60 years), and Omsk hemorrhagic fever virus (isolated infections

every year with intermittent larger outbreaks) are geographically very

restricted but prevalent tick-borne flaviviruses that cause VHF, sometimes with subsequent viral encephalitis. Tick-borne encephalitis virus

has caused VHF in a few patients. There is currently no therapy for

infection with these VHFs, but an inactivated vaccine has been used in

India to prevent Kyasanur Forest disease.

SEVERE DENGUE Although most individuals infected with dengue

virus 1, 2, 3, or 4 have either subclinical infection or fever and myalgia

syndrome, some of these patients enter a critical phase—often as fever

declines—and develop the criteria for severe dengue: plasma leakage

severe enough to cause shock or respiratory distress, severe bleeding,

or severe organ dysfunction. The complex determinants of risk for this

progression include contributing host and viral factors but center most

notably around the potential for immune-mediated enhancement of

disease. Several weeks after convalescence from infection with dengue

virus 1, 2, 3, or 4, the transient protection conferred by that infection

against reinfection with a heterotypic dengue virus usually wanes. Heterotypic reinfection may result in classic dengue without/with warning

signs or, less commonly, in severe dengue. In the past 20 years, yellow

fever mosquitoes (Ae. aegypti) have progressively reinvaded Latin

America and other areas, and frequent travel by infected individuals

has introduced multiple variants of dengue viruses 1–4 from many

geographic areas. Thus, the pattern of hyperendemic transmission of

multiple dengue virus serotypes established in the Americas and the

Caribbean has led to the emergence of severe dengue as a major problem. Among the millions of dengue viruses 1–4 infections, ~500,000

cases of severe dengue occur annually, with a lethality of ~2.5%. The

induction of vascular permeability and shock depends on multiple factors, such as the presence or absence of enhancing and nonneutralizing

antibodies, age (susceptibility to severe dengue drops considerably

after 12 years of age), sex (females are more often affected than males),

race (whites are more often affected than Black people), nutritional status, and timing and sequence of infections (e.g., dengue virus 1 infection followed by dengue virus 2 infection seems to be more dangerous

than dengue virus 4 infection followed by dengue virus 2 infection). In

addition, considerable heterogeneity exists among each dengue virus

population. For instance, South-Eastern Asian dengue virus 2 variants

have more potential to cause severe dengue than do other variants.

Recent evidence points to a key role for the dengue virus NS1 protein

in the vascular leak phenomenon associated with severe dengue.

In milder cases of severe dengue, restlessness, lethargy, thrombocytopenia (<100,000 per μL), and hemoconcentration are detected 2–5

days after the onset of typical dengue, usually at the time of defervescence. The maculopapular rash that often develops in dengue without/

with warning signs may also appear in severe dengue. However, severe

dengue is most notoriously identified as the consequence of a vascular

leak syndrome leading to intravascular volume depletion, hypoalbuminemia, serosal effusions (pleural, ascitic), and, in severe cases,

circulatory collapse (i.e., shock), often with an accompanying narrowed

pulse pressure, hepatomegaly, and cyanosis. Recognizing this critical

period early enough to initiate appropriate supportive care is crucial.

(Shock typically lasts 2 or 3 days.) Bleeding tendencies (evidenced by a

positive tourniquet test and petechiae) or overt bleeding in the absence

of underlying causes (e.g., preexisting gastrointestinal lesions) may be

detected but are less common in children. Organ involvement may

include mild hepatic injury, CNS abnormalities (e.g., altered mental

status, seizures), cardiac abnormalities (e.g., arrhythmias), renal disturbances (e.g., acute kidney injury), and ocular dysfunction.

A virologic diagnosis of severe dengue can be made by the usual

means (nucleic acid amplification or antigen detection) in the first

5 days of infection, after which diagnosis rests on serologic testing.

Combination testing—point-of-care rapid tests for NS1 antigen and

IgM antibody assays—is increasingly used in the clinical setting. However, multiple flavivirus infections result in broad immune responses to

several members of the genus, and this situation may result in a lack of

virus specificity of the IgM and IgG immune responses. A secondary

antibody response can be sought with tests against several flavivirus

antigens to demonstrate the characteristic wide spectrum of reactivity.

Most patients with shock respond promptly to close monitoring,

oxygen administration, and infusion of crystalloid or—in severe

cases—colloid. Lethality varies greatly with case ascertainment and

quality of treatment. However, most patients with severe dengue

respond well to supportive therapy, and the overall lethality at an experienced center in the tropics is probably as low as 1%.

