1632 PART 5 Infectious Diseases

TABLE 209-2 Geographic Distribution of Zoonotic Arthropod-Borne or Rodent-Borne Viral Diseases

AREAa

TYPE OF DISEASEb

ARENAVIRAL BUNYAVIRAL FLAVIVIRAL ORTHOMYXOVIRAL REOVIRAL RHABDOVIRAL TOGAVIRAL

Africa Lassa fever; Lujo

virus infection

Bangui, Batai, Bhanja,

Bunyamwera, and

Bwamba virus infections;

Crimean-Congo

hemorrhagic fever;

Dugbe, Germiston, Ilesha

virus infections; Nairobi

sheep disease virus

infection; Ngari, Nyando,

and Pongola virus

infections; Rift Valley

fever; sandfly fever;

Shokwe, Shuni, Tataguine

virus infections

Alkhurma hemorrhagic

fever; dengue without/

with warning signs/

severe dengue;

Usutu, West Nile virus

infections; yellow fever;

Zika virus disease

Dhori, Quaranfil,

Thogoto virus

infections

Lebombo,

Orungo, Tribecˇ

virus infections

— Chikungunya

virus disease;

o’nyong-nyong

fever; Semliki

Forest, Sindbis

virus infections

Central Asia — Bhanja, Issyk-Kul virus

infections; CrimeanCongo hemorrhagic fever;

sandfly fever; Tˇahynˇa,

Tamdy virus infections

Far Eastern tick-borne

encephalitis; Karshi,

Powassan, West Nile

virus infections

Dhori virus infections — Isfahan virus

infection

Sindbis virus

infection

Eastern Asia — Crimean-Congo

hemorrhagic fever;

hemorrhagic fever with

renal syndrome; sandfly

fever; severe fever

with thrombocytopenia

syndrome; Taˇchéng tick

virus 2 and Tamdy and

So–

nglıˇng virus infections

Dengue without/with

warning signs/severe

dengue; Far Eastern

tick-borne encephalitis;

Japanese encephalitis;

Kyasanur Forest disease

— Banna virus

infection

— —

Southern Asia — Batai, Bhanja virus

infections; CrimeanCongo hemorrhagic fever;

hemorrhagic fever with

renal syndrome; Nairobi

sheep disease virus

infection; sandfly fever

Dengue without/with

warning signs/severe

dengue; Japanese

encephalitis; Kyasanur

Forest disease; West

Nile virus infection; Zika

virus disease

Dhori, Quaranfil,

Thogoto virus

infections

— Chandipura,

Isfahan virus

infections

Chikungunya

virus disease

South-Eastern

Asia

— Batai virus infection;

hemorrhagic fever with

renal syndrome

Dengue without/with

warning signs/severe

dengue; Japanese

encephalitis; West Nile

virus infection; Zika

virus disease

— — — Chikungunya

virus disease

Western Asia — Batai, Bhanja virus

infections; CrimeanCongo hemorrhagic

fever; hemorrhagic fever

with renal syndrome;

sandfly fever; Tamdy virus

infection

Alkhurma hemorrhagic

fever; Central European

tick-borne encephalitis;

dengue without/with

warning signs/severe

dengue; West Nile virus

infection

Dhori, Quaranfil virus

infections

— — Chikungunya

virus disease

Latin/Central

America and

the Caribbean

Argentinian

hemorrhagic

fever; Bolivian

hemorrhagic

fever; “Brazilian

hemorrhagic

fever”; Chapare

virus infection;

lymphocytic

choriomeningitis;

Venezuelan

hemorrhagic

fever

Alenquer, Apeú,

Bunyamwera, Cache

Valley, Candiru´, Caraparú,

Catú, Chagres, Coclé,

Echarate, Fort Sherman,

Guamá, Guaroa virus

infections; hantavirus

pulmonary syndrome;

Itaquí, Juquitiba, Madrid,

Maguari, Maldonado,

Marituba, Mayaro,

Morumbi, Murutucú,

Nepuyo, Oriboca virus

infections; Oropouche

virus disease; Ossa,

Punta Toro, Restan, Serra

Norte, Tacaiuma, Trinidad,

Wyeomyia, Xingu,

Zungarococha virus

infections

Dengue without/with

warning signs/severe

dengue; Rocio viral

encephalitis; St. Louis

encephalitis; yellow

fever; Zika virus disease

— — Piry fever;

vesicular

stomatitis fever

Chikungunya

virus disease;

Madariaga,

Mayaro,

Mucambo,

Tonate,

Una virus

infections;

Venezuelan

equine

encephalitis

(Continued)

1633CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

TABLE 209-2 Geographic Distribution of Zoonotic Arthropod-Borne or Rodent-Borne Viral Diseases

AREAa

TYPE OF DISEASEb

ARENAVIRAL BUNYAVIRAL FLAVIVIRAL ORTHOMYXOVIRAL REOVIRAL RHABDOVIRAL TOGAVIRAL

Northern

America

Lymphocytic

choriomeningitis;

Whitewater

Arroyo virus

infection

Avalon, Cache Valley

virus infections; California

encephalitis; hantavirus

pulmonary syndrome;

Heartland, Nepuyo,

snowshoe hare virus

infections

Dengue without/with

warning signs/severe

dengue; Powassan

virus disease; St. Louis

encephalitis; West Nile

virus infection; Zika

virus disease

Bourbon virus

infection

Colorado tick

fever; Salmon

River virus

infection

Vesicular

stomatitis fever

Eastern equine

encephalitis;

Everglades

virus infection;

western

equine

encephalitis

Europe Lymphocytic

choriomeningitis

Adria, Avalon, Bhanja,

Cristoli virus infections;

California encephalitis;

Crimean-Congo

hemorrhagic fever;

Erve virus infection;

hemorrhagic fever with

renal syndrome; Inkoo

virus infection; sandfly

fever; snowshoe hare,

Tˇahynˇa, Uukuniemi virus

infections

Central European tickborne encephalitis;

dengue without/

with warning signs/

severe dengue; Omsk

hemorrhagic fever;

Powassan, Usutu, West

Nile virus infections

Dhori, Thogoto virus

infections

Eyach,

Kemerovo,

Tribecˇ virus

infections

— Chikungunya

virus disease;

Sindbis virus

infection

Oceania — Gan Gan, Trubanaman

virus infections

Dengue without/with

warning signs/severe

dengue; Edge Hill virus

infection; Japanese

encephalitis; Kokobera

virus infection; Murray

Valley encephalitis;

Stratford, West Nile

virus infections; Zika

virus disease

— — — Barmah

Forest virus

infection; Ross

River disease;

Sindbis virus

infection

a

Geographic names here and throughout the chapter are as recommended by the UN geoscheme (https://unstats.un.org/unsd/methodology/m49/). b

Disease names

according to the World Health Organization’s International Classification of Diseases 11th revision (ICD-11; https://icd.who.int/browse11/l-m/en). Quotation marks indicate

common usage in the absence of ICD-11 recognition. Diseases not acknowledged by the ICD-11 are designated as “virus infection(s).”

cases or epidemics: A large (>2 million cases), albeit isolated, epidemic

was caused by o’nyong-nyong virus from 1959 to 1962 (o’nyong-nyong

fever). Mayaro, Semliki Forest, and Una viruses caused isolated cases

or limited and infrequent epidemics (30 to several hundred cases per

year). Signs and symptoms of infections with these viruses often are

similar to those observed with chikungunya virus disease.

Chikungunya Virus Disease Chikungunya virus is endemic in

rural areas of Africa. Intermittent epidemics take place in towns and

cities of both Africa and Asia. Yellow fever mosquitoes (Aedes aegypti)

are the usual vectors for the disease in urban areas. In 2004, a massive

epidemic began in the Indian Ocean region (specifically on the islands

of Réunion and Mauritius) and was most likely spread by travelers. The

Asian tiger mosquito (Aedes albopictus) was identified as the major

vector of chikungunya virus during that epidemic. In 2013 and 2014,

several thousand chikungunya virus infections were reported (with as

many as 900,000 cases suspected) from Caribbean islands. The virus

was carried to Italy, France, and the United States by travelers from the

Caribbean. Chikungunya virus poses a threat to the continental United

States as suitable vector mosquitoes are present in southern states.

The disease is most common among adults, in whom the clinical

presentation may be dramatic. The abrupt onset of chikungunya virus

disease follows an incubation period of 2–10 days. Fever (often severe)

with a saddleback pattern and severe arthralgia are accompanied by

chills and constitutional symptoms and signs, such as abdominal pain,

anorexia, conjunctival injection, headache, nausea, and photophobia.

Migratory polyarthritis mainly affects the small joints of the ankles,

feet, hands, and wrists, but the larger joints may be involved. Rash may

appear at the outset or several days into the illness; its development

often coincides with defervescence, which occurs around day 2 or 3

of the disease. The rash is most intense on the trunk and limbs and

may desquamate. Young children develop less prominent signs and are

therefore less frequently hospitalized. Children also often develop a bullous rather than a maculopapular/petechial rash. Maternal–fetal transmission has been reported and, in some cases, has led to fetal death.

