Fever and Myalgia

This is the most common syndrome associated with zoonotic viruses. Typically, pts have an acute onset of fever, chills, severe myalgia, malaise, and headache; true arthritis is not found. Complete recovery after 2-5 days of illness is usual. Important examples include the following.

• Lymphocytic choriomeningitis (LCM): This infection is transmitted from chronically infected mice and pet hamsters via aerosols of excreta and secreta. About one-fourth of infected pts have a 3- to 6-day febrile phase, a brief remission, and then recurrent fever, severe headache, nausea, vomiting, and meningeal signs lasting ∼1 week.
  • Other manifestations include transient alopecia, arthritis, pharyngitis, cough, maculopapular rash, and orchitis.
  • Pregnant women can have mild infection yet pass on the virus to the fetus, who can develop hydrocephalus, microcephaly, and/or chorioretinitis.
  • The diagnosis should be considered when an adult has aseptic meningitis and any of the following applies: autumn seasonality, a well-marked febrile prodrome, a low CSF glucose level, or CSF mononuclear cell counts >1000/µL.
  • LCM viremia is most likely in the initial febrile phase of illness. LCM can also be diagnosed by IgM-capture ELISA of serum or CSF or by RT-PCR of CSF.
• Dengue: With ∼390 million cases annually, dengue is probably the most important arthropod-borne viral disease worldwide. The four serotypes of dengue virus are all transmitted by the mosquito Aedes aegypti, which is also a vector for yellow fever. After an incubation period of 4-7 days, pts experience the sudden onset of fever, frontal headache, retroorbital pain, back pain, severe myalgia (break-bone fever), adenopathy, palatal vesicles, and scleral injection.
  • The illness usually lasts 1 week, and a maculopapular rash often appears near the time of defervescence (usually on day 3-5).
  • A second infection with a different dengue serotype can lead to severe dengue (previously called dengue hemorrhagic fever; see “Hemorrhagic Fever Insect- and Animal-Borne Viral Infections,” next).
  • The diagnosis is made by IgM ELISA or paired serologic tests during recovery or by antigen-detection ELISA or RT-PCR during the acute phase. Virus is easily isolated from blood during the acute phase by inoculation of mosquitoes or mosquito cell culture. Leukopenia, thrombocytopenia, and increased serum aminotransferase levels may be documented.
• Zika virus disease: Zika virus was originally discovered in Uganda in 1947, with only 14 cases identified prior to 2007. Since then, there have been several outbreaks throughout Southeast Asia and the South Pacific as well as a larger worldwide epidemic that started in Brazil in 2015. Human infections are typically asymptomatic or benign and self-resolving, with characteristic low-grade fever, headache, malaise, nonpurulent conjunctivitis, myalgia, and arthralgia. In the most recent outbreak, Zika virus infection has been associated with congenital infections (resulting in microcephaly and neurologic birth defects) and Guillain-Barré syndrome. Although most human infections are transmitted by infected female mosquitoes, transmission also occurs perinatally or via sexual intercourse, breastfeeding, or transfusion of blood products.

Encephalitis

Depending on the causative virus, the ratio of clinical to subclinical disease, the mortality rate, and residua vary widely. The pt usually presents with a prodrome of nonspecific signs and symptoms (e.g., fever, abdominal pain, sore throat, respiratory signs) that is followed quickly by headache, meningeal signs, photophobia, and vomiting; involvement of deeper structures leads to lethargy, cognitive deficits, focal neurologic signs, and coma. Acute encephalitis usually lasts from a few days to 2-3 weeks, and recovery may be slow and incomplete. Treatable causes of encephalitis (e.g., HSV) should be ruled out promptly. Some important examples of arboviral encephalitides follow.

• Japanese encephalitis: This infection is present throughout Asia and the western Pacific islands. A Parkinsonian presentation and seizures are typical in severe cases. An effective vaccine (ideally given on days 0 and 28, with the second dose administered ≥1 week prior to travel) is available and is indicated for summer travelers to rural Asia, where the risk can be as high as 1 case per 5000 travelers per week.
• West Nile encephalitis: Present throughout the Western Hemisphere and now the leading cause of arboviral encephalitis in the United States, West Nile virus is a common cause of febrile disease without CNS infection, but it occasionally causes aseptic meningitis or encephalitis. Encephalitis, serious sequelae, and death are more common among elderly pts, diabetic and hypertensive pts, and pts with previous CNS disease. Unusual clinical features include chorioretinitis, flaccid paralysis, and initial presentation with focal neurologic deficits.
• Eastern equine encephalitis (EEE): EEE occurs primarily within endemic swampy foci along the eastern coast of the United States during the summer and early fall. EEE is one of the most severe arboviral diseases and is characterized by rapid onset, rapid progression, high mortality risk (50-75%), and frequent residua. PMN-predominant pleocytosis of the CSF within the first 1-3 days of disease is an indication of severity.

Arthritis and Rash

Alphaviruses are common causes of arthritis accompanied by a febrile illness and maculopapular rash, usually during the summer in temperate climates. Examples include the following.

• Sindbis virus: Found in northern Europe and southern Africa, this virus, which has an incubation period of <1 week, causes a maculopapular rash that often vesiculates on the trunk and extremities. The arthritis of this condition is multiarticular, migratory, and incapacitating, with resolution of the acute phase in a few days; joint pain may persist for months or years.
• Chikungunya virus: Found primarily in Africa, Asia, and the Caribbean, this virus has an incubation period of 2-10 days and results in the abrupt onset of fever, severe arthralgias, migratory polyarthritis mainly affecting small joints, and a rash that begins coincident with defervescence at day 2-3 of illness.
• Barmah Forest and Ross River viruses: As causes of epidemic polyarthritis in Australia and the eastern Pacific Islands, these viruses produce a rash and disabling symmetrical joint pain, typically in the absence of other prominent constitutional symptoms, after an incubation period of 7-9 days. Because of joint pain, only ∼50% and 90% of pts can resume normal activities at 4 weeks and 3 months, respectively. However, 55-75% of infected pts are asymptomatic.