The key to control of both dengue without/with warning signs

and severe dengue is the control of yellow fever mosquitoes, which

also reduces the risk of urban yellow fever and chikungunya virus

circulation. Control efforts have been handicapped by the presence

of nondegradable tires and long-lived plastic containers in trash

repositories—creating perfect mosquito breeding grounds upon filling with water during rainfall—and by insecticide resistance. Urban

poverty and an inability of the public health community to mobilize

the populace to respond to the need to eliminate mosquito breeding

sites are also factors in lack of mosquito control. New approaches that

may be considered in the future of vector control include the release of

Aedes mosquitoes infected with Wolbachia or carrying dominant lethal

genetic mutations that will be passed on to offspring. A tetravalent live

attenuated dengue vaccine based on the attenuated yellow fever virus

17D platform (CYD-TDV, or Dengvaxia) was licensed in 2015 and

registered in 20 countries for individuals 9–45 years of age. However,

retrospective analysis of phase 3 trials in Latin America and Asia suggested protection from severe dengue only in previously seropositive

individuals; indeed, the risk of severe dengue was actually increased

in seronegative vaccine recipients over that in nonvaccinated seronegative individuals, a result suggesting that a “first serologic hit” from

the vaccine predisposes naïve recipients to more severe natural dengue

infection. Strategic revision to avoid vaccine-enhanced disease now

includes prevaccination serologic screening aimed at the restriction

of vaccination to seropositive individuals. At least two live attenuated

candidate vaccines based on modified recombinant dengue viruses

are being evaluated in phase 3 clinical studies; similar concerns about

safety are being addressed.

YELLOW FEVER Yellow fever virus had caused major epidemics in

Africa and Europe before its transmission by yellow fever mosquitoes

(Ae. aegypti) was discovered in 1900. Urban yellow fever became established in the New World as a result of colonization with yellow fever

mosquitoes—originally an African mosquito. Subsequently, different

types of mosquitoes and nonhuman primates were found to maintain

yellow fever virus in Africa and also in Central and South American

jungles. Transmission to humans is incidental, occurring via bites from

mosquitoes that have fed on viremic monkeys. After the identification

of Ae. aegypti as the vector of yellow fever, containment strategies were

aimed at increased mosquito control. Today, urban yellow fever transmission occurs only in some African cities, but the threat exists in the

cities of South America, where reinfestation by yellow fever mosquitoes

has taken place, and dengue viruses 1–4 transmission by these mosquitoes is common. Despite the existence of a highly effective and safe

vaccine, several hundred jungle cases of yellow fever occur annually

in South America, and 84,000–170,000 severe jungle and urban cases

(resulting in 29,000–60,000 deaths) occurred in Africa in 2013 alone.

In 2016, a large urban outbreak (Luanda, Angola) spilled over to generate local transmission in large cities in neighboring countries (e.g.,

Kinshasa, Democratic Republic of the Congo) as well as travel-related

cases in China; the signal of a global threat that included exportation to

Asia stimulated ongoing efforts to identify and vaccinate highest-risk

populations in 40 targeted countries in Africa and South America, to

reactively vaccinate people in outbreak settings, and to increase measures to prevent exportation.

Yellow fever is a typical VHF accompanied by prominent hepatic

necrosis. After an incubation period of 3–6 days, patients present

with a nonspecific febrile illness (fatigue, myalgia, backache, headaches, photophobia, anorexia, nausea or vomiting) associated with

viremia typically lasting 3–4 days. After defervescence, 10–15% of

1645CHAPTER 210 Ebolavirus and Marburgvirus Infections

patients develop recrudescent fever and “intoxication” characterized

by severe dysfunction of the liver and other organs. Hepatic failure

leads to the characteristic jaundice, bleeding (gastrointestinal tract,

nasopharyngeal mucosa), abdominal pain with nausea and vomiting,

and hyperammonemic encephalopathy; acute kidney injury leads to

oliguria, azotemia, and marked albuminuria; and myocardial injury

and encephalitis have been described. Abnormalities in liver function

tests range from modest elevations of hepatic aminotransferase activities in mild cases to severe liver injury, hyperbilirubinemia, and the

synthetic dysfunction of acute hepatic failure. Early leukopenia may

become leukocytosis as disease progresses, and coagulation abnormalities are common. Treatment is supportive only. Although the majority

of infections are subclinical, 50% of patients who enter the toxic phase

die in the next 7–10 days.

Urban yellow fever can be prevented by the control of yellow fever

mosquitoes. The continuing sylvatic cycles require vaccination of all

visitors to areas of potential transmission with live attenuated variant 17D vaccine virus, which cannot be transmitted by mosquitoes.

With few exceptions, reactions to the vaccine are minimal; immunity is provided within 10 days and lasts for at least 25–35 years. An

egg allergy mandates caution in vaccine administration. Although

there are no documented harmful effects of the vaccine on fetuses,

pregnant women should be immunized only if they are definitely at

risk of exposure to yellow fever virus. Because vaccination has been

associated with several cases of encephalitis in children <6 months of

age, it is contraindicated in this age group and not recommended for

infants 6–8 months of age unless the risk of exposure is very high. Rare,

serious, multisystemic adverse reactions (occasionally fatal), including

vaccine-associated “viscerotropic” yellow fever, have been reported,

particularly affecting the elderly, and the risk-to-benefit ratio should be

weighed before vaccine administration to individuals ≥60 years of age.

Nevertheless, the number of deaths of unvaccinated travelers with yellow fever exceeds the number of deaths from vaccination, and a liberal

vaccination policy for travelers to involved areas should be pursued.

