1622 PART 5 Infectious Diseases

in whom Guillain-Barré syndrome is suspected. The absence of an

animal-bite history is common in North America, particularly due to

unrecognized bat exposures. The lack of hydrophobia is not unusual

in rabies. Once rabies is suspected, rabies-specific laboratory tests

should be performed to confirm the diagnosis. Diagnostically useful

specimens include serum, CSF, fresh saliva, skin biopsy samples from

the neck, and brain tissue (rarely obtained before death). Because skin

biopsy relies on the demonstration of rabies virus antigen in cutaneous nerves at the base of hair follicles, samples are usually taken from

hairy skin at the nape of the neck. Corneal impression smears are of

low diagnostic yield and are generally not performed. Negative antemortem rabies-specific laboratory tests never exclude a diagnosis of

rabies, and tests may need to be repeated after an interval for diagnostic

confirmation.

Rabies Virus–Specific Antibodies In a previously unimmunized patient, serum neutralizing antibodies to rabies virus are

diagnostic. However, because rabies virus infects immunologically

privileged neuronal tissues, serum antibodies may not develop until

late in the disease. Antibodies may be detected within a few days after

the onset of symptoms, but some patients die without detectable antibodies. The presence of rabies virus–specific neutralizing antibodies in

the CSF suggests rabies encephalitis, regardless of immunization status.

A diagnosis of rabies is questionable in patients who recover from their

illness without developing serum neutralizing antibodies to rabies

virus.

RT-PCR Amplification Detection of rabies virus RNA by RT-PCR

is highly sensitive and specific. This technique can detect virus in fresh

saliva samples, skin biopsy specimens, CSF (less sensitive), and brain

tissues. In addition, RT-PCR with genetic sequencing can distinguish

among rabies virus variants, permitting identification of the probable

source of an infection.

Direct Fluorescent Antibody Testing Direct fluorescent antibody (DFA) testing with rabies virus antibodies conjugated to fluorescent dyes is highly sensitive and specific for the detection of rabies

virus antigen in tissues; the test can be performed quickly and applied

to skin biopsy and brain tissue samples. In skin biopsy samples, rabies

virus antigen may be detected in cutaneous nerves at the base of hair

follicles.

■ DIFFERENTIAL DIAGNOSIS

The diagnosis of rabies may be difficult without a history of animal

exposure, and no exposure to an animal (e.g., a bat) may be recalled. The

presentation of rabies is usually quite different from that of acute viral

encephalitis due to most other causes, including herpes simplex encephalitis and arboviral (e.g., West Nile) encephalitis. Early neurologic symptoms may occur at the site of the bite, and there may be early features

of brainstem involvement with preservation of consciousness. Anti–Nmethyl-d-aspartate receptor (anti-NMDA) encephalitis occurs in young

patients (especially females) and is characterized by behavioral changes,

autonomic instability, hypoventilation, and seizures. Many other antibodies are also associated with autoimmune encephalitis. Postinfectious

(immune-mediated) encephalomyelitis may follow influenza, measles,

mumps, and other infections; it may also occur as a sequela of immunization with rabies vaccines derived from neural tissues, which are

now infrequently used and only in resource-limited and resource-poor

countries. Rabies may present with unusual neuropsychiatric symptoms

and may be misdiagnosed as a psychiatric disorder. Rabies hysteria (now

classified as a somatic symptom disorder) may occur as a psychological

response to the fear of rabies and is often characterized by a shorter

incubation period than rabies, aggressive behavior, inability to communicate, and a long course with recovery.

As previously mentioned, paralytic rabies may mimic Guillain-Barré

syndrome. In these cases, fever, bladder dysfunction, a normal sensory examination, and CSF pleocytosis favor a diagnosis of rabies.

Conversely, Guillain-Barré syndrome may occur as a complication of

rabies vaccination with a neural tissue–derived product (e.g., suckling

mouse brain vaccine) and may be mistaken for paralytic rabies (i.e.,

vaccine failure).

TREATMENT

Rabies

There is no established treatment for rabies. Aggressive management

with supportive care in critical care units has resulted in the survival

of at least 30 patients with rabies. Many of these survivors have

recently been reported from India. There have been many recent

treatment failures (more than 55) with the combination of antiviral

drugs, ketamine, and therapeutic (induced) coma—measures that

were used in a healthy survivor in whom neutralizing antibodies to

rabies virus were detected at presentation. Expert opinion is recommended before a course of experimental therapy is embarked upon.

A palliative approach may be appropriate for many patients who are

not considered candidates for aggressive management.

■ PROGNOSIS

Rabies is an almost uniformly fatal disease but is nearly always preventable after recognized exposures with appropriate postexposure therapy

during the early incubation period (see below). All but 1 of 30 documented survivors of rabies received 1 or more doses of rabies vaccine

before disease onset. The single survivor who had not received vaccine

had neutralizing antibodies to rabies virus in serum and CSF at clinical

presentation. Most patients with rabies die within several days of the

onset of illness, despite aggressive care in a critical care unit.

■ PREVENTION

Postexposure Prophylaxis Since there is no effective therapy

for rabies, it is extremely important to prevent the disease after an

animal exposure. Figure 208-6 shows the steps involved in making

decisions about PEP. On the basis of the exposure history and local

epidemiologic information, the physician must decide whether initiation of PEP is warranted. Healthy dogs, cats, or ferrets may be confined

and observed for 10 days. PEP is not necessary if the animal remains

healthy. If the animal develops signs of rabies during the observation

period, it should be euthanized immediately; the head should be

transported to the laboratory under refrigeration, rabies virus should

be sought by DFA testing, and viral isolation should be attempted by

cell culture and/or mouse inoculation. Any animal other than a dog,

cat, or ferret should be euthanized immediately and the head submitted for laboratory examination. In high-risk exposures and in areas

where canine rabies is endemic, rabies prophylaxis should be initiated

without waiting for laboratory results. If the laboratory results prove to

be negative, it may safely be concluded that the animal’s saliva did not

contain rabies virus, and immunization should be discontinued. If an

animal escapes after an exposure, it must be considered rabid, and PEP

must be initiated unless information from public health officials indicates otherwise (i.e., there is no endemic rabies in the area). Although

controversial, the use of PEP may be warranted when a person (e.g., a

small child or a sleeping adult) has been present in the same space as a

bat and an unrecognized bite cannot be reliably excluded.

PEP includes local wound care and both active and passive immunization. It is important that current recommendations are followed very

closely because minor deviations can lead to failure of prophylactic

measures. Local wound care is essential and may greatly decrease the

risk of rabies virus infection. Wound care should not be delayed, even

if the initiation of immunization is postponed pending the results of

the 10-day observation period. All bite wounds and scratches should be

washed thoroughly with soap and water. Devitalized tissues should be

debrided, tetanus prophylaxis given, and antibiotic treatment initiated

whenever indicated.

Previously unvaccinated persons (but not those who have previously been immunized) should be passively immunized with rabies

1623CHAPTER 208 Rabies and Other Rhabdovirus Infections

immune globulin (RIG). If RIG is not immediately available, it should

be administered no later than 7 days after the first vaccine dose. After

day 7, endogenous antibodies are being produced, and passive immunization may actually be counterproductive. If anatomically feasible,

the entire dose of RIG (20 IU/kg) should be infiltrated at the site of

the bite, and any RIG remaining after infiltration of the bite site should

be administered IM at a distant site. Recent recommendations by the

World Health Organization indicate that under certain circumstances

the remainder of the dose does not need to be administered after local

infiltration of the wound(s). With multiple or large wounds, the RIG

preparation may need to be diluted in order to obtain a sufficient

volume for adequate infiltration of all wound sites. If the exposure

involves a mucous membrane, the entire dose should be administered

IM. Rabies vaccine and RIG should never be administered at the

same site or with the same syringe. Commercially available RIG in the

United States is purified from the serum of hyperimmunized human

donors. These human RIG preparations are much better tolerated than

are the equine-derived preparations still in use in some countries (see

below). Serious adverse effects of human RIG are uncommon. Local

pain and low-grade fever may occur.