Recovery may require weeks, and a significant portion of middle-aged

to older patients develop chronic arthritis or arthralgia syndromes (typically involving the same joints) that may be disabling. This persistence

of signs and symptoms may be especially common in patients who test

positive for the human leukocyte antigen B27 subtype (HLA-B27). In

addition to arthritis, petechiae are seen occasionally and epistaxis is not

uncommon, but chikungunya virus should not be considered a VHF

agent. A few patients develop leukopenia. Elevated activities of aspartate

aminotransferase (AST) and concentrations of C-reactive protein have

been described, as have mildly decreased platelet counts. Treatment of

chikungunya virus disease relies on nonsteroidal anti-inflammatory

drugs and sometimes chloroquine for refractory arthritis.

Ross River Disease and Barmah Forest Virus Infection Ross

River virus and Barmah Forest virus cause diseases that are indistinguishable on clinical grounds alone (hence the previously common

disease designation of “epidemic polyarthritis” for both infections).

Ross River virus has caused epidemics in Australia, Papua New

Guinea, and the South Pacific since the beginning of the 20th century.

In 1979 and 1980, the virus swept through the Pacific Islands, causing

>500,000 infections. From 1991 to 2011, the virus caused 92,559 infections or disease in rural and suburban areas of Australia. From 2014

to 2015, >10,000 cases were recorded in Australia. Ross River virus is

predominantly transmitted by Aedes normanensis, Aedes vigilax, and

Culex annulirostris mosquitoes. Wallabies and rodents are probably the

main vertebrate hosts. Barmah Forest virus infections have been on

the rise since the early 1990s. For instance, from 1991 to 2011, 21,815

cases of Barmah Forest virus infection were recorded in Australia, and

new data indicate that the disease also occurs in Papua New Guinea.

Barmah Forest virus is transmitted by both Aedes and Culex mosquitoes and has been isolated from biting midges. The vertebrate hosts

remain to be determined, but serologic studies implicate horses and

possums.

Of the human Barmah Forest and Ross River virus infections surveyed, 55–75% were asymptomatic; however, these viral diseases can

(Continued)

1634 PART 5 Infectious Diseases

TABLE 209-3 Clinical Syndromes Caused by Zoonotic Arthropod-Borne or Rodent-Borne Viruses

SYNDROME VIRUS

Arthritis and rash (A/R) Flaviviridae: Kokobera and Zika viruses

Peribunyaviridae: Gan Gan and Trubanaman viruses

Togaviridae: Barmah Forest, chikungunya, Mayaro, o’nyong-nyong, Ross River, Semliki Forest, and Sindbis viruses

Encephalitis (E) Arenaviridae: lymphocytic choriomeningitis and Whitewater Arroyo viruses

Flaviviridae: Japanese encephalitis, Karshi, Murray Valley encephalitis, Powassan, Rocio, St. Louis encephalitis, tick-borne encephalitis,

Usutu, and West Nile viruses

Orthomyxoviridae: Dhori and Thogoto viruses

Peribunyaviridae: California encephalitis, Cristoli, Inkoo, Jamestown Canyon, La Crosse, Lumbo, snowshoe hare, Shuni, and Tˇahynˇ a viruses

Phenuiviridae: Adria, Bhanja, Chios, Rift Valley fever, Taˇchéng tick virus 2, and Toscana viruses

Reoviridae: Banna, Colorado tick fever, Eyach, Kemerovo, Orungo, and Salmon River viruses

Rhabdoviridae: Chandipura virus

Togaviridae: eastern equine encephalitis, Everglades, Madariaga, Mucambo, Tonate, Venezuelan equine encephalitis, and western equine

encephalitis viruses

Fever and myalgia (F/M) Arenaviridae: Lassa and lymphocytic choriomeningitis viruses

Bunyavirales (unclassified): Bangui virus

Flaviviridae: dengue 1–4, Edge Hill, Karshi, tick-borne encephalitis, Stratford, and Zika viruses

Hantaviridae: Choclo virus

Nairoviridae: Dugbe, Issyk-Kul, Nairobi sheep disease, So–

nglıˇng, Tamdy viruses

Orthomyxoviridae: Bourbon, Dhori, and Thogoto viruses

Peribunyaviridae: Apeú, Batai, Bunyamwera, Bwamba, Cache Valley, California encephalitis, Caraparú, Catú, Fort Sherman, Germiston,

Guamá, Guaroa, Ilesha, Inkoo, Iquitos, Itaquí, Jamestown Canyon, La Crosse, Lumbo, Madrid, Maguari, Marituba, Nepuyo, Ngari, Nyando,

Oriboca, Oropouche, Ossa, Pongola, Restan, Shokwe, snowshoe hare, Tacaiuma, Tˇahynˇ a, Tataguine, Wyeomyia, Xingu, and Zungarococha

viruses

Phenuiviridae: Alenquer, Bhanja, Candiru´, Chagres, Echarate, Heartland, Maldonado, Morumbi, Punta Toro, Rift Valley fever, sandfly

fever Cyprus, sandfly fever Ethiopia, sandfly fever Naples, sandfly fever Sicilian, sandfly fever Turkey, Serra Norte, severe fever with

thrombocytopenia syndrome, Toscana, and Uukuniemi viruses

Reoviridae: Colorado tick fever, Eyach, Kemerovo, Lebombo, Orungo, Salmon River, and Tribecˇ viruses

Rhabdoviridae: Chandipura, Isfahan, Piry, vesicular stomatitis Indiana, and vesicular stomatitis New Jersey viruses

Togaviridae: Everglades, Madariaga, Mucambo, Tonate, Una, and Venezuelan equine encephalitis viruses

Pulmonary disease (P) Hantaviridae: Anajatuba, Andes, Araucária, bayou, Bermejo, Black Creek Canal, Blue River, Caño Delgadito, Castelo dos Sonhos, Catacamas,

Choclo, Juquitiba, Laguna Negra, Lechiguanas, Maciel, Monongahela, New York, Orán, Paranoá, Pergamino, Puumala, Rio Mamoré, Sin

Nombre, Tula, and Tunari viruses

Viral hemorrhagic fever

(VHF)

Arenaviridae: Chapare, Guanarito, Junín, Lassa, Lujo, lymphocytic choriomeningitis, Machupo, and Sabiá viruses

Hantaviridae: Amur, Dobrava, go–

u, Hantaan, Kurkino, Muju, Puumala, Saaremaa, Seoul, Sochi, and Tula viruses

Nairoviridae: Crimean-Congo hemorrhagic fever virus

Peribunyaviridae: Ilesha and Ngari viruses

Phenuiviridae: Rift Valley fever and severe fever with thrombocytopenia syndrome viruses

Flaviviridae: Alkhurma hemorrhagic fever, dengue 1–4, Kyasanur Forest disease, Omsk hemorrhagic fever, tick-borne encephalitis, and yellow

fever viruses

be debilitating. The incubation period is 7–9 days, the onset of illness

is sudden, and disease is usually ushered in by disabling symmetrical

joint pain. Generally, a non-itchy, diffuse, maculopapular rash (more

common in Barmah Forest virus infection) develops coincidentally or

follows shortly, but, in some patients, rash can precede joint pain by

several days. Constitutional symptoms (such as low-grade fever, asthenia, headache, myalgia, and nausea) are not prominent or are absent in

many cases. Most patients are incapacitated for considerable periods

(6 months or more) by joint involvement, which interferes with grasping, sleeping, and walking. Ankle, interphalangeal, knee, metacarpophalangeal, and wrist joints are most often involved, although elbows,

shoulders, and toes may also be affected. Periarticular swelling and

tenosynovitis are common, and one-third of patients have true arthritis

(more common in Ross River disease). Myalgia and nuchal stiffness

may accompany joint pains. Only half of all patients with arthritis can

resume normal activities within 4 weeks, and 10% continue to limit

their activities after 3 months. Occasionally, patients are symptomatic

for 1–3 years but without progressive arthropathy.

In the diagnosis of either infection, clinical laboratory values are normal or variable. Tests for rheumatoid factor and antinuclear antibodies

are negative, and the erythrocyte sedimentation rate is acutely elevated.

Joint fluid contains 1000–60,000 mononuclear cells per μL, and viral

antigen can usually be detected in macrophages. IgM antibodies are

valuable in the diagnosis of this infection, although occasionally, such

antibodies persist for years. Isolation of the virus from blood after

mosquito inoculation or growth of the virus in cell culture is possible

early in the illness. Because of the great economic impact of annual

epidemics in Australia, an inactivated Ross River virus vaccine has

been under advanced development; phase 3 trials were completed in

2015 with promising results, but the candidate vaccine has not yet been

developed for the market. Nonsteroidal anti-inflammatory drugs, such

as naproxen or acetylsalicylic acid, are effective for treatment.

Sindbis Virus Infection Sindbis virus is typically transmitted to

birds by infected mosquitoes. Infections with northern European or

southern African variants are particularly likely in rural environments.

After an incubation period of <1 week, Sindbis virus infection begins

with rash and arthralgia. Constitutional clinical signs are not marked,

and fever is modest or lacking altogether. The rash, which lasts ~1

week, begins on the trunk, spreads to the extremities, and evolves from

macules to papules that often vesiculate. The arthritis is polyarticular,

migratory, and incapacitating, with resolution of the acute phase in a

few days. The ankles, elbows, knees, phalangeal joints, wrists, and—to a

much lesser extent—proximal and axial joints are involved. Persistence

of joint pain and occasionally of arthritis is a major problem and may

continue for months or even years despite lack of deformities.

1635CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

Zika Virus Disease Zika virus is an emerging pathogen that is

transmitted to nonhuman primates and humans by Aedes mosquitoes.