Timely information on changes in yellow fever distribution and yellow

fever vaccine requirements can be obtained from the U.S. Centers for

Disease Control and Prevention (http://www.cdc.gov/vaccines/vpd-vac/

yf/default.htm).

Acknowledgment

The authors gratefully acknowledge the major contributions of Clarence

J. Peters and additional contributions by Rémie N. Charrel to this chapter

in previous editions.

■ FURTHER READING

Centers for Disease Control and Prevention: Arbovirus catalog.

Available at https://wwwn.cdc.gov/arbocat/. Accessed May 24, 2021.

Howley PM, Knipe DM (eds): Fields Virology. Volume 1: Emerging

Viruses, 7th ed. Philadelphia, Wolters Kluwer/Lippincott Williams &

Wilkins, 2020.

International Committee on Taxonomy of Viruses (ICTV):

Virus taxonomy: The ICTV report on virus classification and taxon

nomenclature. Available at https://talk.ictvonline.org/ictv-reports/

ictv_online_report/. Accessed May 24, 2021.

Lvov DK et al: Zoonotic Viruses of Northern Eurasia: Taxonomy and

Ecology. London, Elsevier/Academic Press, 2015.

Singh SK, Ruzek D (eds): Viral Hemorrhagic Fevers. Boca Raton, FL,

CRC Press, 2013.

Vasilakis N, Gubler DJ (eds): Arboviruses: Molecular Biology, Evolution and Control. Haverhill, UK, Caister Academic Press, 2016.

■ WEBSITE

International Committee on Taxonomy of Viruses (ICTV).

https://talk.ictvonline.org/. Accessed May 24, 2021.

Several viruses in the family Filoviridae cause severe and frequently

fatal infections in humans. Introduction of filoviruses into human

populations is an extremely rare event that most likely occurs by direct

or indirect contact with reservoir hosts (known and unknown) or by

contact with filovirus-infected, sick, or deceased mammals. Filoviruses

are highly infectious but not exceptionally contagious. Human-tohuman transmission takes place through direct person-to-person contact or exposure to infected body fluids or tissues; there is no evidence of

aerosol or respiratory droplet transmission in natural outbreak settings.

Infections manifest initially with a nonspecific influenza-like febrile

illness that rapidly progresses to commonly include gastrointestinal

manifestations and, in severe illness, coagulopathy, multiple-organ

dysfunction syndrome, shock, and death. Although the prevalence

and source remain controversial, serologic footprints of subclinical

acute filoviral infections have been identified since the first descriptions of filovirus disease outbreaks. Filovirus disease survivors may

be persistently infected in immune-privileged tissue compartments,

commonly the male reproductive tract, central nervous system (CNS),

and intraocular tissues and fluids. Historically, the prevention of filovirus infections has consisted primarily of tried-and-true epidemiologic

approaches (e.g., isolation of cases, tracing of contacts, effective infection prevention and control, safe burial practices), and treatment has

consisted only of limited supportive clinical care (often constrained

by in-field capacity); indeed, filovirus-specific vaccines or therapeutic agents had not been rigorously evaluated in humans prior to the

2013–2016 outbreak of Ebola virus disease (EVD) that occurred in

Western Africa. Building on the knowledge gained in Western Africa

and during the 2018–2020 EVD outbreak in the Democratic Republic

of the Congo, prevention and treatment strategies now include the

widespread deployment of an effective Ebola virus–specific vaccine;

the use of effective therapeutics based on virus-specific monoclonal

antibodies (mAbs), which were identified in a first-of-its-kind randomized controlled trial; and the delivery of more advanced supportive

care. Although these advances have essentially become new standards

for prevention and treatment of EVD, the same cannot yet be said for

other filovirus diseases.

Filoviruses are categorized as World Health Organization (WHO)

Risk Group 4 pathogens. Consequently, all work with material suspected of containing replicating filoviruses should be conducted only

in maximal containment (biosafety level 4) laboratories, or the viruses

should be inactivated prior to analysis in biosafety level 2 laboratories.

Experienced personnel handling these viruses must wear appropriate

personal protective equipment (PPE; see “Control and Prevention,”

below) and follow rigorous standard operating procedures. In addition, when filovirus infections are suspected, the appropriate national

authorities and WHO reference laboratories should be contacted

immediately.

■ ETIOLOGY

The family Filoviridae includes six official and two proposed genera

(Table 210-1 and Fig. 210-1). Human pathogens are found in two

of these genera, Ebolavirus and Marburgvirus. Collectively, these

pathogens cause filovirus disease (FVD; International Classification of

Diseases, Eleventh Revision [ICD-11], code 1D60). FVD is subdivided

into Ebola disease (EBOD; ICD-11, code 1D60.0), caused by four of

six classified ebolaviruses (Bundibugyo virus, Ebola virus, Sudan virus,

and Taï Forest virus), and Marburg disease (MARD; ICD-11, code

1D60.1), caused by the two marburgviruses, Marburg virus and Ravn

virus.

210 Ebolavirus and

Marburgvirus Infections

Jens H. Kuhn, Ian Crozier

1646 PART 5 Infectious Diseases

helical ribonucleoprotein capsids and are covered with GP1,2 spikes

(Fig. 210-2).