Two purified inactivated rabies vaccines are available for rabies PEP

in the United States. They are highly immunogenic and remarkably

safe compared with earlier vaccines. Four 1-mL doses of rabies vaccine

should be given IM in the deltoid area. (The anterolateral aspect of the

thigh also is acceptable in children.) Gluteal injections, which may not

always reach muscle, should not be given and have been associated

with rare vaccine failures. Ideally, the first dose should be given as

soon as possible after exposure; failing that, it should be given without

further delay. The three additional doses should be given on days 3, 7,

and 14; a fifth dose on day 28 is no longer recommended. Pregnancy

is not a contraindication for immunization. Glucocorticoids and other

immunosuppressive medications may interfere with the development

of active immunity and should not be administered during PEP unless

they are essential. Routine measurement of serum neutralizing antibody

titers is not required, but titers should be measured 2–4 weeks after

immunization in immunocompromised persons. Local reactions (pain,

erythema, edema, and pruritus) and mild systemic reactions (fever,

myalgias, headache, and nausea) are common; anti-inflammatory and

antipyretic medications may be used, but immunization should not be

discontinued. Systemic allergic reactions are uncommon, but anaphylaxis does occur rarely and can be treated with epinephrine and antihistamines. The risk of rabies development should be carefully considered

before the decision is made to discontinue vaccination because of an

adverse reaction.

Most of the burden of rabies PEP is borne by persons with the fewest

resources. In addition to the rabies vaccines discussed above, vaccines

grown in either primary cell lines (hamster or dog kidney) or continuous cell lines (Vero cells) are satisfactory and are available in many

countries outside the United States. Less expensive vaccines derived

from neural tissues are still used in a diminishing number of developing countries; however, these vaccines are associated with serious

neuroparalytic complications, including postinfectious encephalomyelitis and Guillain-Barré syndrome. The use of these vaccines should be

discontinued as soon as possible, and progress has been made in this

regard. Worldwide, more than 10 million individuals receive postexposure rabies vaccine each year.

If human RIG is unavailable, purified equine RIG can be used in

the same manner at a dose of 40 IU/kg. The incidence of anaphylactic

reactions and serum sickness has been low with recent equine RIG

products.

Preexposure Rabies Vaccination Preexposure rabies prophylaxis should be considered for people with an occupational or recreational risk of rabies exposures and also for certain travelers to

rabies-endemic areas. The primary schedule consists of three doses

of rabies vaccine given on days 0, 7, and 21 or 28. Serum neutralizing

antibody tests help determine the need for subsequent booster doses.

When a previously immunized individual is exposed to rabies, two

booster doses of vaccine should be administered on days 0 and 3.

Wound care remains essential. As stated above, RIG should not be

administered to previously vaccinated persons.

OTHER RHABDOVIRUSES

■ OTHER LYSSAVIRUSES

A growing number of lyssaviruses other than rabies virus have been

discovered to infect bat populations in Europe, Africa, Asia, and

Australia. Six of these viruses have produced a very small number

of cases of a human disease indistinguishable from rabies: European

bat lyssaviruses 1 and 2, Australian bat lyssavirus, Irkut virus, and

Duvenhage virus. Mokola virus, a lyssavirus that has been isolated

from shrews with an unknown reservoir species in Africa, may also

produce human disease indistinguishable from rabies.

■ VESICULAR STOMATITIS VIRUS

Vesicular stomatitis is a viral disease of cattle, horses, pigs, and some

wild mammals. Vesicular stomatitis virus is a member of the genus

Vesiculovirus in the family Rhabdoviridae. Outbreaks of vesicular

stomatitis in horses and cattle occur sporadically in the southwestern

United States. The animal infection is associated with severe vesiculation and ulceration of oral tissues, teats, and feet and may be clinically

indistinguishable from the more dangerous foot-and-mouth disease.

Epidemics are usually seasonal, typically beginning in the late spring,

and are probably due to arthropod vectors. Direct animal-to-animal

spread can also occur, although the virus cannot penetrate intact

skin. Transmission to humans usually results from direct contact

with infected animals (particularly cattle) and occasionally follows

laboratory exposure. In human disease, early conjunctivitis is followed

by an acute influenza-like illness with fever, chills, nausea, vomiting,

headache, retrobulbar pain, myalgias, substernal pain, malaise, pharyngitis, and lymphadenitis. Small vesicular lesions may be present on the

Did the animal bite the patient

or did saliva contaminate a

scratch, abrasion, open wound,

or mucous membrane?

Rabies prophylaxis

No

Yes

Is rabies known or suspected

to be present in the species

and the geographic area? None

None

No

Yes

Was the animal captured? RIG and vaccine

RIG and vaccine

No

Yes

Was the animal a normally

behaving dog, cat, or ferret?

Yes

Yes

No

No

Does laboratory examination of

the brain by fluorescent antibody

staining confirm rabies?

Yes

No

Does the animal

become ill under

observation over

the next 10 days?

None

FIGURE 208-6 Algorithm for rabies postexposure prophylaxis. RIG, rabies immune

globulin. (Reproduced with permission from L Corey, in Harrison’s Principles of

Internal Medicine, 15th ed. E Braunwald et al [eds]: New York, McGraw-Hill, 2001.)

1624 PART 5 Infectious Diseases

This chapter summarizes the major features of selected arthropodborne and rodent-borne viruses. Numerous viruses of this category

are transmitted in nature among animals without ever infecting

humans. Other viruses incidentally infect humans, but few induce disease. In addition, some viruses are regularly introduced into human

populations or spread among humans by arthropods (specifically,

insects and ticks) or by chronically infected rodents. These zoonotic

viruses are taxonomically diverse and therefore differ fundamentally

from one another in terms of virion morphology, replication strategies, genomic organization, and genome sequence. Although a virus’s

classification in a taxon is enlightening regarding natural maintenance

strategies, sensitivity to antiviral agents, and aspects of pathogenesis,

the classification does not necessarily predict which clinical signs and

symptoms (if any) the virus will cause in humans. Zoonotic viruses

are evolving, and “new” zoonotic viruses are regularly discovered.

The epizootiology and epidemiology of zoonotic viruses continue

to change because of environmental alterations affecting vectors,

reservoirs, wildlife, livestock, and humans. Zoonotic viruses are most

numerous in the tropics but are also found in temperate and even

frigid climates. The distribution and seasonal activity of zoonotic

viruses may vary, and the rate at which they change is likely to depend

largely on ecologic conditions (e.g., rainfall and temperature), which

can affect the density of virus vectors and reservoirs and the development of infection.

Arthropod-borne viruses (arboviruses) infect their vectors after

ingestion of blood meals from viremic, usually nonhuman vertebrates; some arthropods may also become infected by saliva-activated

transmission. The arthropod vectors then develop chronic systemic

infection as the viruses penetrate the gut and spread throughout the

body to the salivary glands; such virus dissemination, referred to as

extrinsic incubation, typically lasts 1–3 weeks in mosquitoes. At this

209

point, if the salivary glands become involved, the arthropod vector is

competent to continue the chain of transmission by infecting a vertebrate during a subsequent blood meal. An alternative mechanism for

virus maintenance in its arthropod vector is transovarial transmission.