The virus was discovered 1947 in a sentinel rhesus monkey (Macaca

mulatta) and Aedes africanus mosquitoes in the Zika Forest in what

was then the British Protectorate of Uganda. Human Zika virus infection was first documented during a yellow fever outbreak in 1954 in

Nigeria. Later, Zika virus infections were recognized in South-Eastern

Asia and Southern Asia. Prior to 2007, only 14 clinically identified

cases of Zika virus disease had been reported. In recent years, the

number of Zika virus infections reported has increased steadily and

rapidly, with large, but generally mild, disease outbreaks on Yap Island,

Micronesia (2007), and in Cambodia (2010), the Philippines (2012),

and French Polynesia (2013–2014). Invasion of the New World was

first reported on Easter Island, Chile (2014), and in Brazil (2015). An

estimated 440,000 to 1.3 million cases had occurred in Brazil by the

end of 2015. At the end of May 2017, Zika virus infections had been

recorded on five continents in 85 countries, including Mexico and

the United States. Beginning in 2018, the global activity of Zika virus

declined rather rapidly for unknown reasons.

Phylogenetic analysis of all available African Zika virus isolates

revealed two geographically overlapping clades (Western Africa and

Eastern Africa). A descendant Asian lineage, represented by viruses

collected from mosquitoes trapped in homes in Malaysia, was first

reported in 1969. All Zika virus isolates causing human cases outside

of Africa trace back to this Asian lineage.

Human infections are usually asymptomatic or benign and selfresolving and are most likely misdiagnosed as dengue without/with

warning signs or influenza. Typically, Zika virus disease is characterized by low-grade fever, headache, and malaise. An itchy maculopapular rash, nonpurulent conjunctivitis, myalgia, and arthralgia usually

accompany or follow those manifestations. Vomiting, hematospermia,

and hearing impairments are relatively common clinical signs. In

severe cases, Zika virus infection is associated with serious complications, such as Guillain-Barré syndrome or fetal microcephaly after

congenital transmission. Other neurologic complications of Zika virus

infection are encephalitis, meningoencephalitis, transverse myelitis,

peripheral neuropathies, retinopathies, and neurologic birth defects.

Although most human Zika virus infections are acquired after bites by

infected female mosquitoes, transmission may also occur perinatally

or via heterosexual or homosexual contact with an infected person,

breastfeeding, or transfusion of blood products. Specifically worrisome is viral persistence in the testes, which can last up to at least 160

days, as sexual virus transmission be may be possible throughout that

period. Unfortunately, antiviral treatments (curative or preventive) and

licensed vaccines against Zika virus are not yet available.

■ ENCEPHALITIS

The major encephalitis viruses are found in the families Flaviviridae,

Peribunyaviridae, Rhabdoviridae, and Togaviridae. However, individual agents of other families, including Dhori virus and Thogoto virus

(Orthomyxoviridae) and Banna virus (Reoviridae), have been known to

cause isolated cases of encephalitis as well. Arboviral encephalitides are

seasonal diseases, commonly occurring in the warmer months. Their

incidence varies markedly with time and place, depending on ecologic

factors. The causative viruses differ substantially in terms of case-toinfection ratio (i.e., the ratio of clinical to subclinical infections), lethality,

and residual disease. Humans are not important amplifiers of these viruses.

All the viral encephalitides discussed in this section have a similar

pathogenesis. An infected arthropod ingests blood from a human and

thereby initiates infection. The initial viremia is thought to originate

from the lymphoid system. Viremia leads to multifocal entry into the

CNS, presumably through infection of olfactory neuroepithelium,

with passage through the cribriform plate, “Trojan horse” entry with

infected macrophages, or infection of brain capillaries. During the

viremic phase, there may be little or no recognizable disease except in

tick-borne flavivirus encephalitides, which may manifest with clearly

delineated phases of fever and systemic illness.

CNS lesions arise partly from direct neuronal infection and subsequent damage and partly from edema, inflammation, and other indirect

effects. The usual pathologic features of arboviral encephalitides are

focal necroses of neurons, inflammatory glial nodules, and perivascular

lymphoid cuffing. Involved areas display the “luxury perfusion” phenomenon, with normal or increased total blood flow and low oxygen

extraction. The typical patient presents with a prodrome of nonspecific

constitutional signs and symptoms, including fever, abdominal pain,

sore throat, and respiratory signs. Headache, meningeal signs, photophobia, and vomiting follow quickly. The severity of human infection

varies from an absence of signs/symptoms to febrile headache, aseptic

meningitis, and full-blown encephalitis. The proportions and severity

of these manifestations vary with the infecting virus. Involvement of

deeper brain structures may be signaled by lethargy, somnolence, and

intellectual deficit (as disclosed by a mental status examination). More

severely affected patients are obviously disoriented and may become

comatose. Tremors, loss of abdominal reflexes, cranial nerve palsies,

hemiparesis, monoparesis, difficulty swallowing, limb-girdle syndrome,

and frontal lobe signs are all common. Spinal and motor neuron

diseases are documented after West Nile virus and Japanese encephalitis virus infections. Seizures and focal signs may be evident early or

may appear during the course of the disease. Some patients present

with an abrupt onset of fever, convulsions, and other signs of CNS

involvement. The acute encephalitis usually lasts from a few days to

2–3 weeks. The infections may be fatal, or recovery may be slow (with

weeks or months before the return of maximal recoverable function) or

incomplete (with persisting long-term deficits). Difficulty concentrating, fatigability, tremors, and personality changes are common during

recovery.

The diagnosis of arboviral encephalitides depends on the careful

evaluation of a febrile patient with CNS disease and the performance of

laboratory studies to determine etiology. Clinicians should (1) consider

empirical acyclovir treatment for herpesvirus meningoencephalitis

and antibiotic treatment for bacterial meningitis until test results are

received; (2) exclude intoxination and metabolic or oncologic causes,

including paraneoplastic syndromes, hyperammonemia, liver failure,

and anti-N-methyl-d-aspartate (NMDA) receptor encephalitis; and

(3) rule out a brain abscess or a stroke. Leptospirosis, neurosyphilis,

Lyme disease, cat-scratch disease, and more recently described viral

encephalitides (e.g., Nipah virus infection), among others, should be

considered if epidemiologically relevant. CSF examination usually

shows a modest increase in leukocyte counts—in the tens or hundreds

or perhaps a few thousand. Early in the process, a significant proportion of these leukocytes may be polymorphonuclear, but mononuclear

cells are usually predominant later. CSF glucose concentrations are

generally normal. There are exceptions to this pattern of findings: In

eastern equine encephalitis, for example, polymorphonuclear leukocytes may predominate during the first 72 h of disease, and hypoglycorrhachia may be detected. In lymphocytic choriomeningitis, lymphocyte

counts may be in the thousands, and glucose concentrations may be

diminished. A humoral immune response is usually detectable at or

near the onset of disease. Both serum (acute- or convalescent-phase)

and CSF should be examined for IgM antibodies, and viruses should

be detected by plaque-reduction neutralization assay and/or RT-PCR.

Virus generally cannot be isolated from blood or CSF, although

Japanese encephalitis virus has been recovered from CSF of patients

with severe disease. RT-PCR analysis of CSF may yield positive results.

Viral antigen is present in brain tissue, although its distribution may be

focal. Electroencephalography usually shows diffuse abnormalities and

is not directly helpful.

Experience with medical imaging is still evolving. Both computed

tomography (CT) and magnetic resonance imaging (MRI) scans may

be normal except for evidence of preexisting conditions or occasional

diffuse edema. Imaging is generally nonspecific, as most patients do not

present with pathognomonic lesions, but it can be used to rule out other

suspected causes of disease. It is important to remember that imaging

may yield negative results if done early in the disease course but may

later detect abnormalities. For example, eastern equine encephalitis

(focal abnormalities) and severe Japanese encephalitis (hemorrhagic

bilateral thalamic lesions) have caused abnormalities detectable by

medical imaging.

1636 PART 5 Infectious Diseases

Comatose patients may require management of intracranial pressure elevations, inappropriate secretion of antidiuretic hormone,

respiratory failure, or seizures. Specific therapies for these viral encephalitides are not available. The only practical preventive measures are

vector management and personal protection against the arthropod

transmitting the virus. For Japanese or Central European/Far Eastern

tick-borne encephalitides, vaccination should be considered in certain

circumstances (see relevant sections below).

Flavivirids The most significant flavivirus encephalitides are Central European/Far Eastern tick-borne encephalitides, Japanese encephalitis, St. Louis encephalitis, and West Nile virus infection. Murray

Valley encephalitis and Rocio virus infection resemble Japanese

encephalitis but are documented only occasionally in Australia and

Brazil. Powassan virus has caused ~144 cases of often-severe disease

(lethality, ~8%), frequently occurring among children in eastern

Canada and the United States. Usutu virus has caused only individual

cases of human infection, but such infections may be underdiagnosed.