■ EPIDEMIOLOGY

The majority of recorded FVD outbreaks, including the 2013–2016

EVD outbreak, can be traced back to single index patients who

transmitted the infection to others. Although small outbreaks may

have been missed historically, the epidemiology of these transmission

chains suggests that only ~50 natural host-to-human spillover events

have occurred since the discovery of filoviruses in 1967. Outbreak frequency, size, and overall case–fatality rate are likely the result of complex interactions of the specific filovirus, the reservoir hosts (known

and unknown), the susceptible human population (e.g., varying with

age, unknown genetic determinants of susceptibility and disease severity, risk behavior), and the geographic setting (e.g., local public health

capacity, socioeconomic conditions, cultural practices).

As of August 25, 2021, 35,311 human filovirus infections and 15,758

deaths had been recorded (Fig. 210-3). These numbers emphasize

both the high case–fatality rate (number of deaths per number of sick

people; 44.6%) and the overall low mortality rate (reflecting the impact

on the healthy population) of filovirus infections. Of these totals,

28,652 infections and 11,325 deaths occurred during the 2013–2016

EVD (ICD-11 EBOD subcategory code 1D60.01) outbreak in Western

Africa; this was the largest of all recorded FVD outbreaks. Natural FVD

outbreaks had not been considered a global threat until regional and

then global spread during this outbreak challenged that tenet. Filoviruses that are pathogenic in humans appear to be exclusively endemic

to equatorial (Western, Middle, and Eastern) Africa (Fig. 210-4),

although this distribution may change if natural or artificial environmental alterations lead to filovirus host migration and increased

contacts between nonhuman hosts and humans.

Outbreaks have been contained when high-risk activities (e.g., ritual

washing as part of burial practices) have been limited or been made

safer with appropriate infection prevention and control. Of particular

importance is accessibility to health care centers with staff trained

and equipped (e.g., with PPE) for adequate prevention and control of

infections, which have a crucial effect on overall case numbers. The

incidence of FVD may have increased over the past two decades (Figs.

210-3 and 210-4), but debate continues as to whether this increase is

due to increased filovirus activity, more frequent human interaction

with filovirus hosts, or improvement in surveillance capabilities.

FVD outbreaks are associated with distinct meteorologic and geographic conditions and are probably associated with distinct hosts or

reservoirs. The four ebolaviruses that cause disease in humans appear

to be endemic in humid rainforests. EVD outbreaks in particular have

often been associated with hunting in forests or contact with bushmeat

(i.e., meat from apes, other nonhuman primates, duikers, or bush

pigs). Ecologic studies indicate that Ebola virus may play a role in

extensive and frequently fatal epizootics among wild ape populations.

However, only one ebolavirus, Taï Forest virus, has been isolated from

nonhuman primates in the wild. Marburgviruses, on the other hand,

seem to infect hosts inhabiting arid woodlands. MARD outbreaks have

almost always been epidemiologically linked to individuals visiting or

working in natural or engineered caves or mines. A pteropodid (fruit)

bat, the cave-dwelling Egyptian rousette (Rousettus aegyptiacus), serves

as a natural and subclinically infected reservoir for both Marburg virus

and Ravn virus. Although bats are suspected hosts for ebolaviruses as

well, definitive proof is lacking. To date, the nonpathogenic Bombali

virus is the only ebolavirus that has been isolated directly from bats.

Ebola virus and Reston virus have been loosely connected to frugivorous and insectivorous bats by means of antibody or genome fragment

detection, whereas the hosts of Bundibugyo virus, Sudan virus, and Taï

Forest virus are enigmatic.

■ PATHOGENESIS

Human infections typically occur through direct exposure of skin

lesions or mucosal surfaces to contaminated body fluids or material

or by parenteral inoculation (e.g., via accidental needlesticks or reuse

TABLE 210-1 Current Filovirus Taxonomy

Realm Riboviria

Kingdom Orthornavirae

 Phylum Negarnaviricota

 Subphylyum Haploviricotina

 Class Monjiviricetes

 Order Mononegavirales

 Family Filoviridae

 Genus Cuevavirus

 Species Lloviu cuevavirus

 Virus: Lloviu virus (LLOV)

 Genus Dianlovirus

 Species Mengla dianlovirus

 Virus: Meˇnglà virus (MLAV)

 Genus Ebolavirus

 Species Bombali ebolavirus

 Virus: Bombali virus (BOMV)

 Species Bundibugyo ebolavirus

 Virus: Bundibugyo virus (BDBV)

 Species Reston ebolavirus

 Virus: Reston virus (RESTV)

 Species Sudan ebolavirus

 Virus: Sudan virus (SUDV)

 Species Tai Forest ebolavirus

 Virus: Taï Forest virus (TAFV)

 Species Zaire ebolavirus

 Virus: Ebola virus (EBOV)

 Genus Marburgvirus

 Species Marburg marburgvirus

 Virus 1: Marburg virus (MARV)

 Virus 2: Ravn virus (RAVV)

 Genus “Oblavirus”

 Species “Oblavirus percae”

 Virus: Oberland virus (OBLV)

 Genus Striavirus

 Species Xilang striavirus

 Virus: Xῑlaˇng virus (XILV)

 Genus “Tapjovirus”

 Species “Tapjovirus bothropis”

 Virus: Tapajós virus (TAPV)

 Genus Thamnovirus

 Species Huangjiao thamnovirus

 Virus: Huángjia–

o virus (HUJV)

 Species “Thamnovirus kanderense”

 Virus: Kander virus (KNDV)

 Species “Thamnovirus percae”

 Virus: Fiwi virus (FIWIV)

Filoviruses that are known to infect humans are depicted in color. Officially

proposed taxa are indicated by quotation marks.