Generally, the arthropod is unharmed by the infection and usually

the natural vertebrate partner has only transient viremia with no overt

disease.

Rodent-borne viruses (sometimes called roboviruses) are maintained in nature by transmission among rodents, which become

chronically infected. Usually, a high degree of rodent–virus specificity

is observed, and overt disease in the reservoir host is rare.

ETIOLOGY

Arthropod-borne and rodent-borne zoonotic viruses belong mostly to

the orders Amarillovirales (family Flaviviridae), Articulavirales (family

Orthomyxoviridae), Bunyavirales (families Arenaviridae, Hantaviridae,

Nairoviridae, Peribunyaviridae, Phenuiviridae), Martellivirales (family

Togaviridae), Mononegavirales (family Rhabdoviridae), and Reovirales

(family Reoviridae) (Table 209-1). An exception is Syr-Darya Valley

fever virus, an ixodid tick-borne cardiovirus (Picornavirales: Picornaviridae) that causes febrile disease in Central Asia.

■ AMARILLOVIRALES: FLAVIVIRIDAE

The family Flaviviridae currently includes only one genus (Flavivirus)

that comprises arthropod-borne human viruses. Flaviviruses sensu

stricto have single-stranded positive-sense RNA genomes (~11 kb)

and form spherical enveloped particles 40–60 nm in diameter. The

flaviviruses discussed here belong to two phylogenetically and antigenically distinct groups that are transmitted among vertebrates by

mosquitoes and ixodid ticks, respectively. Vectors are usually infected

when they feed on viremic hosts; as in the case of most other viruses

discussed here, humans are accidental hosts usually infected by arthropod bites. Arthropods maintain flavivirus infections horizontally,

although transovarial transmission has been documented. Under certain circumstances, flaviviruses can also be transmitted by aerosol or

via contaminated food products; in particular, raw milk can transmit

tick-borne encephalitis virus.

■ ARTICULAVIRALES: ORTHOMYXOVIRIDAE

The family Orthomyxoviridae includes two genera of medically relevant arthropod-borne viruses: Quaranjavirus and Thogotovirus. Quaranjaviruses are transmitted among birds by ixodid ticks, whereas

thogotoviruses have a predilection for mammalian host reservoirs and

can be transmitted by both ixodid ticks and mosquitoes.

■ BUNYAVIRALES: ARENAVIRIDAE

The members of the family Arenaviridae that infect humans are all

assigned to the genus Mammarenavirus. The members of this genus are

divided into two main phylogenetic branches: Old World viruses (the

Lassa–lymphocytic choriomeningitis serocomplex) and New World

viruses (the Tacaribe serocomplex). Mammarenaviruses form spherical, oval, or pleomorphic enveloped and spiked virions (~50–300 nm

in diameter) that bud from the plasma membrane of the infected cell.

The particles contain two genomic single-stranded RNAs (S, ~3.5 kb;

and L, ~7.5 kb), encoding structural proteins in an ambisense orientation. Most mammarenaviruses persist in nature by chronically

infecting rodents. The human Old World mammarenaviruses are

maintained by murid rodents that often are persistently viremic and

commonly transmit viruses vertically and horizontally. One Old World

mammarenavirus associated with human infections is maintained by

shrews. Human New World mammarenaviruses are found in cricetid

rodents; horizontal transmission is typical, vertical infection may

occur, and persistent viremia may be observed. Strikingly, each mammarenavirus is predominantly adapted to one particular type of rodent.

Humans usually become infected through inhalation of or direct contact with infected rodent excreta or secreta (e.g., aerosols of rodents in

harvesting machines, aerosolized dried rodent urine or feces in barns

or houses, direct contact with rodents in traps). Person-to-person

transmission of mammarenaviruses is uncommon.

Arthropod-Borne and

Rodent-Borne Virus

Infections

Jens H. Kuhn, Ian Crozier

buccal mucosa or on the fingers. Encephalitis is very rare. The illness

usually lasts 3–6 days, with complete recovery. Subclinical infections

are common. A serologic diagnosis can be made on the basis of a rise

in titer of complement-fixing or neutralizing antibodies. Therapy is

symptom-based.

■ FURTHER READING

Fooks AR et al: Current status of rabies and prospects for elimination.

Lancet 384:1389, 2014.

Fooks AR, Jackson AC (eds). Rabies: Scientific Basis of the Disease

and Its Management, 4th ed. London, Elsevier Academic Press, 2020.

Jackson AC: Treatment of rabies. In: Post TW, ed. UpToDate.

Waltham, Massachusetts: Wolters Kluwer, 2021. www.uptodate.com.

Letchworth GJ et al: Vesicular stomatitis. Vet J 157:239, 1999.

Manning SE et al: Human rabies prevention—United States, 2008:

Recommendations of the Advisory Committee on Immunization

Practices. MMWR Recomm Rep 57(RR-3):1, 2008.

World Health Organization: WHO Expert Consultation on Rabies:

Third Report (WHO Technical Report Series No. 1012). Geneva,

World Health Organization, 2018. Available at apps.who.int/iris/

bitstream/handle/10665/272364/9789241210218-eng.pdf. Accessed

June 17, 2021.

1625CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

Alphaviruses (Barmah

Forest serocomplex)

Barmah Forest virus (BFV) Horses, possums Biting midges (Culicoides

marksi), mosquitoes (Aedes

camptorhynchus, A. normanensis,

A. notoscriptus, A. vigilax, Culex

annulirostris)

A/R

Alphaviruses (eastern

equine encephalitis

serocomplex)

Eastern equine encephalitis

virus (EEEV)

Freshwater swamp passeriform birds,

but also opportunistic amphibians,

other birds (emu, gallinaceous poultry,

pheasants), reptiles, and mammals

(goats, horses, pigs)

Mosquitoes (Aedes, Coquillettidia,

Culex spp.; Culiseta melanura,

Mansonia perturbans, Psorophora

spp.)

E

Madariaga virus (MADV) Likely birds and reptiles Mosquitoes (Culex, Culiseta spp.) F/M, E

Alphaviruses (Semliki Forest

serocomplex)

Chikungunya virus (CHIKV) Bats, nonhuman primates Mosquitoes (Aedes, Culex spp.) A/Rc

Mayaro virus (MAYV) Nonhuman primates, possums,

rodents; possibly caimans, horses,

sheep

Mosquitoes (predominantly

Haemagogus spp., but also Aedes,

Culex, Mansonia, Psorophora,

Sabethes)

A/R

O’nyong-nyong virusd

 (ONNV) Unknown Mosquitoes (in particular Anopheles

gambiae, A. funestus, Mansonia

spp.)

A/R

Una virus (UNAV) Birds, horses, rodents Mosquitoes (Aedes, Anopheles,

Coquillettidia, Culex, Ochlerotatus,

Psorophora spp.)

F/M

Ross River virus (RRV) Macropods, rodents Mosquitoes (Aedes normanensis, A.

vigilax, Culex annulirostris)

A/R

Semliki Forest virus (SFV) Birds, rodents Mosquitoes (Aedes, Culex spp.) A/R

Alphaviruses (Venezuelan

equine encephalitis

serocomplex) 

Everglades virus (EVEV) Hispid cotton rats (Sigmodon hispidus) Mosquitoes (Culex cedecei) F/M, E

Mucambo virus (MUCV) Nonhuman primates, rodents Mosquitoes (Culex, Ochlerotatus

spp.)