CENTRAL EUROPEAN/FAR EASTERN TICK-BORNE ENCEPHALITIDES

Tick-borne encephalitis viruses are currently subdivided into four

groups: the western/European subtype (previously called central

European encephalitis virus), the (Ural-)Siberian subtype (previously

called Russian spring–summer encephalitis virus), the Far Eastern

subtype, and the louping ill (“leaping” behavior described in ill sheep

with severe neurologic manifestations) subtype (previously called

louping ill virus, or, in Japan, Negishi virus). Small mammals, grouse,

deer, and sheep are the vertebrate amplifiers for these viruses, which

are transmitted by ticks. The risk of infection varies by geographic area

and can be highly localized within a given area. Human infections usually follow outdoor activities resulting in tick bites or consumption of

raw (unpasteurized) milk from infected goats or, less commonly, from

infected cows or sheep. Milk seems to represent the main transmission

route for louping ill subtype viruses, which cause disease very rarely.

Several thousand infections with tick-borne encephalitis virus are

recorded each year among people of all ages. Tick-borne encephalitis

occurs between April and October, with a peak in June and July.

Western/European viruses classically caused bimodal disease. After

an incubation period of 7–14 days, the illness begins with an influenzalike fever-myalgia phase (arthralgia, fever, headaches, myalgia, and

nausea) that lasts for 2–4 days and is thought to correlate with viremia.

A subsequent remission for several days is followed by the recurrence

of fever and the onset of meningeal signs. The CNS phase (7–10 days

before onset of improvement) varies from mild aseptic meningitis,

which is more common among younger patients, to severe (meningo)

encephalitis with coma, seizures, tremors, and motor signs. Spinal

and medullary involvement can lead to typical limb-girdle paralysis

and respiratory paralysis. Most patients with western/European virus

infections recover (lethality, 1%), and only a minority of patients have

significant deficits. However, the lethality from (Ural-)Siberian virus

infections reaches 7–8%.

Infections with Far Eastern viruses generally run a more abrupt

course. The encephalitic syndrome caused by these viruses sometimes

begins without a remission from the fever-myalgia phase and has more

severe manifestations than the western/European syndrome. Lethality

is high (20–40%), and major sequelae—most notably, lower motor

neuron paralyses of the proximal muscles of the extremities, trunk,

and neck—are common, developing in approximately half of patients.

Thrombocytopenia sometimes develops during the initial febrile illness, resembling the early hemorrhagic phase of some other tick-borne

flavivirus infections, such as Kyasanur Forest disease. In the early stage

of the illness, virus may be detected by PCR or isolated from the blood;

however, after the onset of CNS manifestations, virus cannot typically

be detected in or isolated from the CSF, and diagnosis requires detection of IgM antibodies in serum and/or CSF.

Diagnosis of Central European/Far Eastern tick-borne encephalitides primarily relies on serology and detection of viral genomes by

RT-PCR. There is no specific therapy for infection. However, effective

alum-adjuvanted, formalin-inactivated virus vaccines (FSME-IMMUN and Encepur) are produced in Austria, Germany, and Russia

in chicken embryo cells. Two doses of the Austrian vaccine separated

by an interval of 1–3 months appear to be effective in the field, and

antibody responses are similar when vaccine is given on days 0 and 14.

Because rare cases of postvaccination Guillain-Barré syndrome have

been reported, vaccination should be reserved for people likely to

experience rural exposure in an endemic area during the season of

transmission. Cross-neutralization for the western/European and Far

Eastern variants has been established, but there are no published field

studies on cross-protection among formalin-inactivated vaccines.

Because 0.2–4% of ticks in endemic areas may be infected, the use

of immunoglobulin prophylaxis of Central European/Far Eastern

tick-borne encephalitides has been increased. Prompt administration of high titer specific immmunoglobulin is routine in some areas

(e.g., Russia), but has been discontinued in many European countries

because of concerns for antibody-mediated enhancement of infections

and disease.

JAPANESE ENCEPHALITIS Japanese encephalitis is the most significant

viral encephalitis in Asia. Each year ~68,000 cases and ~13,600–20,400

deaths are reported. Japanese encephalitis virus is found throughout

Asia—including in the Russian Far East, Japan, China, India, Pakistan,

and South-Eastern Asia—and causes occasional epidemics on western

Pacific islands. The virus has been detected in the Torres Strait islands,

and five human encephalitis cases have been identified on the nearby

Australian mainland. The virus is particularly common in areas where

irrigated rice fields attract the natural avian vertebrate hosts and provide abundant breeding sites for Culex tritaeniorhynchus mosquitoes,

which transmit the virus to humans. Additional amplification by pigs,

which suffer abortion, and horses, which develop encephalitis, may be

significant as well. Vaccination of these additional amplifying hosts

may reduce the transmission of the virus.

After an incubation period of 5–15 days, clinical signs of Japanese

encephalitis range from nonspecific febrile illness (nausea, vomiting,

diarrhea, cough) to aseptic meningitis, meningoencephalitis, acute

flaccid paralysis, and severe encephalitis. Common findings are cerebellar signs, cranial nerve palsies, and cognitive and speech impairments. A Parkinsonian presentation and seizures are typical in severe

cases. Case fatality in hospitalized patients is high (20–30%) and longterm neurologic dysfunction and disability are common in survivors.

Effective vaccines are available. Vaccination is indicated for summer

travelers to rural Asia, where the risk of acquiring Japanese encephalitis is considered to be about 1 per 5000 to 1 per 20,000 travelers per

week if travel duration exceeds 3 weeks. Usually, two intramuscular

doses of the vaccine are given 28 days apart, with the second dose

administered at least 1 week prior to travel.

ST. LOUIS ENCEPHALITIS St. Louis encephalitis virus is transmitted

between mosquitoes and birds. This virus causes a low-level endemic

infection among rural residents of the central and Western United

States, where Culex tarsalis mosquitoes serve as vectors. The more

urbanized mosquitoes (Culex pipiens and Culex quinquefasciatus) have

been responsible for epidemics resulting in hundreds or even thousands

of cases in cities of the central and eastern United States. In this country,

most cases occur in June through October, but sporadic cases of the disease have also been noted throughout the year in Latin/Central America

and the Caribbean. The urban mosquitoes breed in accumulations of

stagnant water and sewage with high organic content and readily feed on

humans in and around houses at dusk. The elimination of open sewers

and trash-filled drainage systems is expensive and may not be possible.

However, screening of houses and implementation of personal protective measures may be effective approaches to the prevention of infection.

The rural mosquito vector is most active at dusk and outdoors; bites can

be avoided by modification of activities and use of repellents.

Most infections are subclinical; when present, disease severity

increases with age. St. Louis encephalitis virus infections that result

in aseptic meningitis or mild encephalitis are concentrated among

children and young adults, whereas severe and fatal cases primarily

affect the elderly. Infection rates are similar in all age groups; the

pathophysiologic explanation for susceptibility to disease in older

individuals is unexplained. After an incubation period of 4–21 days,

1637CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

patients typically present with a non-specific prodrome (fever, malaise,

myalgia, headache) followed by rapid-onset CNS manifestations that

include mcneurologic abnormalities. Common findings include, nuchal

rigidity, hypotonia, hyperreflexia, myoclonus, and tremors are common.

Severe cases can include cranial nerve palsies, hemiparesis, and seizures.

Of interest, during and after the prodrome, patients often report dysuria

and may have viral antigen in urine as well as pyuria. The overall lethality is generally ~7% but may reach 20% among patients >60 years of

age. Recovery is slow. Emotional lability, difficulties with concentration

and memory, asthenia, and tremors are commonly prolonged in older

convalescent patients. The CSF of patients with St. Louis encephalitis

usually contains tens to hundreds of leukocytes, with a lymphocytic

predominance and a left shift. The CSF glucose concentration is normal

in these patients.

WEST NILE VIRUS INFECTION West Nile virus is now the primary

cause of arboviral encephalitis in the United States. From 1999 to 2018,

24,657 cases of neuroinvasive disease (e.g., meningitis, encephalitis,

acute flaccid paralysis), with 2199 deaths, and 26,173 cases of nonneuroinvasive infection, with 131 deaths, were reported. West Nile virus

was initially described as being transmitted among wild birds by Culex

mosquitoes in Africa, Asia, and southern Europe. In addition, the virus

has been implicated in severe and fatal hepatic necrosis in Africa. West

Nile virus was introduced into New York City via diseased birds in

1999 and subsequently spread to other areas of the northeastern United

States, causing die-offs among crows, exotic zoo birds, and other birds.

The virus has continued to spread and is now found in almost all of

the United States as well as in Canada, Mexico, South America, and the

Caribbean islands. C. pipiens mosquitoes remain the major vectors in

the northeastern United States, but mosquitoes of several other Culex

species and Asian tiger mosquitoes (A. albopictus) are also involved.

Jays compete with crows and other corvids as amplifiers and lethal

targets in other areas of the country.

West Nile virus is a common cause of febrile disease without CNS

involvement (incubation period, 3–14 days), but it occasionally causes

aseptic meningitis and severe encephalitis, particularly among the

elderly. The fever-myalgia syndrome caused by West Nile virus differs

from that caused by other viruses in terms of the frequent—rather

than occasional—appearance of a maculopapular rash concentrated

on the trunk (especially in children) and the development of lymphadenopathy. Back pain, fatigue, headache, myalgia, retroorbital pain,

sore throat, nausea and vomiting, and arthralgia (but not arthritis) are

common accompaniments that may persist for several weeks. Overall,

only 1 in 50 patients develops neuroinvasive disease, characterized typically, though with overlap, as meningitis, encephalitis, or acute flaccid

paralysis syndromes. The risk of encephalitis, neurologic sequelae,

and death is increased in elderly, diabetic, and hypertensive patients

and patients with previous CNS insults. In addition to the more severe

motor and cognitive sequelae, milder findings may include tremor,

slight abnormalities in motor skills, and loss of executive functions.