Mammalian filoviruses have linear, nonsegmented, negative-sense

RNA genomes that are ~19 kb in length. These genomes contain

seven genes that encode seven structural proteins: nucleoprotein

(NP), polymerase cofactor (VP35), matrix protein (VP40), glycoprotein (GP1,2), transcriptional activator (VP30), ribonucleoprotein

complex-associated protein (VP24), and large protein (L) that contains

an RNA-directed RNA polymerase domain. Ebolaviruses, but not marburgviruses, additionally encode three nonstructural proteins of

unknown function (sGP, ssGP, and Δ-peptide). Filovirions are unique

among human virus particles in that they are predominantly pleomorphic filaments but also assume torus-like or 6-like shapes (width

~91–98 nm; average length <1 μm). These enveloped virions contain

1647CHAPTER 210 Ebolavirus and Marburgvirus Infections

of needles in poorly equipped hospitals). Numerous studies, both in

vitro and in vivo (in several animal models of human disease), have

illuminated aspects of FVD pathogenesis (Fig. 210-5). The GP1,2 spikes

on the surface of filovirions determine their cell and tissue tropism by

engaging yet-unidentified cell-surface molecules and the intracellular

filovirus receptor NPC intracellular cholesterol transporter 1.

One of the hallmarks of filovirus pathogenesis is a pronounced modulation and dysregulation of immune responses. The first targets of

filovirions are local macrophages, monocytes, and dendritic cells. Several structural proteins of filovirions (i.e., VP35, VP40, and/or VP24)

then suppress intrinsic and innate immune responses by, for example,

inhibiting the type I interferon antiviral pathways. This immunomodulation ultimately enables a productive filovirus infection, resulting in

very high viral titers (>106

 plaque-forming units [PFU]/mL of serum

in humans) with dissemination to most tissues. In tissues, filovirions

infect additional phagocytic cells, including other macrophages (alveolar, peritoneal, and pleural macrophages; Kupffer cells in the liver; and

microglia in the CNS), epithelial cells (e.g., adrenal cortical cells, hepatocytes), stromal cells (fibroblasts), and endothelial cells. Infection is

cytolytic in some—but not all—infected cells (e.g., hepatocyte necrosis

likely contributes to elevated aminotransferase activities, and hepatic

synthetic dysfunction contributes to coagulopathy). Infection leads

to the secretion of soluble signaling molecules (varying with the cell

type) that most likely contribute to forward dysregulation of immune

responses and ultimately to multiorgan dysfunction syndrome. For

instance, infected macrophages react by secreting proinflammatory

cytokines, a response that leads to further recruitment of macrophages

to the site of infection. In contrast, infected dendritic cells are not activated to secrete cytokines, and expression of major histocompatibility

class II antigens is partially suppressed, with consequently deficient

antigen presentation. Immunosuppression also occurs in part by massive lymphoid depletion in lymph nodes, spleen, and thymus in the

absence of effective humoral and cell-mediated immune responses,

especially in lethal infections. Results from animal studies suggest that

depletion is a direct consequence of considerable lymphocyte death;

this explanation would also account for the severe lymphopenia that

develops in patients. In addition to potential florid filovirus dissemination, another consequence may be susceptibility of FVD patients to

secondary bacterial and fungal infections.

Other pathogenic hallmarks of filovirus infections include coagulopathy and endothelial dysfunction. Along with hepatic synthetic

dysfunction, disseminated intravascular coagulation may contribute

Cuevavirus

Dianlovirus

Ebolavirus

Marburgvirus

New genus?

Striavirus

“Oblavirus”

Thamnovirus

MN510772.2 FIWIV/P.flu/CHE/17/CH17

MW093492.1 KNDV/P.flu/CHE/17/CH17

MN510773.2 OBLV/P.flu/CHE/17/CH17

1

1

0.90

1

0.99 0.95

1 1

1

1

1

1

1

1

1

0.3

MF319185.1 BOMV/M.con/SLE/16/Nor-PREDICT_SLAB000156

KX371873.1 “Bat2162”

DQ447649.1 RAVV/H.sap/KEN/87/KiC-810040

AF522874.1 RESTV/M.fas/USA/89/Phi89-Pen

FJ217162.1 TAFV/H.sap/CIV/94/Pau-CI

KP233864.1 “BtFV/WD04”