F/M, E

Tonate virus (TONV) Birds, Suriname crested oropendolas

(Psarocolius decumanus)

Mosquitoes (Anopheles,

Coquillettidia, Culex, Mansonia,

Uranotaenia, Wyeomyia spp.),

sandflies (Lutzomyia spp.)

F/M, E

Venezuelan equine encephalitis

virus (VEEV)

Equids, rodents Mosquitoes (Aedes, Culex spp.,

Psorophora confinnis)

F/M, E

Alphaviruses (western

equine encephalitis

serocomplex)

Sindbis viruse

 (SINV) Typically birds, but also frogs and rats Typically mosquitoes (Culex,

Culiseta spp.), but tick isolation has

been reported

A/R

Western equine encephalitis

virus (WEEV)

Equids, lagomorphs, passeriform birds,

pheasants

Mosquitoes (Aedes spp., Culex

tarsalis, Culiseta spp.)

E

Bandaviruses (Bhanja

serocomplex)

Bhanja virusf

 (BHAV) Cattle, four-toed hedgehog (Atelerix

albiventris), goats, sheep, striped

ground squirrels (Xerus erythropus)

Ixodid ticks (Amblyomma,

Dermacentor, Haemaphysalis,

Hyalomma, Rhipicephalus spp.)

E, F/M

Heartland virus (HRTV) Cattle, deer, elk, goats, raccoons,

sheep?

Ixodid ticks (Amblyomma

americanum)

F/M

Severe fever with

thrombocytopenia syndrome

virusg

 (SFTSV)

Cats, cattle, chickens, dogs, goats,

rodents, sheep?

Ixodid ticks (Amblyomma

testudinarium, Haemaphysalis

concinna, H. flava, H. longicornis,

Ixodes nipponensis, Rhipicephalus

microplus)

F/M, VHF

Bunyavirals (family and

genus undetermined)

Bangui virus (BGIV) Unknown Unknown F/M

Coltiviruses Colorado tick fever virus (CTFV) Bushy-tailed woodrats (Neotoma

cinerea), Columbian ground squirrels

(Spermophilus columbianus),

deermice (Peromyscus maniculatus),

golden-mantled ground squirrels

(Spermophilus lateralis), least

chipmunks (Tamias minimus), North

American porcupines (Erethizon

dorsata), yellow pine chipmunks

(Tamias amoenus)

Ixodid ticks (predominantly

Dermacentor andersoni)

E, F/M

Eyach virus (EYAV) Lagomorphs, rodents Ixodid ticks (Ixodes ricinus,

I. ventalloi)

E, F/M

Salmon River virus (SRV) Unknown Ixodid ticks (Ixodes spp.) E, F/M

(Continued)

1626 PART 5 Infectious Diseases

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

Flaviviruses

(mosquito-borne)

Dengue viruses 1–4 (DENV 1–4) Nonhuman primates Mosquitoes (predominantly Aedes

aegypti, A. albopictus)

F/M, VHF

Edge Hill virus (EHV) Bandicoots, dogs, wallabies Mosquitoes (Aedes vigilax, Culex

annulirostris)

F/M

Japanese encephalitis virus

(JEV)

Ardeid wading birds (in particular

herons), horses, pigs

Mosquitoes (Culex spp., in particular

C. tritaeniorhynchus)

E

Kokobera virus (KOKV) Macropods, horses Mosquitoes (Culex spp.) A/R

Murray Valley encephalitis

virush

 (MVEV)

Birds Mosquitoes (predominantly

C. annulirostris)

E

Rocio virus (ROCV) Rufous-collared sparrows (Zonotrichia

capensis)

Mosquitoes (Aedes, Culex,

Psorophora spp.)

E

St. Louis encephalitis virus

(SLEV)

Columbiform and passeriform birds

(finches, sparrows)

Mosquitoes (predominantly Culex

spp., in particular C. nigripalpus,

C. pipiens, C. quinquefasciatus,

C. tarsalis)

E

Usutu virus (USUV) Passeriform birds Mosquitoes (Culex spp., in particular

C. pipiens)

(E)

Stratford virus (STRV) Unknown Mosquitoes (A. vigilax) F/M

West Nile virus (WNV)i Passeriform birds (blackbirds, crows,

finches, sparrows), small mammals,

horses

Mosquitoes (Culex spp., in particular

C. pipiens, C. quinquefasciatus,

C. restuans, C. tarsalis)

E

Yellow fever virus (YFV) Nonhuman primates (Alouatta, Ateles,

Cebus, Cercopithecus, Colobus spp.)

Mosquitoes (Aedes spp., in

particular Ae. aegypti)

VHF

Zika virus (ZIKV) Nonhuman primates (Macaca, Pongo

spp.)

Mosquitoes (Aedes spp.) A/R, F/M

Flaviviruses (tick-borne) Alkhurma hemorrhagic fever

virus (AHFV)j

Unknown Sand tampans (Ornithodoros

savignyi)

VHF

Karshi virus (KSIV) Great gerbils (Rhombomys opimus) Argasid ticks (Ornithodoros

capensis), ixodid ticks (Hyalomma

asiaticum)

E, F/M

Kyasanur Forest disease virus

(KFDV)k

Indomalayan vandeleurias

(Vandeleuria oleracea), roof rats

(Rattus rattus)

Ixodid ticks (predominantly

Haemaphysalis spinigera)

VHF

Omsk hemorrhagic fever virus

(OHFV)

Migratory birds, rodents Ixodid ticks (predominantly

Dermacentor spp.)

VHF

Powassan virus (POWV) Red squirrels (Tamiasciurus

hudsonicus), white-footed deermice

(Peromyscus leucopus), woodchucks

(Marmota monax), other small mammals

Ixodid ticks (in particular Ixodes

cookei, other Ixodes spp.,

Dermacentor spp.)

E

Tick-borne encephalitis virus

(TBEV)

Passeriform birds, deer, eulipotyphla,

goats, grouse, small mammals,

rodents, sheep

Ixodid ticks (Ixodes gibbosus, I.

persulcatus, I. ricinus; sporadically

Dermacentor, Haemaphysalis,

Hyalomma spp.)

E, F/M, (VHF)

Mammarenaviruses (Old

World)

Lassa virus (LASV) Natal mastomys (Mastomys

natalensis), likely other rodents

None F/M, VHF

Lujo virus (LUJV) Unknown None VHF

Lymphocytic choriomeningitis

virus (LCMV)

House mice (Mus musculus) None E, F/M, (VHF)

Mammarenaviruses (New

World)

Chapare virus (CHAPV) Unknown None VHF

Guanarito virus (GTOV) Short-tailed zygodonts (Zygodontomys

brevicauda)

None VHF

Junín virus (JUNV) Drylands lauchas (Calomys

musculinus)

None VHF

Machupo virus (MACV) Big lauchas (Calomys callosus) None VHF

Sabiá virus (SBAV) Unknown None VHF

Whitewater Arroyo virus

(WWAV)l

White-throated woodrats (Neotoma

albigula)

None (E)

Orbiviruses Kemerovo virus (KEMV) Birds, rodents Ixodid ticks (Ixodes persulcatus) E, F/M

Lebombo virus (LEBV) Unknown Mosquitoes (Aedes, Mansonia spp.) F/M

Orungo virus (ORUV) Camels, cattle, goats, nonhuman

primates, sheep

Mosquitoes (Aedes, Anopheles,

Culex spp.)