Pulmonary Disease

After a prodrome (e.g., fever, malaise, myalgias, GI disturbances) of ∼3-4 days, pts with hantavirus (cardio)pulmonary syndrome [H(C)PS] enter a cardiopulmonary phase marked by tachycardia, tachypnea, and mild hypotension. Over the next few hours, the illness may rapidly progress to severe hypoxemia and respiratory failure; the mortality rate is ∼30-40% with good management. Pts surviving the first 2 days of hospitalization usually recover with no residua.

• The disease is linked to rodent exposure. Sin Nombre virus infects the deer mouse and is the most important virus causing H(C)PS in the United States.
• Thrombocytopenia (an important early clue), hemoconcentration, proteinuria, and hypoalbuminemia are typical.
• IgM testing of acute-phase serum may give positive results, even during the prodromal stage, and can confirm the diagnosis. RT-PCR of blood clots or tissue usually gives a positive result in the first 7-9 days of illness.
• Treatment is nonspecific and requires intensive respiratory management and other supportive measures.

Viral Hemorrhagic Fever

The VHF syndrome is a constellation of findings based on vascular instability and decreased vascular integrity. All VHF syndromes begin with the abrupt onset of fever and myalgia and can progress to severe prostration, headache, dizziness, photophobia, abdominal and/or chest pain, anorexia, and GI disturbances. On initial physical examination, there is conjunctival suffusion, muscular or abdominal tenderness to palpation, hypotension, petechiae, and periorbital edema. Laboratory examination usually reveals elevated serum aminotransferase levels, proteinuria, and hemoconcentration. Shock, multifocal bleeding, and CNS involvement (encephalopathy, coma, convulsions) are poor prognostic signs. Early recognition is important; appropriate supportive measures and, in some cases, virus-specific therapy can be instituted.

• Lassa fever: Endemic and epidemic in West Africa, Lassa fever has a more gradual onset than other VHF syndromes. Bleeding is evident in 15-30% of cases. A maculopapular rash is often noted in light-skinned pts with Lassa fever.
  • Pregnant women have higher mortality rates, and the fetal death rate is ∼90%.
  • Pts with high-level viremia or a serum aspartate aminotransferase level of >150 IU/mL are at an elevated risk of death. The administration of ribavirin (32 mg/kg IV × 1 dose, followed by 16 mg/kg q6h for 4 days and then 8 mg/kg q8h for 6 days), which appears to reduce this risk, should be considered.
• Junin/Argentinian and Machupo/Bolivian HF syndromes: These syndromes resemble Lassa fever; however, thrombocytopenia, bleeding, and CNS dysfunction (e.g., confusion, cerebellar signs) are common.
  • Passive antibody treatment for Junin/Argentinian HF is effective, and an effective vaccine exists.
  • Ribavirin at the doses recommended for Lassa fever is likely to be effective in all South American VHF syndromes.
• Rift Valley fever: Although Rift Valley fever virus typically causes fever and myalgia, VHF can occur with prominent liver involvement, renal failure, and probably DIC.
  • Retinal vasculitis can occur in ∼10% of otherwise mild infections, and pts' vision can be permanently impaired.
  • There is no proven therapy for Rift Valley fever. A live attenuated vaccine is in trials.
• HF with renal syndrome (HFRS): This entity is most often caused in Europe by Puumala virus, in the Balkans by Dobrava-Belgrade virus, and in eastern Asia by Hantaan virus.
  • Severe cases of HFRS evolve in identifiable stages: the febrile stage with myalgia, lasting 3 or 4 days; the hypotensive stage, often associated with shock and lasting from a few hours to 48 h; the oliguric stage with renal failure, lasting 3-10 days; and the polyuric stage with diuresis and hyposthenuria.
  • Infections with Puumala virus result in a much-attenuated picture but the same general presentation.
  • IgM-capture ELISA is positive within 2 days of admission and confirms the diagnosis.
  • The mainstay of therapy is expectant management of shock and renal failure. Ribavirin may reduce rates of mortality and morbidity in severe cases if treatment is begun within the first 4 days of illness.
• Yellow fever: A former cause of major epidemics, yellow fever causes a typical VHF syndrome with prominent hepatic necrosis, most commonly in urban South America and Africa. Pts are viremic for 3-4 days and can have jaundice, hemorrhage, black vomit, anuria, and terminal delirium. Vaccination of visitors to endemic areas and control of the mosquito vector A. aegypti prevent disease.
• Severe dengue: Previous infection with a heterologous dengue virus serotype may elicit nonprotective antibodies and exacerbate disease if pts are reinfected. In mild cases, lethargy, thrombocytopenia, and hemoconcentration occur 2-5 days after typical dengue fever, usually at the time of defervescence. In severe cases, frank shock occurs, with cyanosis, hepatomegaly, ascites and pleural effusions, and GI bleeding. The period of shock lasts 1-2 days.
  • The risk decreases considerably after age 12. Severe dengue is more common among females than among males, among whites than among blacks, and among well-nourished than among malnourished persons; it is also more common if dengue virus 1-as opposed to dengue virus 4-precedes infection with dengue virus 2.
  • With good care, the overall mortality rate is as low as 1%. Control of A. aegypti, the mosquito vector, is the key to control of the disease.