AF086833.2 EBOV/H.sap/COD/76/Yam-May

FJ217161.1 BDBV/H.sap/UGA/07/But-811250

DQ217792.1 MARV/H.sap/KEN/80/MtE-Mus

AY729654.1 SUDV/H.sap/UGA/00/Gul-808892

JF828358.1 LLOV/M.sch/ESP/03/Ast-Bat86

MG599980.1 XILV/A.str/CHN/17/W n-XYHYS28627

MG599981.1 HUJV/T.sep/CHN/17/W n-LQMMTII17328

KX371887.2 MLAV/Rousettus/CHN/15/Sh -Bat9447-1

FIGURE 210-1 Filovirus phylogeny/evolution. Midpoint-rooted maximum-likelihood tree inferred by using filovirus large gene (L) sequences. Bootstrap values are shown at

each node. The scale bar indicates nucleotide substitutions per site. Tips of branches are labeled with GenBank accession numbers followed by filovirus isolate designation.

BDBV, Bundibugyo virus; BOMV, Bombali virus; EBOV, Ebola virus; FIWIV, Fiwi virus; HUJV, Huángjia–

o virus; KNDV, Kander virus; LLOV, Lloviu virus; MARV, Marburg virus;

MLAV, Meˇnglà virus; OBLV, Oberland virus; RAVV, Ravn virus; RESTV, Reston virus; SUDV, Sudan virus; TAFV, Taï Forest virus; XILV, Xῑlaˇng virus. (Adapted and expanded from

JH Kuhn et al: Filoviridae, in Fields Virology, Vol 1, 7th ed, PM Howley et al (eds). Philadelphia, Wolters Kluwer/Lippincott Williams & Wilkins, 2020, pp 449–503. Analysis

courtesy of Nicholas Di Paola, PhD, USAMRIID, Fort Detrick, MD, USA. Figure courtesy of Jiro Wada, NIH/NIAID/DCR/IRF-Frederick, Fort Detrick, MD, USA.)

FIGURE 210-2 Ultrastructure of filovirions. Left: Colorized scanning electron micrograph of Ebola virus particles (green) attached to the surface of an infected grivet

(Chlorocebus aethiops) Vero E6 producer cell (blue). Right: Colorized transmission electron micrograph of a Marburg virus particle collected from purified Vero E6 producer

cell supernatant. (Figure courtesy of John G. Bernbaum and Jiro Wada, NIH/NIAID/DCR/IRF-Frederick, Fort Detrick, MD, USA.)

1648 PART 5 Infectious Diseases

37 149

34 62

71 211

280 318

 1 1

32 52

245 317

1 1

21 31

46 62

97 124

10 11

128 143

29 35

1 1

 9 11

186 264

15 32

11,325 28,652

49 69

 4 8

33 54

 2287 3470

55 130

 6 12

12 23

 0 1

14,872 33,822

 0 1

0 1

151 284

0 1

22 34

224 425

 7 17

 1 1

17 24

 4 7

426 793

 0 1

0 1

15,369 34,828

 7 31

 1 3

 1 2

1 1

 0 1

128 153

227 252

 1 3

 0 1

 1 1

15 26

 1 1

 3 4

 1 1

387 480

 1 1

 1 1

 0 1

2 3

389 483

15,758 35,311

Country (Year)

MARV

Uganda Netherlands (2008)

Uganda USA (2008)

USSR (1988)

USSR (1990)

Kenya (1980)

Uganda (2007)

Rhodesia )5791( acirfA htuoS

Uganda (2017)

Uganda West Germany,

 Yugoslavia (1967)

COD (1998−2000)

Angola (2004−2005)

BDBV

COD (2012)

Uganda (2007−2009)

EBOV

Russia (2004)

Russia (1996)

Zaire (1977)

COG (2005)

COG Gabon (2002)

COD (2008−2009)

Gabon (1996)

Gabon (1994−1995)

COG (2003−2004)

Gabon South Africa (1996−1997)

Gabon; COG (2001−2002)

COD (2007)

COD (2017)

COG (2002−2003)

Zaire (1995)

Zaire (1976)

Guinea France, Germany, Italy, Liberia,

Mali, Netherlands, Nigeria,

Norway, Senegal, Sierra Leone,

Spain, Switzerland, UK, USA

(2013−2016)

SUDV

UK (1976)

Uganda (2011)

Uganda (2012)

Uganda (2012)

Sudan (2004)

Sudan (1979)

Sudan (1976)

Uganda (2000−2001)

TAFV

Côte d'Ivoire Switzerland (1994)

Ebolaviruses total:

Marburgviruses total:

Filoviruses total:

RAVV

Uganda (2007)

Kenya (1987)

COD (1998−2000)

Uganda (2012)

Deceased

Total cases

Uganda (2014)

COD (2014)

COD (2018)

COD Uganda (2018−2020)

COD (2020)

COD (2021−)*,†

Guinea (2021−)*,‡

Côte d'Ivoire (2021−)*,‡

RESTV

USA (1989)

0

Guinea (2021−)*

Lethality (%)