E, F/M

Tribeˇc virus (TRBV)m Bank voles (Myodes glareolus),

birds, common pine voles (Microtus

subterraneus), goats, hares

Ixodid ticks (Ixodes persulcatus,

I. ricinus)

F/M

(Continued)

(Continued)

1627CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

Orthobunyaviruses

(Anopheles A serogroup)

Tacaiuma virus (TCMV) Nonhuman primates Mosquitoes (Anopheles,

Haemagogus spp.)

F/M

Orthobunyaviruses

(Bunyamwera serogroup)

Batai virus (BATV)n Birds, camels, cattle, goats, rodents,

sheep

Mosquitoes (Aedes abnormalis, A.

curtipes, Anopheles barbirostris,

Culex gelidus, other spp.)

F/M

Bunyamwera virus (BUNV) Birds, cows, goats, horses, sheep Mosquitoes (Aedes spp.) F/M

Cache Valley virus (CVV) Cattle, deer, foxes, horses, nonhuman

primates, raccoons

Mosquitoes (Aedes, Anopheles,

Culiseta spp.)

F/M

Fort Sherman virus (FSV) Cattle, goats, horses, sheep? Mosquitoes? F/M

Germiston virus (GERV) Rodents Mosquitoes (Culex spp.) F/M

Guaroa virus (GROV) Unknown Mosquitoes (Anopheles spp.) F/M

Ilesha virus (ILEV) Unknown Mosquitoes (Anopheles gambiae) F/M, (VHF)

Maguari virus (MAGV) Birds, cattle, horses, sheep, water

buffalo

Mosquitoes (Aedes, Anopheles,

Culex, Psorophora, Wyeomyia spp.)

F/M

Ngari virus (NRIV) Unknown Mosquitoes (Aedes, Anopheles spp.) F/M, VHF

Shokwe virus (SHOV) Rodents Mosquitoes (Aedes, Anopheles,

Mansonia spp.)

F/M

Xingu virus (XINV) Unknown Unknown F/M

Orthobunyaviruses

(Bwamba serogroup)

Bwamba virus (BWAV) Unknown Mosquitoes (Aedes, Anopheles,

Mansonia spp.)

F/M

Pongola virus (PGAV) Cattle, donkeys, goats, sheep Mosquitoes (Aedes, Anopheles,

Mansonia spp.)

F/M

Orthobunyaviruses

(California serogroup)

California encephalitis virus

(CEV)

Lagomorphs, rodents Mosquitoes (Aedes, Culex, Culiseta,

Psorophora spp.)

E, F/M

Inkoo virus (INKV) Cattle, foxes, hares, moose, rodents Mosquitoes (Aedes spp.) E, F/M

Jamestown Canyon virus (JCV) Bison, deer, elk, moose Mosquitoes (Aedes, Culiseta,

Ochlerotatus spp.)

E, F/M

La Crosse virus (LACV) Chipmunks, squirrels Mosquitoes (Ochlerotatus

triseriatus)

E, F/M

Lumbo virus (LUMV) Unknown Mosquitoes (Aedes pembaensis) E, F/M

Snowshoe hare virus (SSHV) Snowshoe hares, squirrels, other small

mammals

Mosquitoes (Aedes, Culiseta,

Ochlerotatus spp.)

E, F/M

Tˇahynˇ a virus (TAHV) Cattle, dogs, eulipotyphla, foxes, hares,

horses, pigs, rodents

Mosquitoes (Aedes, Culex, Culiseta

spp.)

E, F/M

Orthobunyaviruses (group C

serogroup)

Apeú virus (APEUV) Bare-tailed woolly opossums

(Caluromys philander) and other

opossums; rodents; tufted capuchins

(Cebus apella)

Mosquitoes (Aedes, Culex spp.) F/M

Caraparú virus (CARV) Rodents, tufted capuchins (C. apella) Mosquitoes (Culex spp.) F/M

Itaquí virus (ITQV) Capuchins (Cebus spp.), opossums,

rodents

Mosquitoes (Culex spp.) F/M

Madrid virus (MADV) Capuchins (Cebus spp.), opossums,

rodents

Mosquitoes (Culex spp.) F/M

Marituba virus (MTBV) Capuchins (Cebus spp.), opossums,

rodents

Mosquitoes (Culex spp.) F/M

Murutucú virus (MURV) Capuchins (Cebus spp.), opossums,

pale-throated sloths (Bradypus

tridactylus), rodents

Mosquitoes (Coquillettidia, Culex

spp.)

F/M

Nepuyo virus (NEPV) Bats (Artibeus spp.), rodents Mosquitoes (Culex spp.) F/M

Oriboca virus (ORIV) Capuchins (Cebus spp.), opossums,

rodents

Mosquitoes (Aedes, Culex,

Mansonia, Psorophora spp.)

F/M

Ossa virus (OSSAV) Rodents Mosquitoes (Culex spp.) F/M

Restan virus (RESV) Unknown Mosquitoes (Culex spp.) F/M

Zungarococha virus (ZUNV) Unknown Unknown F/M

Orthobunyaviruses (Guamá

serogroup)

Catú virus (CATUV) Bats, capuchins (Cebus spp.),

opossums, rodents

Mosquitoes (Culex spp.) F/M

Guamá virus (GMAV) Bats, capuchins (Cebus spp.), howlers

(Alouatta spp.), marsupials, rodents

Mosquitoes (Aedes, Culex,

Limatus, Mansonia, Psorophora,

Trichoprosopon spp.)

F/M

Orthobunyaviruses

(Mapputta serogroup) 

Gan Gan virus (GGV) Unknown Mosquitoes (Aedes, Culex spp.) A/R

Trubanaman virus (TRUV) Unknown Mosquitoes (Anopheles, Culex spp.) (A/R)

(Continued)

(Continued)

1628 PART 5 Infectious Diseases

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

Orthobunyaviruses (Nyando

serogroup)

Nyando virus (NDV) Unknown Mosquitoes (Aedes, Anopheles

spp.), sandflies (Lutzomyia spp.)

F/M

Orthobunyaviruses (Simbu

serogroup)

Iquitos virus (IQTV) Unknown Unknown F/M

Oropouche virus (OROV) Marmosets (Callithrix spp.), palethroated sloths (B. tridactylus)

Biting midges (Culicoides

paraensis), mosquitoes

(Coquillettidia venezuelensis, Culex

quinquefasciatus, Mansonia spp.,

Ochlerotatus serratus)

F/M

Shuni virus (SHUV) Horses, livestock Mosquitoes (Culex theileri,

Culicoides spp.)

