32-05: Other Systemic Viral Diseases

General Considerations

Zika virus is a flavivirus, akin to the viruses that cause dengue fever, Japanese encephalitis, and West Nile infection. It was originally isolated from macaques in 1947, in the Zika forest near the Entebbe airport of Uganda. The virus was named Zika in 1952, and the first human cases were noted in Nigeria in 1968 although earlier cases probably occurred in Uganda and Tanzania.

The virus was noted in Africa and Asia during the 1950s–1980s, but first spread beyond those two continents during 2007 when an outbreak occurred in Yap State, Federated States of Micronesia. A large outbreak occurred in French Polynesia in 2013. A smaller outbreak occurred on Easter Island during 2014. The virus then spread to the Western hemisphere and was first noted in northeastern Brazil in 2015, and 239,742 cases were subsequently reported between 2015 and 2018. Zika virus spread rapidly throughout the Americas, including the United States and worldwide (http://www.who.int/csr/disease/zika/en/). Autochthonous transmission of Zika virus has been reported in 87 countries and territories. In October, 2019, the first mosquito-transmitted, locally acquired cases of Zika virus were reported in Europe (Southern France). Despite distinct lineages, Zika virus exists as only one serotype.

Aedes species mosquitoes, particularly Aedes aegypti, are primarily responsible for transmission of Zika virus. The biodistribution of the species largely determines the area of prevalence for Zika virus. Aedes species mosquitoes are found primarily in the southeastern United States, but one species Aedes albopictus (the Asian tiger mosquito known to sequester in tires) may be seen as far north as Pennsylvania and New Jersey. Rarely, a few other mosquito species including Anopheles and Culex may be competent for the Zika virus. Sexual transmission is reported from males and females to partners via vaginal, anal, or oral sex. Vertical transmission from pregnant woman to fetus is prominent. Transmission via platelet transfusion is also reported.

Since the onset of the first reported cases in the United States in 2015, the number of reported Zika cases is over 43,000, with most cases from US territories (largely Puerto Rico). The territorial cases are largely locally acquired and the US state cases are largely travel-acquired. The number of annual cases is diminishing markedly in the United States with a peak in 2016 of 4897 travel-associated cases and 224 locally acquired cases (Florida, 218; Texas, 6). As of November 7, 2019, there have been 15 cases (14 in travelers and 1 laboratory-acquired case) in the US states and 51 (49 locally acquired cases and 2 travel-associated cases) in the US territories.

Clinical Findings

A. Symptoms and Signs

The incubation period is 3–14 days. The majority (50–80%) of Zika virus infections are asymptomatic. Symptoms include acute onset fever, maculopapular rash that is usually pruritic, nonpurulent conjunctivitis, and arthralgias, the latter mimicking the symptoms of the chikungunya virus. Rash may outlast the fever but is not always present. Symptoms last up to 7 days. Most infections are asymptomatic. Viral infections most often confused with Zika include dengue and chikungunya virus infections.

B. Laboratory Findings and Diagnostic Studies

The CDC recommends that persons with symptoms of Zika infection be tested if they live in or have traveled recently to an area with active transmission. The CDC no longer recommends testing for asymptomatic pregnant women.

Diagnosis is made by detecting viral RNA (nucleic acid testing) in patients presenting with onset of symptoms less than 7 days. Nucleic acid testing can be performed within 14 days of illness onset. Persons being tested 14 days or more after symptom onset should be tested using IgM serology. The Trioplex RT-PCR assay, which detects Zika virus, chikungunya virus, and dengue virus RNA, and the Zika MAC-ELISA, which detects Zika virus IgM antibodies (usually present up to 12 weeks after illness onset), are available. Matched serum and urine specimens should be tested simultaneously. Although not routinely recommended, RT-PCR can be performed on amniotic fluid, CSF, and placental tissue. A positive RT-PCR test definitively makes the diagnosis of Zika virus infection and does not require additional confirmatory testing. A negative test does not exclude the presence of the virus in other tissues and does not rule out infection. Persons with negative nucleic acid tests and symptoms of Zika infection should undergo further testing for Zika virus IgM antibody and other arboviral infections. Serologic testing for Zika virus should only be conducted by laboratories with experience in performing flavivirus serology. Recommended serologic assays include enzyme immunoassays and immunofluorescence assays (which detect IgM antibodies using viral lysate, cell culture supernatant, or recombinant proteins) as well as neutralization assays (such as plaque-reduction neutralization tests). The Zika MAC-ELISA can be performed on serum or CSF. Anti-Zika IgM antibodies are observed in CSF of children with congenital infection. Neutralizing antibodies can cross-react with dengue and other flaviviruses, so samples testing positive should be sent to public health laboratories for confirmation.