20 40 60 80 100

FIGURE 210-3 Characteristics of outbreaks of human filovirus disease. Seven of 12 classified filoviruses have caused infections in humans. Left column: Outbreaks are listed by

virus in chronological order in the left column. Laboratory infections are in gray italicized text. International case exportations are indicated with arrows. Right column: Numbers

of lethal cases and total cases are summarized. Middle column: The lethality or case–fatality rate (colored dots) for each outbreak is plotted on a 0–100% scale along with 99%

confidence intervals (gray horizontal bars). The overall case–fatality rate for disease caused by a particular virus is delineated by vertical colored lines, with vertical colored dashed

lines indicating the corresponding 99% confidence intervals. The overall case–fatality rates for all ebolavirus infections, all marburgvirus infections, and all filovirus infections are

shown by (underlaid) vertical gray bars. BDBV, Bundibugyo virus; COD, Democratic Republic of the Congo (formerly Zaire); COG, Republic of the Congo; EBOV, Ebola virus; MARV,

Marburg virus; RAVV, Ravn virus; RESTV, Reston virus; SUDV, Sudan virus; TAFV, Taï Forest virus; UK, United Kingdom; USSR, Union of Soviet Socialist Republics (today Russia). *, as

of August 25, 2021. †, possibly connected to the 2018–2020 EVD outbreak. ‡, possibly connected to the 2013–2016 EVD outbreak. (Adapted and expanded from JH Kuhn et al: Evaluation

of perceived threat differences posed by filovirus variants. Biosecur Bioterror 9:361, 2011. Figure courtesy of Jiro Wada, NIH/NIAID/DCR/IRF-Frederick, Fort Detrick, MD, USA.)

1649CHAPTER 210 Ebolavirus and Marburgvirus Infections

to the clotting dysfunction seen in filovirus-infected patients. Thrombocytopenia, increased concentrations of tissue factor, consumption of

clotting factors, increased concentrations of fibrin degradation products (d-dimers), and declining concentrations of protein C are typical

features of infection. Consequently, fibrin deposition and microthrombotic small-vessel occlusion and necrotic/hypoxic infarction may

occur in some tissues, particularly in the gonads and less often in the

kidneys and spleen. In addition, petechiae, ecchymoses, extensive

visceral effusions, and other hemorrhagic signs are observed in internal organs, mucous membranes, and skin. Actual severe blood loss,

however, is a rare event (although it frequently occurs during or after

childbirth). Most likely, aberrance in cytokines or other factors, such as

nitric oxide, and direct infection and activation of endothelial cells are

responsible for upregulated permeability of blood-vessel endothelia.

This upregulation leads to fluid redistribution; interstitial tissue edema

and hypovolemic or septic shock are common developments.

Despite this long list of pathogenetic hallmarks, increasing evidence

from humans suggests that effective filovirus-specific adaptive immune

responses do develop, coinciding with control and clearance of viremia

and subsequent clinical improvement in surviving patients. However,

depending on the severity of illness (including organ dysfunction and

late complications), clinical illness may be protracted and recovery

incomplete.

■ CLINICAL MANIFESTATIONS

EBOD and MARD cannot be distinguished by clinical observation

and for all practical purposes may be considered the same disease,

although this situation may change as higher-resolution characterization of human FVD accrues. The incidence of clinical signs

does not differ significantly among human infections caused by

disparate filoviruses (with the exception of the possibly apathogenic

Reston virus), although, apart from the patients in the 2013–2016

EVD outbreak, the numbers of thoroughly observed patients are

very low. The incubation period is 2–25 days (most commonly

6–10 days), after which infected people develop a nonspecific influenzalike syndrome characterized by sudden onset of fever and chills, severe

headaches, cough, myalgia, pharyngitis, arthralgia of the larger joints,

development of a maculopapular rash, and other signs/symptoms. This

stage is followed by a second phase (~5–7 days after disease onset and

thereafter) initially involving the gastrointestinal tract (nausea and

vomiting and/or diarrhea, sometimes with abdominal pain), respiratory tract (chest pain, cough), vascular system (postural hypotension,

edema), and CNS (confusion, headache, coma). Common hemorrhagic manifestations include subconjunctival injection, petechial rash,

gingival bleeding, and bleeding at injection sites; epistaxis, hematemesis, hematuria, and melena occur but are less common. Patients usually

succumb to acute disease 4–14 days after infection, often with severe

Netherlands

West

Germany and

Yugoslavia

South Africa South Africa

Liberia

Senegal

Mali

USA and three

European countries

USA and five European countries

USA

Nigeria Sierra Leone

Côte d'Ivoire

COG

Gabon

Kenya

Uganda

Uganda

South Sudan

(Sudan)

Angola

Zimbabwe

(Rhodesia)

COD

(Zaire)

COD

(Zaire)

Guinea

Switzerland

'01−'02

'94−'95

'96

'02

'02−'03 '03−'04

'05

COG

Gabon

'00−'01

'00−'01

'11,'12

'12 '11

'00−'01

'18−'20; '21*

'07

'07−'09

'07

'67

'08

'12

'14

'17

MARV

RAVV

BDBV

SUDV

TAFV

EBOV

'76,'79 '76

'75

'87

'98−'00

'98−'00

'04−'05

'21*

'12

'76

'95

'07

'08−'09

'96−'97

'13−'16; '21*

'21*

'94

'77

'20'14

'18

'17

'80

'04

FIGURE 210-4 Geographic distribution of human filovirus disease outbreaks and years of occurrence. Arrows indicate international case exportations. BDBV, Bundibugyo

virus; COD, Democratic Republic of the Congo (formerly Zaire); COG, Republic of the Congo; EBOV, Ebola virus; MARV, Marburg virus; RAVV, Ravn virus; SUDV, Sudan virus;

TAFV, Taï Forest virus. (Figure courtesy of Jiro Wada, NIH/NIAID/DCR/IRF-Frederick, Fort Detrick, MD, USA.)