E

Orthobunyaviruses (Turlock

serogroup)

Cristoli virus Unknown Mosquitoes? E

Orthobunyaviruses

(Wyeomyia serogroup)

Wyeomyia virus (WYOV) Unknown Mosquitoes (Wyeomyia spp.) F/M

Orthobunyaviruses (other) Tataguine virus (TATV) Unknown Mosquitoes (Anopheles spp.) F/M

Orthohantaviruses (Old

World)

Amur virus (AMRV) Korean field mice (Apodemus

peninsulae)

None VHF

Dobrava virus (DOBV) Caucasus field mice (Apodemus

ponticus), striped field mice

(Apodemus agrarius), yellow-necked

field mice (Apodemus flavicollis)

None VHF

Go–

u virus (GOUV) Brown rats (Rattus norvegicus), roof

rats (R. rattus), Oriental house rats

(Rattus tanezumi)

None VHF

Hantaan virus (HTNV) Striped field mice (A. agrarius) None VHF

Kurkino virus (KURV) Striped field mice (A. agrarius) None VHF

Muju virus (MUJV) Korean red-backed voles (Myodes

regulus)

None VHF

Puumala virus (PUUV) Bank voles (Myodes glareolus) None (P), VHF

Saaremaa virus (SAAV) Striped field mice (A. agrarius) None VHF

Seoul virus (SEOV) Brown rats (R. norvegicus), roof rats

(R. rattus)

None VHF

Sochi virus (SOCV) Caucasus field mice (A. ponticus) None VHF

Tula virus (TULV) Common voles (Microtus arvalis), East

European voles (Microtus levis), field

voles (Microtus agrestis)

None (P), VHF

Orthohantaviruses (New

World)

Anajatuba virus (ANJV) Fornes’ colilargos (Oligoryzomys

fornesi)

None P

Andes virus (ANDV) Long-tailed colilargos (Oligoryzomys

longicaudatus)

None P

Araraquara virus (ARAV) Hairy-tailed akodonts (Necromys

lasiurus)

None P

Araucária virus (ARAUV) Black-footed colilargos (Oligoryzomys

nigripes)

None P

Bayou virus (BAYV) Marsh rice rats (Oryzomys palustris) None P

Bermejo virus (BMJV) Chacoan colilargos (Oligoryzomys

chacoensis)

None P

Black Creek Canal virus (BCCV) Hispid cotton rats (S. hispidus) None P

Blue River virus (BRV) White-footed deermice (P. leucopus) None P

Caño Delgadito virus (CADV) Alston’s cotton rats (Sigmodon alstoni) None P

Castelo dos Sonhos virus

(CASV)

Brazilian colilargos (Oligoryzomys

eliurus)

None P

Catacamas virus (CATV) Coues’ oryzomys (Oryzomys couesi) None P

Choclo virus (CHOV) Fulvous colilargos (Oligoryzomys

fulvescens)

None F/M, P

Juquitiba virus (JUQV) Black-footed colilargos (O. nigripes) None P

Laguna Negra virus (LANV) Little lauchas (Calomys laucha) None P

Lechiguanas virus (LECV) Flavescent colilargos (Oligoryzomys

flavescens)

None P

Maciel virus (MCLV) Dark-furred akodonts (Necromys

obscurus)

None P

Maripa virus (MARV) Unknown None P

Monongahela virus (MGLV) North American deermice

(P. maniculatus)

None P

(Continued)

(Continued)

1629CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

New York virus (NYV) White-footed deermice (P. leucopus) None P

Orán virus (ORNV) Long-tailed colilargos

(O. longicaudatus)

None P

Paranoá virus (PARV) Unknown None P

Pergamino virus (PRGV) Azara’s akodonts (Akodon azarae) None P

Rio Mamoré virus (RIOMV) Common bristly mice (Neacomys

spinosus)

None P

Sin Nombre virus (SNV) North American deermice

(P. maniculatus)

None P

Tunari virus (TUNV) Unknown None P

Orthonairoviruses (CrimeanCongo hemorrhagic fever

virus group)

Crimean-Congo hemorrhagic

fever virus (CCHFV)

Cattle, dogs, goats, hares, hedgehogs,

mice, ostriches, sheep

Predominantly ixodid ticks

(Hyalomma spp.)

VHF

Orthonairoviruses (Dugbe

virus group)

Dugbe virus (DUGV) Northern giant pouched rats

(Cricetomys gambianus), Zébu cattle

(Bos primigenius)

Biting midges (Culicoides spp.),

ixodid ticks (Amblyomma,

Hyalomma, Rhipicephalus spp.)

F/M

Nairobi sheep disease viruso

(NSDV)

Sheep Ixodid ticks (Haemaphysalis,

Rhipicephalus spp.), mosquitoes

(Culex spp.)

F/M

Orthonairoviruses (Sakhalin

virus group)

Avalon virus (AVAV) European herring gulls

(Larus argentatus)

Ixodid ticks (Ixodes uriae) (Polyradiculoneuritis?)

Orthonairoviruses (Thiafora

virus group)

Erve virus (ERVEV) Greater white-toothed shrews

(Crocidura russula)

? (Thunderclap

headache?)

Orthonairoviruses (other) Issyk-Kul virus (ISKV) Bats, birds Biting midges (Culicoides schultzei),

horseflies (Tabanus agrestis),

mosquitoes (Aedes caspius,

Anopheles hyrcanus), argasid ticks

(Argas vespertilionis, A. pusillus),

ixodid ticks (Ixodes vespertilionis)

F/M

Sönglïng virus (SGLV) Unknown Ixodid ticks (Ixodes crenulatus,

Ixodes persulcatus, Haemaphysalis

concinna, and Haemaphysalis

longicornis)

F/M

Tamdy virus (TAMV) Gerbils, other mammals (including

Bactrian camels), birds

Ixodid ticks (Hyalomma spp.) F/M

Phleboviruses (Candiru´ serocomplex) 

Alenquer virus (ALEV) Unknown Unknown F/M

Candiru´ virus (CDUV) Unknown Unknown F/M

Escharate virus (ESCV) Unknown Unknown F/M

Maldonado virus (MLOV) Unknown Unknown F/M

Morumbi virus (MRBV) Unknown Unknown F/M

Serra Norte virus (SRNV) Unknown Unknown F/M

Phleboviruses (Punta Toro

serocomplex) 

Coclé virus (CCLV) Unknown Sandflies F/M

Punta Toro virus (PTV) Unknown Sandflies (Lutzomyia spp.) F/M

Phleboviruses (sandfly fever

serocomplex) 

Chagres virus (CHGV) Unknown Sandflies (Lutzomyia spp.) F/M

Chios virus Unknown Unknown E

Granada virus (GRV) Unknown Sandflies F/M

Rift Valley fever virus (RVFV) Cattle, sheep Mosquitoes (Aedes, Anopheles,

Coquillettidia, Culex, Eretmapodites,

Mansonia spp.)

E, F/M, VHF

Sandfly fever Cyprus virus

(SFCV)

Unknown Unknown F/M

Sandfly fever Ethiopia virus

(SFEV)

Unknown Sandflies F/M

Sandfly fever Naples virus

(SFNV)

Unknown Sandflies (Phlebotomus papatasi,

P. perfiliewi, P. perniciosus)

F/M

Sandfly fever Sicilian virus

(SFSV)

Eulipotyphla, least weasels

(Mustela nivalis), rodents

Sandflies (particularly Phlebotomus

papatasi)

F/M

Sandfly fever Turkey virus

(SFTV)

Unknown Sandflies (Phlebotomus spp.) F/M

Toscana virus (TOSV) Unknown Sandflies (Phlebotomus papatasi,

P. perfiliewi)

E, F/M

Phleboviruses (Salehabad

serocomplex)

Adria virus (ADRV) Unknown Sandflies E

(Continued)

(Continued)

1630 PART 5 Infectious Diseases

TABLE 209-1 Zoonotic Arthropod- and Rodent-Borne Viruses That Infect Humans

VIRUS GROUP VIRUS (ABBREVIATION) MAJOR NONHUMAN HOST(S)a VECTOR(S) SYNDROMEb

Phleboviruses (Uukuniemi

serocomplex)

Taˇchéng tick virus 2 (TcTV-2) Unknown Ixodid ticks (Dermacentor

marginatus, Dermacentor nuttalli,

Dermacentor silvarum, Hyalomma

asiaticum)

E?