Intense clinical interest and the availability of laboratory diagnostic

methods have made it possible to define a number of unusual clinical

features. Such features include chorioretinitis, flaccid paralysis with

histologic lesions resembling poliomyelitis, and initial presentation

with fever and focal neurologic deficits in the absence of diffuse

encephalitis. Immunosuppressed patients may have fulminant courses

or develop persistent CNS infection. Virus transmission through both

transplantation and blood transfusion has necessitated screening of

blood and organ donors by nucleic-acid–based tests. Occasionally,

pregnant women infect their fetuses with West Nile virus. Diagnosis

rests upon detection of IgM antibodies in serum or CSF. Treatment

is supportive only, and ventilatory support may be required for severe

neuroinvasive disease. Although an equine vaccine is available, prevention of West Nile virus infection in humans relies on avoidance of

mosquito bites, vector control, and safe handling of potentially infected

carcasses.

Peribunyavirids •  CALIFORNIA ENCEPHALITIS The isolation of California encephalitis virus established California serogroup

orthobunyaviruses as causes of encephalitides. However, California

encephalitis virus has been implicated in only a very few cases of encephalitis (California encephalitis sensu stricto), whereas its close relative,

La Crosse virus, is the major cause of encephalitis in this serogroup

(~80–100 cases per year in the United States). La Crosse encephalitis is

most commonly reported from the upper midwestern United States but

is also found in other areas of the central and eastern parts of the country, such as West Virginia, Tennessee, North Carolina, and Georgia. The

serogroup includes 13 other viruses, some of which (e.g., Inkoo, Jamestown Canyon, Lumbo, snowshoe hare, and Ťahyňa viruses) also cause

human disease (California encephalitis sensu lato, including La Crosse

encephalitis). Transovarial infection is a strong component of transmission of the California serogroup viruses in Aedes and Ochlerotatus

mosquitoes. The vector of La Crosse virus is the Ochlerotatus triseriatus

mosquito. These mosquitos are infected by transovarial transmission,

feeding on viremic chipmunks and other mammals, and by venereal

transmission. O. triseriatus breeds in sites such as tree holes and abandoned tires and bites during daylight hours. The habits of this mosquito

correlate with the risk factors for human cases: recreation in forested

areas, residence at a forest’s edge, and the presence of water-containing

abandoned tires around the home. Intensive environmental modification based on these findings has reduced the incidence of disease in a

highly endemic area in the midwestern United States.

Most humans are infected from July through September. Asian

tiger mosquitoes (A. albopictus) efficiently transmit La Crosse virus to

mice and also transmit the agent transovarially in the laboratory. This

aggressive anthropophilic mosquito has the capacity to urbanize, and

its possible impact on transmission of virus to humans is of concern.

The prevalence of antibody to La Crosse virus in humans is 20% or

higher in endemic areas, indicating that infection is common but

often asymptomatic. CNS disease has been recognized primarily in

children <15 years of age.

The illness from La Crosse virus varies from aseptic meningitis

accompanied by confusion to severe and occasionally fatal encephalitis

(lethality, <0.5%). The incubation period is ~3–7 days. Although there

may be prodromal symptoms/signs, the onset of CNS disease is sudden,

with fever, headache, and lethargy often with nausea and vomiting,

convulsions (in half of patients), and coma (in one third of patients).

Focal seizures, hemiparesis, tremor, aphasia, chorea, Babinski signs,

and other evidence of significant neurologic dysfunction are common

acutely, but residual sequelae are not, although approximately 10% of

patients have recurrent seizures in the succeeding months. Other serious sequelae of La Crosse virus infection are rare, although a decrease

in scholastic standing among children has been reported, and mild

personality change has occasionally been suggested.

The blood leukocyte count is commonly elevated in patients with

La Crosse virus infection, sometimes reaching 20,000 per μL, usually

with a left shift. CSF leukocyte counts are typically 30–500 per μL, usually with a mononuclear cell predominance (although 25–90% of cells

are polymorphonuclear in some patients). The blood protein concentration is normal or slightly increased, and the glucose concentration

is normal. Specific virologic diagnosis based on IgM-capture assays of

serum and CSF is efficient. The only human anatomic site from which

virus has been isolated is the brain.

Treatment is supportive over a 1- to 2-week acute phase during

which status epilepticus, cerebral edema, and inappropriate secretion of

antidiuretic hormone are important concerns. A phase 2B clinical trial

of intravenous (IV) ribavirin in children with La Crosse virus infection

was discontinued during dose escalation because of adverse effects.

Jamestown Canyon virus has been implicated in several cases of

encephalitis in adults (~30 cases per year since 2013), usually with

a significant respiratory illness at onset. Human infection with this

virus has been documented in Massachusetts, New York, Wisconsin,

Ohio, Michigan, Ontario, and other areas of Northern America (both

in the United States and Canada), where the vector mosquito (Aedes

stimulans) feeds on its main host, the white-tailed deer (Odocoileus virginianus). Ťahyňa virus can be found in Africa, China, Central Europe,

and Russia. The virus is a prominent cause of febrile disease but can

also cause pharyngitis, pulmonary syndromes, aseptic meningitis, or

meningoencephalitis.

1638 PART 5 Infectious Diseases

Rhabdovirids •  CHANDIPURA VIRUS INFECTION Chandipura

virus is an emerging and increasingly significant human virus in India,

where it is transmitted among hedgehogs by mosquitoes and sandflies.

In humans, the disease begins as an influenza-like illness, with fever,

headache, abdominal pain, nausea, and vomiting. These manifestations are followed by neurologic impairment and infection-related or

autoimmune-mediated encephalitis. Chandipura virus infection is

characterized by high lethality in children. Several hundred cases of

infection are recorded in India every year. Infections with other arthropod-borne rhabdovirids (Isfahan, Piry, vesicular stomatitis Indiana,

vesicular stomatitis New Jersey viruses) may imitate the early febrile

stage of Chandipura virus infection.

Togavirids •  EASTERN EQUINE ENCEPHALITIS This disease is

encountered primarily in swampy foci along the east coast of the

United States, with a few inland foci as far removed as Michigan. In

recent years, virus activity appears to be increasing. Infected humans

present for medical care from June through October. During this

period, the bird–Culiseta mosquito cycle spills over into other vectors,

such as Aedes sollicitans or Aedes vexans mosquitoes, which are more

likely to feed on mammals. There is concern over the potential role of

introduced Asian tiger mosquitoes (A. albopictus), which have been

found to be infected with eastern equine encephalitis virus and are an

effective experimental vector in the laboratory. Horses are a common

target for the virus. Contact with unvaccinated horses may be associated with human disease, but horses probably do not play a significant

role in amplification of the virus.

Most of those infected do not develop neurologic manifestations;

however, after an incubation period of approximately 5–10 days, 2%

(adults) and 6% (children) develop sudden and rapidly progressive

encephalitis leading to profoundly altered mental status and coma that is

highly lethal (at least 30–50%) and leaves survivors with frequent sequelae. Acute polymorphonuclear CSF pleocytosis, often occurring during

the first 1–3 days of disease, is another indication of severity. In addition,

leukocytosis with a left shift is a common feature. Extensive necrotic

lesions and polymorphonuclear infiltrates are found at postmortem

examination of the brain. A formalin-inactivated vaccine has been used

to protect laboratory workers but is not generally available or applicable.

VENEZUELAN EQUINE ENCEPHALITIS Venezuelan equine encephalitis viruses are separated into epizootic viruses (subtypes IA/B and

IC) and enzootic viruses (subtypes ID, IE, and IF). Closely related

enzootic viruses are Everglades virus, Mucambo virus, and Tonate

virus. Enzootic viruses are found primarily in humid tropical-forest

habitats and are maintained between culicoid mosquitoes and rodents.

These viruses cause acute febrile human disease but are not pathogenic

for horses and do not cause epizootics. Everglades virus has caused

encephalitis in humans in Florida. Extrapolation from the rate of

genetic change suggests that Everglades virus may have been introduced into Florida <200 years ago. Everglades virus is most closely

related to the ID-subtype viruses that appear to have given evolutionary rise to the epizootic variants active in South America.

Epizootic viruses have an unknown natural cycle but periodically

cause extensive epizootics/epidemics in equids and humans in the

Americas. These epizootics/epidemics are the result of high-level

viremia in horses and mules, which transmit the infection to several

types of mosquitoes. Infected mosquitoes in turn infect humans.

Humans also have high-level viremia, but their role in virus transmission is unclear. Relatively restricted epizootics of Venezuelan equine

encephalitis occurred repeatedly in South America at intervals of

10 years or less from the 1930s until 1969, when a massive epizootic,

including tens of thousands of equine and human infections, spread

throughout Central America and Mexico, reaching southern Texas in

1971. Genetic sequencing suggested that the virus from that outbreak

originated from residual “un-inactivated” IA/B-subtype virus in veterinary vaccines. The outbreak was terminated in Texas with a live

attenuated vaccine (TC-83) originally developed for human use by the

U.S. Army; the epizootic virus was then used for further production

of inactivated veterinary vaccines. No further major epizootic disease

outbreaks occurred until 1995 and 1996, when large epizootics of

Venezuelan equine encephalitis occurred in Colombia/Venezuela and

Mexico, respectively. Of the >85,000 clinical cases, 4% (more children

than adults) included neurologic symptoms/signs, and 300 cases ended

in death. The viruses involved in these epizootics as well as previously

epizootic IC viruses are close phylogenetic relatives of known enzootic

ID viruses. This finding suggests that active evolution and selection of

epizootic viruses are underway in South America.