1650 PART 5 Infectious Diseases

multiorgan failure, including shock and acute renal failure or respiratory failure.

Typical laboratory findings are leukopenia (with cell counts as low

as 1000 per μL) with a left shift prior to leukocytosis, thrombocytopenia (with counts as low as 50,000 per μL), increased activities of

liver enzymes (aspartate aminotransferase > alanine aminotransferase,

γ-glutamyltransferase), increased creatinine and urea concentrations

with proteinuria, electrolyte derangement (hypokalemia or hyperkalemia, hyponatremia, hypocalcemia), hypoglycemia, hypoalbuminemia, prolonged prothrombin and partial thromboplastin times, and

elevated creatine phosphokinase activities. Nonspecific markers of

systemic inflammation (e.g., C-reactive protein concentrations) may

be markedly elevated in severely ill patients.

■ DIAGNOSIS

Filovirus infections cannot be diagnosed on the basis of clinical presentation alone. Numerous diseases common in equatorial Africa need to

be considered in the differential diagnosis of a febrile patient. Almost

all of these diseases occur at a much higher incidence than filovirus

infections and are much more likely differential diagnoses in nonoutbreak settings; however, during and in peri-outbreak periods, the

importance of accurate laboratory diagnosis to rule in or rule out filovirus infection cannot be diminished. The most important infectious

diseases that closely mimic FVD are falciparum malaria and typhoid

fever; also important are enterohemorrhagic Escherichia coli enteritis,

gram-negative septicemia (including shigellosis), meningococcal septicemia, rickettsial infections, fulminant viral hepatitis, leptospirosis,

measles, and other high-consequence viral infections (in particular,

Lassa and yellow fevers). Noninfectious possibilities, including venomous snakebites, warfarin intoxication, and the many causes of acquired

or inherited coagulopathy, also must be considered in the bleeding

patient. An exposure history—including exposure to caves or mines;

direct contact with bats, nonhuman primates, or bushmeat; direct

contact with severely ill local residents; or admission to rural hospitals

with patient-to-patient or patient-to-health-care-worker clusters of

illness—should raise the index of suspicion.

If FVD is suspected on the basis of epidemiologic and/or clinical

manifestations, infectious disease specialists and the proper publichealth authorities (including WHO) should be notified immediately.

Laboratory diagnosis of FVD is relatively straightforward but ideally

requires maximal containment (biosafety level 4) capacity, which

usually is not available in filovirus-endemic countries. Increasingly,

Onset of signs and and symptoms

Incubation Early phase Peak phase Incubation

anorexia, myalgia, and headache

Nonspecific prodrome: fever, fatigue,

Gastrointestinal symptoms: nausea,

vomiting, diarrhea, and abdominal pain

Rash

Hemorrhagic manifestations

Hemodynamic instability, Shock

Renal failure

Respiratory failure

Neurologic manifestations

Cardiac dysfunction (myocarditis and pericarditis)

Hepatic injury: ↑AST, ↑ALT

Hypoglycemia

Hypoalbuminemia

Days since disease onset

0 1 7 4 21 28

Magnitude

Coagulopathy: ↑PT, ↑PTT, ↑D-dimer

Renal dysfunction: ↑BUN, ↑creatinine

Uveitis

Metabolic acidosis: ↑lactate, ↓HCO3

–

Abnormal electrolytes: ↓Na+, ↑ or ↓K+, ↓Ca++, ↓Mg++

↓WBCs, ↓PLTs ↑WBCs (↑PMNs), ↓Hb, ↓HCT ↑PLTs

↑CPK, myoglobinuria

10 to –7a

Clinical presentation

Innate immune response

Viremia (nonsurvivor)

Laboratory findings

Viremia (survivor)

IgM

Cellular immune response

Humoral immune response (IgG)

FIGURE 210-5 Ebola virus disease course. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CPK, creatine phosphokinase;

Hb, hemoglobin; HCT, hematocrit; PLTs, platelets; PMNs, polymorphonuclear leukocytes; PT, prothrombin time; PTT, partial thromboplastin time; WBCs, white blood cells.

(Adapted and expanded from JH Kuhn et al: Filoviridae, in Fields Virology, 7th ed, Vol. 1. Howley PM et al. (eds). Philadelphia, Wolters Kluwer/Lippincott Williams & Wilkins,

2020, pp 449–503. Figure courtesy of Jiro Wada, NIH/NIAID/DCR/IRF-Frederick, Fort Detrick, MD, USA.)