Uukuniemi virus (UUKV) Birds, cattle, rodents Ixodid ticks (Ixodes spp.) F/M

Quaranjaviruses Quaranfil virus (QRFV) Birds Argasid ticks (Argas arboreus) F/M

Seadornaviruses Banna virus (BAV) Cattle, pigs Mosquitoes (Aedes, Anopheles,

Culiseta spp.)

E

Thogotoviruses Bourbon virus (BRBV) Unknown Ticks? F/M

Dhori virus (DHOV)p Bats, camels, horses Mosquitoes (Aedes, Anopheles,

Culex spp.), argasid ticks

(Ornithodoros spp.), ixodid ticks

(Dermacentor, Hyalomma spp.)

E, F/M

Thogoto virus (THOV) Camels, cattle Ixodid ticks (Amblyomma,

Hyalomma, Rhipicephalus spp.)

E, F/M

Uukuviruses Uukuniemi virus (UUKV) Birds, cattle, rodents Ixodid ticks (Ixodes spp.) F/M

Vesiculoviruses Chandipura virus (CHPV) Hedgehogs Mosquitoes (Aedes aegypti),

sandflies (Phlebotomus,

Sergentomyia spp.)

E, F/M

Isfahan virus (ISFV) Great gerbils (Rhombomys opimus) Sandflies (Phlebotomus papatasi) F/M

Piry virus (PIRYV) Gray four-eyed opossums (Philander

opossum)

Mosquitoes (Aedes, Culex,

Toxorhynchites spp.)

F/M

Vesicular stomatitis Indiana

virus (VSIV)

Cattle, horses, pigs Sandflies (Lutzomyia spp.) F/M

Vesicular stomatitis

New Jersey virus (VSNJV)

Cattle, horses, pigs Biting midges (Culicoides spp.),

chloropid flies, mosquitoes (Culex,

Mansonia spp.), muscoid flies

(Musca spp.), simuliid flies

F/M

a

Mammalian names as listed in Wilson & Reeder’s Mammal Species of the World, 3rd edition (https://www.departments.bucknell.edu/biology/resources/msw3/). b

Abbreviations refer to the syndromes most associated with the viruses: A/R, arthritis/rash; E, encephalitis; F/M, fever/myalgia; P, pulmonary; VHF, viral hemorrhagic fever.

Abbreviations are placed in parentheses when cases are either extremely rare or controversial. c

In the older literature, chikungunya virus often is also listed as a causative

agent of VHF. However, later studies revealed that, in most cases, people with “chikungunya hemorrhagic fever” were co-infected with one or more dengue viruses, an

observation suggesting that the VHF was severe dengue. d

Also known as Igbo-Ora virus. e

Also known as Ockelbo virus (OCKV), Pogosta virus, and Karelian fever virus (KFV). f

Also known as Palma virus (PALV). g

Alternatives used in the literature are Huáiyángsha– n virus (HYSV) and Hénán fever virus (HNFV). h

Also known as Alfuy virus (ALFV). i

Also includes Kunjin virus (KUNV). j

Also spelled Alkhumra hemorrhagic fever virus (AHFV) and known as Alkhurma/Alkhumra virus (ALKV). k

Also known as Nánjiànyí(n)

virus. l

Whitewater Arroyo virus is often listed as a causative agent of VHF in the literature, but convincing data associating this virus with VHF have not been published. mAlso known as Brezová virus, Cvilín virus, Kharagysh virus, Koliba virus, or Lipovník virus. n

Also known as Cˇalovo virus (CVOV) or Chittoor virus (CHITV). o

Also known as

Ganjam virus (GV). p

Also known as Astra virus and Batken virus (BKNV).

■ BUNYAVIRALES: HANTAVIRIDAE, NAIROVIRIDAE,

PERIBUNYAVIRIDAE, AND PHENUIVIRIDAE

The members of all these families that infect humans form spherical

to pleomorphic enveloped virions containing three genomic RNAs (S,

~1–2 kb; M, 3.6–5.3 kb; and L, 6.4–12.3 kb) of negative (hantavirids,

nairovirids, peribunyavirids) or ambisense (phenuivirids) polarity.

These bunyavirals mature into particles ~80–120 nm in diameter in

the Golgi complex of infected cells and exit these cells by exocytosis.

Hantavirids that infect humans are classified in the genus Orthohantavirus and are maintained in nature by rodents that chronically

shed virions. Old World orthohantaviruses are harbored by murid and

cricetid rodents, and New World orthohantaviruses are maintained by

cricetid rodents. As with mammarenaviruses, individual orthohantaviruses are usually specifically adapted to a particular type of rodent. However, orthohantaviruses do not cause chronic viremia in their rodent

hosts and are transmitted only horizontally from rodent to rodent. Similar to mammarenaviruses, orthohantaviruses infect humans primarily

through inhalation of or direct contact with rodent excreta or secreta,

and person-to-person transmission is not a common event (with the

notable exception of Andes virus). Although there is overlap, the human

Old World orthohantaviruses are usually the etiologic agents of hemorrhagic fever with renal syndrome (HFRS), whereas the New World

orthohantaviruses usually cause hantavirus pulmonary syndrome.

Nairovirids that infect humans are classified in the genus Orthonairovirus. Orthonairoviruses are maintained by ixodid ticks, which

transmit these viruses vertically (transovarially and transstadially)

to progeny tick generations and horizontally spread them through

viremic vertebrate hosts. Humans are usually infected via a tick bite or

during handling of infected vertebrates.

Peribunyavirids of one genus (Orthobunyavirus) infect humans.

Orthobunyaviruses are largely mosquito-borne and rarely midge-borne

and have viremic vertebrate intermediate hosts. Many orthobunyaviruses are transmitted transovarially to their mosquito hosts. Numerous

orthobunyaviruses have been associated with human infection and disease. They have been considered as members of ~19 serogroups based

on antigenic cross-reactions, but this grouping is undergoing revision

through accumulation of new genomic data and phylogenetic analyses.

Humans are infected by viruses in at least 10 serogroups.

Phenuivirids are transmitted vertically (transovarially) in their

arthropod hosts and horizontally through viremic vertebrate hosts.

Human phenuivirids are found in three genera: Bandavirus, Phlebovirus,

and Uukuvirus. Bandaviruses and uukuviruses are transmitted by ticks,

whereas viruses of the phlebovirus sandfly fever group are transmitted

by sandflies. Phleboviruses are assigned to at least 10 serocomplexes;

human pathogens are found in at least three of these serocomplexes.

■ MARTELLIVIRALES: TOGAVIRIDAE

The members of the family Togaviridae have linear, positive-stranded

RNA genomes (~9.7–11.8 kb) and form enveloped icosahedral virions

(~60–70 nm in diameter) that bud from the plasma membrane of the

infected cell. The togavirids discussed here are all members of the

genus Alphavirus and are transmitted to vertebrates by mosquitoes.

■ MONONEGAVIRALES: RHABDOVIRIDAE

Rhabdovirids have linear, typically nonsegmented, negative-sense

RNA genomes (~11–15 kb) and form bullet-shaped to pleomorphic

enveloped particles (100–430 nm long and 45–100 nm wide). Only

the genus Vesiculovirus includes confirmed human arthropod-borne

viruses, all of which are transmitted by insects (biting midges,

(Continued)

1631CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

mosquitoes, and sandflies). The general properties of rhabdovirids

are discussed in more detail in Chap. 208.