During epizootics, extensive human infection is typical, with clinical

disease occurring in 10–60% of infected individuals. Most infections

result in notable acute febrile disease, whereas relatively few infections

(5–15%) result in neurologic disease. A low rate of CNS invasion

is supported by the absence of encephalitis among the many infections

resulting from exposure to aerosols in the laboratory setting or from

vaccination accidents.

The prevention of epizootic Venezuelan equine encephalitis depends

on vaccination of horses with the attenuated TC-83 vaccine or with an

inactivated vaccine prepared from that variant. Enzootic viruses are

genetically and antigenically different from epizootic viruses, and

protection against the former with vaccines prepared from the latter is

relatively ineffective. Humans can be protected by immunization with

similar vaccines prepared from Everglades virus, Mucambo virus, and

Venezuelan equine encephalitis virus, but the use of the vaccines is

restricted to laboratory personnel because of reactogenicity, possible

fetal pathogenicity, and limited availability.

WESTERN EQUINE ENCEPHALITIS The primary maintenance cycle

of western equine encephalitis virus in the western United States

and Canada involves Aedes, C. tarsalis, and Culiseta mosquitoes and

birds (principally sparrows and finches). Equids and humans become

infected, and both suffer encephalitis without amplifying the virus in

nature. St. Louis encephalitis virus is transmitted in a similar cycle in

the same regions harboring western equine encephalitis virus; disease

caused by the former occurs about a month earlier than that caused

by the latter (July through October). Large epidemics of western

equine encephalitis occurred in the western and central United States

and Canada from the 1930s through the 1950s, but the disease subsequently has been uncommon. From 1964 through 2010, only 640

cases were reported in the United States. This decline in incidence

may reflect, in part, the integrated approach to mosquito management

employed in irrigation projects and, in part, the increasing use of agricultural pesticides. The decreased incidence of western equine encephalitis almost certainly reflects the increased tendency for humans to be

indoors behind closed windows at dusk—the peak biting period of the

major vector.

After an incubation period of ~5–10 days, western equine encephalitis virus causes a typical diffuse viral meningo-encephalitis, with an

increased attack rate and increased morbidity among the young, particularly children <2 years of age. In addition, lethality is high among

the young and the very elderly (3–7% overall). One third of individuals

who have convulsions during the acute illness have subsequent seizure

activity. Infants <1 year of age—particularly those in the first months

of life—are at serious risk of motor and intellectual damage. Of those

5–9 years of age, twice as many males as females develop clinical

encephalitis. This difference in incidence may be related to greater

outdoor exposure of boys to the vector but may also be due in part to

biologic differences. A formalin-inactivated vaccine has been used to

protect laboratory workers but is not generally available.

■ FEVER AND MYALGIA

The fever and myalgia syndrome is the most common clinical presentation associated with zoonotic virus infection. Many of the viruses

listed in Table 209-1 probably cause at least a few cases of this syndrome, but only some of these viruses have prominent associations

with the syndrome and are of biomedical importance. The fever and

myalgia syndrome typically begins with the abrupt onset of fever, chills,

intense myalgia, and malaise. Patients may also report joint or muscle

pains, but true arthritis is not found. Anorexia is characteristic and may

be accompanied by nausea or even vomiting. Headache is common

and may be severe, with photophobia and retroorbital pain. Physical

1639CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

findings are minimal and are usually confined to conjunctival injection

with pain on palpation of muscles or the epigastrium. The duration of

symptoms/signs is quite variable (generally 2–5 days), with a biphasic

course in some instances. The spectrum of disease varies from subclinical to temporarily incapacitating. Less common findings include

a nonpruritic maculopapular rash, epistaxis (not necessarily indicating

a bleeding diathesis), and aseptic meningitis. Even in the presence of

headache, meningismus, or photophobia, the lack of opportunity to

examine the CSF in remote areas makes diagnosis difficult. Although

pharyngitis or radiographic evidence of pulmonary infiltrates is found

in some patients, the agents causing this syndrome are not primary

respiratory pathogens.

The fever and myalgia syndrome is also the most nonspecific of

the disease syndromes caused by arthropod-borne and rodent-borne

viruses. Furthermore, the early stages of other syndromes discussed in

this chapter may begin similarly and are encompassed in a broad differential diagnosis that includes community-acquired parasitic infections (e.g., malaria), bacterial infections (e.g., anicteric leptospirosis,

rickettsial diseases), and other viral infections. The fever and myalgia

syndrome is often described as “influenza-like,” but the usual absence

of cough and coryza makes influenza an unlikely confounder except at

the earliest stages. Treatment is supportive, but acetylsalicylic acid is

avoided because of the potential for exacerbated bleeding or Reye’s syndrome. Complete recovery is the general outcome for people with this

syndrome, although prolonged asthenia and nonspecific symptoms

have been described in some patients, particularly after infection with

lymphocytic choriomeningitis virus or dengue viruses 1–4.

Efforts to prevent viral infection are best based on vector control,

which, however, may be expensive or impossible. For mosquito control,

destruction of breeding sites is generally the most economically and

environmentally sound approach. Emerging containment technologies

include the release of genetically modified mosquitoes and the spread

of Wolbachia bacteria to limit mosquito multiplication rates. Depending on the vector and its habits, other possible approaches include the

use of screens or other barriers (e.g., permethrin-impregnated bed nets)

to prevent the vector from entering dwellings, judicious application of

arthropod repellents (such as N,N,-diethyltoluamide [DEET]) to the

skin, use of long-sleeved (ideally permethrin-impregnated) clothing,

and avoidance of the vectors’ habitats and times of peak activity.

Bunyavirals Numerous bunyavirals cause fever and myalgia. Many

of these viruses cause individual infections and usually do not result

in epidemics. These viruses include arenavirids, such as lymphocytic

choriomeningitis mammarenavirus; hantavirids, such as the orthohantavirus Choclo virus; nairovirids, such as the orthonairoviruses Dugbe

virus, Nairobi sheep disease virus, and Sōnglıˇng virus; peribunyavirids,

such as the viruses of the orthobunyavirus Anopheles A serogroup

(e.g., Tacaiuma virus), the Bunyamwera serogroup (Bunyamwera,

Batai, Cache Valley, Fort Sherman, Germiston, Guaroa, Ilesha, Ngari,

Shokwe, and Xingu viruses), the Bwamba serogroup (Bwamba virus,

Pongola virus), the Guamá serogroup (Catú virus, Guamá virus), the

Nyando serogroup (Nyando virus), the Wyeomyia serogroup (Wyeomyia virus), and the ungrouped orthobunyavirus Tataguine virus; and

phenuivirids, such as bandaviruses (Bhanja virus, Heartland virus)

and the phlebovirus Candirú complex (Alenquer, Candirú, Echarate,

Maldonado, Morumbi, and Serra Norte viruses).

ARENAVIRIDS Lymphocytic choriomeningitis is the only human

mammarenavirus infection resulting predominantly in fever and

myalgia. Lymphocytic choriomeningitis virus is transmitted to humans

from the common house mouse (Mus musculus) by aerosols of excreta

or secreta. The virus is maintained in the mouse mainly by vertical

transmission from infected dams. Infected mice remain viremic and

shed virus for life, with high concentrations of virus in all tissues.

Infected colonies of pet hamsters also can serve as a link to humans. In

addition, infections among scientists and animal caretakers can occur

because the virus is widely used in immunology laboratories to study

T-lymphocyte function and can silently infect cell cultures and passaged tumor lines. Moreover, patients may have a history of residence

in rodent-infested housing or other exposure to rodents. An antibody

prevalence of ~5–10% has been reported among adults from Argentina,

Germany, and the United States.

Lymphocytic choriomeningitis differs from the general syndrome of

fever and myalgia in that the onset is gradual. Conditions occasionally

associated with the disease are orchitis, transient alopecia, arthritis,

pharyngitis, cough, and maculopapular rash. An estimated one fourth

of patients (or fewer) experience a febrile phase of 3–6 days. After a brief

remission, many develop renewed fever accompanied by severe headache, nausea and vomiting, and meningeal signs lasting for ~1 week (the

CNS phase). These patients virtually always recover fully, as do the rare

patients with clear-cut signs of encephalitis. Recovery may be delayed

by transient hydrocephalus. During the initial febrile phase, leukopenia

and thrombocytopenia are common, and virus can usually be isolated

from blood. During the CNS phase, the virus may be found in the CSF,

and antibodies are present in the blood. The pathogenesis of lymphocytic choriomeningitis is thought to resemble manifestations following

direct intracranial inoculation of the virus into adult mice. The onset

of the immune response leads to T cell–mediated immunopathologic

meningitis. During the meningeal phase, CSF mononuclear-cell counts

range from the hundreds to the low thousands per microliter, and

hypoglycorrhachia is found in one third of patients.