■ REOVIRALES: REOVIRIDAE

The family Reoviridae was established for viruses with linear, multisegmented, double-stranded RNA genomes (~16–29 kb in total).

These viruses produce particles that have icosahedral symmetry and

are 60–80 nm in diameter. In contrast to all other virions discussed

here, reovirions are not enveloped and thus are insensitive to detergent inactivation. Human arthropod-borne viruses are found within

the genera Coltivirus (subfamily Spinareovirinae), Orbivirus (subfamily Sedoreovirinae), and Seadornavirus (subfamily Sedoreovirinae).

Arthropod-borne coltiviruses possess 12 genome segments. Coltiviruses are transmitted by numerous tick types transstadially but not

transovarially. Overall maintenance of the transmission cycle therefore

involves viremic mammalian hosts infected by tick bites. Arthropodborne orbiviruses have 10 genome segments and are transmitted by

mosquitoes or ixodid ticks, whereas relevant seadornaviruses have 12

genome segments and are transmitted exclusively by mosquitoes.

EPIDEMIOLOGY

The distributions of arthropod-borne and rodent-borne viruses are

restricted by the areas inhabited by their reservoir hosts and/or vectors. Consequently, a patient’s geographic origin or travel history can

provide important clues in the differential diagnosis. Table 209-2 lists

the approximate geographic distribution of most arthropod-borne and

rodent-borne infections. Many of these diseases can be acquired in

either rural or urban settings; the diseases include yellow fever, dengue

without/with warning signs (previously called dengue fever), severe

dengue (previously called dengue hemorrhagic fever and dengue shock

syndrome), chikungunya virus disease, HFRS caused by Seoul virus,

sandfly fever caused by sandfly fever Naples and Sicilian viruses, and

Oropouche virus disease.

DIAGNOSIS

In patients with suspected viral infection, a recognized history of

mosquito bite(s) has little diagnostic significance, but a history of tick

bite(s) is more useful. Exposure to rodents is sometimes reported by

people infected with mammarenaviruses or orthohantaviruses. Laboratory diagnosis is required in all cases, although epidemics occasionally

provide enough clinical and epidemiologic clues for a presumptive etiologic diagnosis. For most arthropod-borne and rodent-borne viruses,

acute-phase serum samples (collected within 3 or 4 days of onset) have

yielded isolates. Paired serum samples have been used to demonstrate

rising antibody titers. Intensive efforts to develop rapid tests for viral

hemorrhagic fevers (VHFs) have resulted in reliable antigen-detection

enzyme-linked immunosorbent assays (ELISAs), IgM-capture ELISAs,

and multiplex polymerase chain reaction (PCR) assays. These tests can

provide a diagnosis based on a single serum sample within a few hours

and are particularly useful in patients with severe disease. More sensitive reverse-transcription PCR (RT-PCR) assays may yield diagnoses

based on samples without detectable antigen and may also provide

useful genetic information about the etiologic agent.

Orthohantavirus infections differ from other viral infections discussed

here in that severe acute disease is immunopathologic; patients present

with serum IgM that serves as the basis for a sensitive and specific test. At

diagnosis, patients with encephalitides generally are no longer viremic or

antigenemic and usually do not have virions in cerebrospinal fluid (CSF).

In this situation, serologic methods for IgM determination and RT-PCR

are highly valuable. Increasingly, IgM-capture ELISA is used for the

simultaneous testing of serum and CSF. IgG ELISA or classic serology

is useful in the evaluation of past exposure to viruses, many of which

circulate in areas with minimal medical infrastructures and sometimes

cause only mild or subclinical infections.

CLINICAL DISEASE SYNDROMES

There is a wide spectrum of possible human responses to infection with

arthropod-borne or rodent-borne viruses, and knowledge of the outcome of most of these infections is limited. People infected with these

viruses may not develop symptoms or signs of illness. If viral disease

is recognized, it can usually be grouped into one of five broad syndromic categories: arthritis and rash, encephalitis, fever and myalgia,

pulmonary disease, or VHF (Table 209-3). Although a useful clinical

heuristic, it should be recognized that these categories often overlap in

complex spectra of disease caused by arthropod-borne or rodent-borne

viruses. Indeed, illness caused by many of these viruses is often best

known by the most severe disease phenotypes, which are typically not

the most common disease manifestation. For example, infections with

West Nile virus and Venezuelan equine encephalitis virus are discussed

here as encephalitides, but during epidemics, many patients present

with much milder febrile syndromes. Similarly, Rift Valley fever virus

is best known as a cause of VHF, but the attack rates for febrile disease

are far higher, with encephalitis and blindness occurring occasionally

as well. Lymphocytic choriomeningitis virus is classified here as a cause

of fever and myalgia because this syndrome is the most common disease manifestation. Even when central nervous system (CNS) disease

evolves during infection with this virus, neurologic manifestations

are usually mild and preceded by fever and myalgia. However, this

virus may also cause fetal microcephaly. Overlap between syndromic

categories is further complicated by evolving nomenclature around

their classification. For example, infection with any dengue virus (1,

2, 3, or 4) is considered as a cause of fever and myalgia because this

syndrome, historically called “dengue fever,” is by far the most common

manifestation worldwide. However, severe manifestations of dengue

virus infection have a complicated pathogenesis: the historical classification of disease as “dengue hemorrhagic fever” included a subset

of patients with “dengue shock syndrome,” which is of tremendous

consequence for pediatric populations in certain areas of the world.

Further complicating this overlap, recent World Health Organization

revision of disease classification recommended a less descriptive but

more pragmatic use of “dengue without warning signs,” “dengue with

warning signs,” and “severe dengue” to describe the same spectrum and

enhance clinical management and case reporting. Unfortunately, most

of the known arthropod-borne or rodent-borne viral diseases have not

been studied in detail with modern medical approaches. Thus, available data may be incomplete or biased. Data on geographic distribution

are often difficult to interpret: Frequently, the literature is not clear as

to whether the data pertain to the distribution of a particular virus or

to the areas where human disease has been observed. In addition, the

designations for viruses and viral diseases have changed multiple times

over decades. Here, virus and taxon names are in line with the latest

reports of the International Committee on Taxonomy of Viruses, and

disease names are in accordance with the World Health Organization’s

International Classification of Diseases 11th revision (ICD-11). When

needed for clarity or historical reference, other nomenclature will be

specifically identified. In light of this syndromic approach, the reader

should be aware that the variable clinical manifestations of particular

viruses may be captured over a number of sections.

■ ARTHRITIS AND RASH

Arthritides are common clinical presentations (or manifestations) of

several viral diseases, such as hepatitis B, parvovirus B19 infection,

and rubella, and occasionally accompany infection due to adenovirids,

enteroviruses, herpesvirids, or mumps virus. Two orthobunyaviruses—

Gan Gan virus and Trubanaman virus—and the flavivirus Kokobera

virus have been associated with single cases of polyarthritic disease.

Arthropod-borne alphaviruses are also common causes of arthritides—usually acute febrile diseases accompanied by the development

of a maculopapular rash. Rheumatic involvement includes arthralgia

alone, periarticular swelling, and (less commonly) joint effusions. Most

alphavirus infections are less severe and have fewer articular manifestations in children than in adults. In temperate climates, these ailments

are summer diseases. No specific therapies or licensed vaccines exist.

The most significant alphavirus arthritides are chikungunya virus

disease, Ross River disease, Barmah Forest virus infection, and Sindbis

virus infection. Also of interest is the emerging Zika virus infection.

Less significant but historically notable are viruses that caused isolated