IgM-capture ELISA, immunochemistry, and RT-PCR are used in

the diagnosis of lymphocytic choriomeningitis. IgM-capture ELISA of

serum and CSF usually yields positive results; RT-PCR assays have been

developed for probing CSF. In particular, patients who have fulminant

infections transmitted by recent organ transplantation do not mount

an immune response, so immunohistochemistry or RT-PCR is required

for diagnosis. Infection should be suspected in acutely ill febrile

patients with marked leukopenia and thrombocytopenia. In patients

with aseptic meningitis, any of the following suggests lymphocytic choriomeningitis: a well-marked febrile prodrome, adult age, occurrence

in the autumn, low CSF glucose levels, or CSF mononuclear-cell counts

of >1000 per μL. In pregnant women, infection may lead to fetal invasion, with consequent congenital hydrocephalus, microcephaly, and/or

chorioretinitis. Because the maternal infection may be mild, causing

only a short febrile illness, antibodies to the virus should be sought in

both the mother and the fetus under suspicious circumstances, particularly in TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes

simplex, and HIV-1/2)–negative neonatal hydrocephalus.

ORTHOBUNYAVIRUS GROUP C SEROGROUP Apeú, Caraparú, Itaquí,

Madrid, Marituba, Murutucú, Nepuyo, Oriboca, Ossa, Restan, and

Zungarococha viruses are among the most common causes of arboviral

infection in humans entering South American jungles. These viruses

cause acute febrile disease and are transmitted by mosquitoes in neotropical forests.

ORTHOBUNYAVIRUS SIMBU SEROGROUP Oropouche virus is transmitted in Central and South America by biting midges (Culicoides

paraensis), which often breed to high density in cacao husks and other

vegetable detritus found in towns and cities. Explosive epidemics

involving thousands of patients have been reported from several towns

in Brazil and Peru. Rash and aseptic meningitis have been detected in a

number of patients. Iquitos virus, a recently discovered reassortant and

close relative of Oropouche virus, causes disease that is easily mistaken

for Oropouche virus disease; its overall epidemiologic significance

remains to be determined.

PHLEBOVIRUS SANDFLY FEVER GROUP The phlebovirus sandfly fever

group consists of numerous viruses that may cause human infection.

Sandfly fever Cyprus virus, sandfly fever Ethiopia virus, sandfly

fever Sicilian virus, and sandfly fever Turkey virus (and the encephalitis-causing Chios virus) are very closely related genetically and

antigenically. In contrast, sandfly fever Naples virus is only distantly

related genetically and antigenically to these viruses. Sandfly fever

Naples virus has not been detected in sandflies, humans, or nonhuman vertebrates since the 1980s and therefore may be extinct. Sandfly

fever Naples virus is the type virus of the species Sandfly fever Naples

phlebovirus, which includes other human viruses, such as Granada

virus and Toscana virus. Toscana virus is thus far the only phlebovirus

1640 PART 5 Infectious Diseases

transmitted by sandflies that is known to cause diseases affecting the

central and peripheral nervous systems, such as encephalitis, meningitis, myositis, or polymyeloradiculopathy. Phlebotomus sandflies

transmit the virus, probably by biting small mammals and humans.

Female sandflies may be infected by the oral route as they take a blood

meal and may transmit the virus to offspring when they lay their eggs

after a second blood meal. This prominent transovarial transmission

confounds virus control.

Sandfly fever is found in the circum-Mediterranean area, extending to the east through the Balkans into parts of China as well as into

Western Asia. Sandflies are found in both rural and urban settings and

are known for their short flight ranges and their small sizes; the latter

enables them to penetrate standard mosquito screens and netting. Epidemics have been described in the wake of natural disasters and wars.

After World War II, extensive spraying in parts of Europe to control

malaria greatly reduced sandfly populations and transmission of sandfly fever Naples virus; the incidence of sandfly fever continues to be low.

A common pattern of disease in endemic areas consists of high

attack rates among travelers and military personnel and little or no

disease in the local population, who are protected after childhood

infection. Toscana virus infection is common during the summer

among rural residents and vacationers, particularly in Italy, Spain, and

Portugal; a number of cases have been identified in travelers returning

to Germany and Scandinavia. The disease may manifest as an uncomplicated febrile illness but is often associated with aseptic meningitis,

with virus isolated from the CSF.

Coclé virus and Punta Toro virus are phleboviruses that are not part

of the sandfly fever serocomplex but, like the members of this complex,

are transmitted by sandflies. These two viruses cause a sandfly-feverlike disease in Latin American and Caribbean tropical forests, respectively, where the vectors rest on tree buttresses. Epidemics have not

been reported, but antibody prevalence among inhabitants of villages

in endemic areas indicates a cumulative lifetime exposure rate of >50%

in the case of Punta Toro virus.

Flavivirids The most clinically significant flaviviruses that cause

the fever and myalgia syndrome are dengue viruses 1–4. In fact,

dengue without/with warning signs (“dengue,” historically called

“dengue fever”—to be distinguished from severe dengue) is probably

the most prevalent arthropod-borne viral disease worldwide, with

~400 million infections occurring per year, of which ~100 million

(25%) cause clinical illness. Dengue is endemic in >100 countries

worldwide, including in Africa, the Americas, the eastern Mediterranean, South-Eastern Asia, and the western Pacific. More than half of

the world’s population is considered at risk, although Asia bears 70%

of the global burden, with alarming increases over the past decade

including, for example, >400,000 cases in 2019 in the Philippines. Yearround transmission of dengue viruses 1–4 occurs between latitudes

25°N and 25°S, but seasonal forays of the viruses into the United States

and Europe have been documented. The principal vectors for all four

viruses are yellow fever mosquitoes (Ae. aegypti). Through increasing spread of mosquitoes throughout the tropics and subtropics and

international travel by infected humans, large areas of the world have

become vulnerable to the introduction of dengue viruses 1–4. Thus,

dengue and severe dengue (see “Viral Hemorrhagic Fever,” below) are

becoming increasingly common. For instance, conditions favorable to

dengue viruses 1–4 transmission via yellow fever mosquitoes exist in

Hawaii and the southern United States. The range of a lesser vector

of dengue viruses 1–4 (A. albopictus) now extends from Asia to the

continental United States, the Indian Ocean, parts of Europe, and

Hawaii. Also anthrophilic, Ae. aegypti mosquitoes typically breed near

human habitation, using relatively fresh water from sources such as

water jars, vases, discarded containers, coconut husks, and old tires.

These mosquitoes usually bite during the day. Bursts of dengue and

severe dengue cases are to be expected in the southern United States,

particularly along the Mexican border, where containers of water

may be infested with yellow fever mosquitoes. Closed habitations

with air-conditioning may inhibit transmission of many arboviruses,

including dengue viruses 1–4.

After dengue virus infection and an incubation period averaging

4–7 days, three evolving phases are described: a febrile phase, a critical phase, and a recovery phase. The majority of patients presenting

with fever and myalgia do not go through a critical phase, although

early recognition of the critical phase consistent with severe dengue

must be considered in all patients. (For further discussion of severe

dengue—previously called “dengue hemorrhagic fever” and including

dengue shock syndrome—see “Viral Hemorrhagic Fever,” below.) In

most patients, dengue begins with the typical sudden onset of fever,

frontal headache, retroorbital pain, back pain, and severe myalgias.

These symptoms gave rise to the colloquial designation of dengue as

“break-bone fever.” Often a transient macular rash appears on the first

day, as do adenopathy, palatal vesicles, and scleral injection. The illness

may last a week, with additional symptoms and clinical signs including

anorexia, nausea or vomiting, and marked cutaneous hypersensitivity. Near the time of defervescence on days 3–5, a maculopapular

rash begins on the trunk and spreads to the extremities and the face.

Epistaxis and scattered petechiae are often noted in uncomplicated

dengue without/with warning signs, and preexisting gastrointestinal

lesions may bleed during the acute illness. A positive tourniquet

test—i.e., the detection of 10 or more new petechiae in one square inch

of the upper arm after a 5-min blood pressure cuff inflation to midway

between systolic and diastolic pressure—may demonstrate microvascular fragility associated with dengue but is more likely to be associated

with severe disease.

Laboratory findings of dengue without/with warning signs include

leukopenia, thrombocytopenia, and, in many cases, modest elevations

of serum aminotransferase concentrations without hepatic synthetic

dysfunction. The diagnosis is made by IgM ELISA or paired serology

during recovery or by antigen-detection ELISA or RT-PCR during the

acute phase. Virus is readily isolated from blood in the acute phase if

mosquito inoculation or mosquito cell culture is used.

Orthomyxovirids Bourbon virus was recently identified as the

cause of a rare, severe, and sometimes fatal febrile disease of humans

in the midwestern and southern United States.

Reovirids Several coltiviruses (Colorado tick fever, Eyach, and

Salmon River viruses) and orbiviruses (Lebombo, Kemerovo, Orungo,

and Tribeč viruses) can cause fever and myalgia in humans. With the

exception of Lebombo and Orungo viruses, all are transmitted by ticks.

The most significant reoviral arthropod-borne disease is Colorado tick

fever. Several hundred patients with this disease are reported annually

in the United States and Canada. The infection is acquired between

March and November through the bite of an infected ixodid tick, the

Rocky Mountain wood tick (Dermacentor andersoni), in mountainous

western regions at altitudes of 1200–3000 m. Small mammals serve as

amplifying hosts. The most common presentation is fever and myalgia,

often with headache; meningoencephalitis is not uncommon, and hemorrhagic disease, pericarditis, myocarditis, orchitis, and pulmonary

presentations have also been reported. Rash develops in a minority

of patients. Leukopenia and thrombocytopenia are also noted. The

disease usually lasts 7–10 days and is often biphasic. The most important differential diagnostic considerations since the beginning of the

20th century have been Rocky Mountain spotted fever (although

Colorado tick fever is much more common in Colorado) and tularemia. Colorado tick fever virus replicates for several weeks in erythropoietic cells and can be found in erythrocytes. This feature, detected

in erythroid smears stained by immunofluorescence, can be diagnostically helpful and is important during screening of blood donors.

■ PULMONARY DISEASE

Hantavirus pulmonary syndrome (HPS) was first described in 1993,

but retrospective identification of cases by immunohistochemistry

(1978) and serology (1959) supports the idea that HPS is a recently discovered rather than a truly new disease. The causative agents are orthohantaviruses of a distinct phylogenetic lineage that is associated with

the cricetid rodent subfamily Sigmodontinae. Sin Nombre virus, which

chronically infects North American deermice (Peromyscus maniculatus), is the most important agent of HPS in the United States. Several

1641CHAPTER 209 Arthropod-Borne and Rodent-Borne Virus Infections

other related viruses (Anajatuba, Andes, Araraquara, Araucária, bayou,

Bermejo, Black Creek Canal, Blue River, Caño Delgadito, Castelo dos

Sonhos, Catacamas, Choclo, Juquitiba, Laguna Negra, Lechiguanas,

Maciel, Maripa, Monongahela, New York, Orán, Paranoá, Pergamino,

Rio Mamoré, and Tunari viruses) cause the disease in Northern

America and South America. Andes virus is unusual in that it has been

implicated in human-to-human transmission. HPS particularly affects

rural residents living in dwellings permeable to rodent entry or people

working in occupations that pose a risk of rodent exposure. Each type

of rodent has its own particular habits; in the case of deermice, these

behaviors include living in and around human habitation.

HPS begins with a prodrome of ~3–4 days (range, 1–11 days) comprising fever, malaise, myalgia, and—in many cases—gastrointestinal

disturbances (such as abdominal pain, nausea, and vomiting). Dizziness

is common, and vertigo is occasional. Severe prodromal symptoms/

signs may bring some patients to medical attention, but most cases are

recognized as the pulmonary phase begins. Typical signs are slightly

lowered blood pressure, tachycardia, tachypnea, mild hypoxemia,

thrombocytopenia, and early radiographic signs of pulmonary edema.

Physical findings in the chest are often surprisingly scant. The conjunctival and cutaneous signs of vascular involvement seen in hantavirus

VHFs (see “Viral Hemorrhagic Fever,” below) are uncommon. During

the next few hours, decompensation may progress rapidly to severe

hypoxemia and respiratory failure.

The differential diagnosis of HPS includes abdominal surgical

conditions and pyelonephritis as well as rickettsial disease, sepsis,

meningococcemia, plague, tularemia, influenza, and relapsing fever. A

specific diagnosis is best made by IgM antibody testing of acute-phase

serum, which has yielded positive results even in the prodrome. Tests

using a Sin Nombre virus antigen detect antibodies to the related HPScausing orthohantaviruses. Occasionally, heterotypic viruses will react

only in the IgG ELISA, but such a finding is highly suspicious given

the very low seroprevalence of these viruses in normal populations.

RT-PCR is usually positive when used to test blood clots obtained in

the first 7–9 days of illness and when used to test tissues. This assay is

useful in identifying the infecting virus in areas outside the home range

of deermice and in atypical cases.

During the prodrome, the differential diagnosis of HPS is difficult,

but by the time of presentation or within 24 h thereafter, a number of

diagnostically helpful clinical features become apparent. Usually, cough

is not present at the outset. Interstitial edema is evident on chest x-ray.

Later, bilateral alveolar edema with a central distribution develops

in the setting of a normal-sized heart; occasionally, the edema is initially unilateral. Pleural effusions are often seen. Thrombocytopenia,

circulating atypical lymphocytes, and a left shift (often with leukocytosis) are almost always evident; thrombocytopenia is a particularly

important early clue. Hemoconcentration, hypoalbuminemia, and

proteinuria should also be sought for diagnosis. Although thrombocytopenia virtually always develops and prolongation of the partial

thromboplastin time is the rule, clinical evidence of coagulopathy

or laboratory indications of disseminated intravascular coagulation

(DIC) are found in only a minority of severely ill patients. Patients with

severe illness also have acidosis and elevated serum lactate concentrations. Mildly increased values in renal function tests are common, but

patients with severe HPS often have markedly elevated serum creatinine concentrations. Some New World orthohantaviruses other than

Sin Nombre virus (e.g., Andes virus) have been associated with greater

kidney involvement, but few such cases have been studied.

Management of HPS during the first few hours after presentation

is critical. The goal is to prevent severe hypoxemia by oxygen therapy,

with intubation and intensive respiratory management if needed.

During this period, hypotension and shock with increasing hematocrit

invite aggressive fluid administration, but this intervention should be

undertaken with great caution. Because of low cardiac output with

myocardial depression and increased pulmonary vascular permeability, shock should be managed expectantly with vasopressors and

modest infusion of fluid guided by pulmonary capillary wedge pressure. Mild cases can be managed by frequent monitoring and oxygen

administration without intubation. Many patients require intubation

to manage hypoxemia and shock. Extracorporeal membrane oxygenation is instituted in severe cases, ideally before the onset of shock. The

procedure is indicated in patients who have a cardiac index of 2.3 L/

min/m2

 or an arterial oxygen tension to fractional inspired oxygen

(Pao2

:Fio2

) ratio of <50 and who are unresponsive to conventional support. Lethality remains at ~30–40%, even with good management, but

most patients surviving the first 48 h of hospitalization are extubated

and discharged within a few days with no apparent long-term residua.

The antiviral drug ribavirin inhibits orthohantaviruses in vitro but

showed no marked effect on patients treated in an open-label study.

■ VIRAL HEMORRHAGIC FEVER

VHF is a syndromic constellation of findings based on vascular instability and decreased vascular integrity. A direct or indirect assault on

the microvasculature leads to increased permeability and (particularly

when platelet function is decreased) to actual disruption and local

hemorrhage (a positive tourniquet sign). Blood pressure is decreased,

and in severe cases, shock supervenes. Cutaneous flushing and conjunctival suffusion are examples of common, observable abnormalities

in the control of local circulation. Hemorrhage occurs infrequently.

In most patients, hemorrhage is an indication of widespread vascular

damage rather than a life-threatening loss of blood volume. In some

VHFs, specific organs may be particularly impaired. For instance,

the kidneys are primary targets in HFRS, and the liver is a primary

target in yellow fever and filovirus diseases. However, in all of these

diseases, generalized circulatory disturbance appears centrally in clinical manifestations. The pathogenesis of VHF is poorly understood

and varies among the viruses regularly implicated in the syndrome. In

some viral infections, direct damage to the vascular system or even to

parenchymal cells of target organs is an important factor; in other viral

infections, soluble mediators are thought to play a major role in the

development of hemorrhage or fluid redistribution.

The acute phase in most cases of VHF is associated with ongoing

virus replication and viremia. VHFs begin with fever and myalgia, usually of abrupt onset. (Mammarenavirus infections are the exceptions, as

they often develop gradually.) Within a few days, the patient presents

for medical attention because of increasing prostration that is often

accompanied by abdominal or chest pain, anorexia, dizziness, severe

headache, hyperesthesia, photophobia, nausea or vomiting, and other

gastrointestinal disturbances. Initial examination often reveals only

an acutely ill patient with conjunctival suffusion, tenderness to palpation of muscles or abdomen, and borderline hypotension or postural

hypotension (perhaps with tachycardia). Petechiae (often best visualized in the axillae), flushing of the head and thorax, periorbital edema,

and proteinuria are common. AST activities are usually elevated at presentation or within a day or two thereafter. Hemoconcentration from

vascular leakage, which is usually evident, is most marked in HFRS

and in severe dengue. The seriously ill patient progresses to more

severe clinical signs and develops shock and other findings typical of

the causative virus. Shock, multifocal bleeding, and CNS involvement

(encephalopathy, coma, seizures) are all poor prognostic signs.

One of the major diagnostic clues to VHF is travel to an endemic

area within the incubation period for a given syndrome. Except in

infections with Seoul virus, dengue viruses 1–4, and yellow fever virus,

which have urban hosts/vectors, travel to a rural setting is especially

suggestive of a diagnosis of VHF. In addition, several diseases considered in the differential diagnosis—falciparum malaria, shigellosis,

typhoid fever, leptospirosis, relapsing fever, and rickettsial diseases—

are treatable and potentially lethal.

Early recognition of VHF is important because of the need for

virus-specific therapy and supportive measures. Such measures include

prompt, atraumatic hospitalization; judicious fluid therapy that takes into

account the patient’s increased capillary permeability; administration of

cardiotonic drugs; use of vasopressors to maintain blood pressure at

levels that will support renal perfusion; treatment of the relatively common secondary bacterial (and the rarer fungal) infections; replacement

of clotting factors and platelets as indicated; and the usual precautionary

measures used in the treatment of patients with hemorrhagic diatheses.

DIC should be treated only if clear laboratory evidence of its existence