In the United States, testing for asymptomatic pregnant women is not currently recommended by the CDC even after travel to an area with Zika activity. The WHO however does still recommends testing via IgM antibody for asymptomatic pregnant women who could have had contact with vectorborne or sexually transmitted Zika virus. In areas with active Zika transmission, asymptomatic pregnant women should be tested for IgM antibody as part of routine obstetric care. Persistent Zika virus RNA in serum has been reported in pregnancy. Pregnant women with confirmed or suspected Zika virus infection may be monitored by serial ultrasounds at 3- to 4-week intervals, assessing fetal anatomy and growth. With a declining prevalence of Zika virus infection, positive antibody tests run the risk of more likely being false-positives and thus the need for the outlined assessments exists.

Complications

Two neurologic complications are of particular concern: (1) congenital microcephaly, often associated with brain calcifications and other abnormalities, first noted during the outbreak in Brazil and subsequently recognized to have occurred in French Polynesia as well; and (2) Guillain-Barré syndrome, first noted during the outbreak in French Polynesia. The incidence of Guillain-Barré syndrome is estimated at 2–3 cases per 10,000 Zika virus infections. In addition to microcephaly, Zika causes a spectrum of birth defects of the CNS that collectively are termed “congenital Zika syndrome.” These include fetal brain disruption sequence, subcortical calcifications, pyramidal and extrapyramidal signs, ocular lesions of chorioretinal atrophy, and focal pigmented mottling of the retina, and congenital contractures. Newborns of women infected with Zika virus during pregnancy have a 5–14% risk of congenital Zika syndrome and a 4–6% risk of Zika virus–associated microcephaly. Spontaneous abortions and rare deaths related to Zika virus infection are reported.

As with Ebola virus, the Zika virus can persist in semen for months; in the male reproductive tract the prostate gland and the testes are the presumed reservoirs. Persistence does not appear to occur in the female reproductive tract.

Treatment

There are no antivirals approved for treatment of Zika virus; thus, management should focus on supportive care. Sofosbuvir, which is FDA-approved to treat hepatitis C, another flavivirus, shows some ability to inhibit Zika replication and infection in vitro and in mice and appears to also be synergistic with interferon-alpha and with interferon-beta. Sofosbuvir also prevents vertical transmission in a mouse model. Aspirin and NSAIDs are avoided during illness caused by the flavivirus dengue because of its propensity to cause hemorrhage. Zika virus infections, however, do not appear to be associated with major hemorrhagic complications.

Prevention

The most effective means is environmental control of mosquitoes and removal of areas where water is stagnant or builds up. Such measures include screens on houses; removal of old tires and debris from endemic areas of infection; and movement toward better living conditions, including air conditioning in impoverished areas. Because of the association between microcephaly and Zika virus infection during pregnancy, pregnant women are advised to avoid travel to areas where Zika virus is circulating (http://www.who.int/csr/disease/zika/information-for-travelers/en/). Guidelines for testing of pregnant women potentially exposed are available through the CDC. Infected individuals should refrain from blood donations for several months.

No approved vaccine against Zika virus exists; however, more than 10 vaccine candidates have advanced to phase 1 clinical trials and one has begun phase 2 clinical trials. Vaccine candidate evaluation has been hampered by the declining incidence of Zika virus. The existence of only a single serotype is encouraging for vaccine development, but the need to target maternal infection and fetal neurologic tissue is a stringent and relatively unique arboviral requirement. The antibody-determined enhancement seen with dengue does not appear to be as significant with Zika patients who have previously been vaccinated against dengue virus. The encouraging current trials include 1 with Inovio® and 2 from the NIH VRC (Vaccine Research Center) with the agents entitled VRC 5283 showing the best results to date (NCT03110770). Monoclonal antibodies appear to provide some relief.

Chikungunya (“that which bends up” in the Bantu language Kimakonde) fever is an alphavirus infection transmitted to humans by A aegypti and A albopictus and is considered a classic “arthritogenic” virus. The virus originated with two strains, one in West Africa and the other in East/Central/Southern Africa. The first documented clinical cases in India were derivative of the E/C/S African strains with later reports of outbreaks in Kenya in 2004. Subsequently, there were reports from areas that adjoin the Indian Ocean, Southeast Asia and its neighboring islands (2005–2007), South India (2005), and the island of La Réunion (2005–2006), with further spread including autochthonous cases in Italy and France (2007). In 2013, the first autochthonous case of chikungunya reported in the western hemisphere occurred on Saint Martin in the Caribbean, with isolates derivative of the East/Central/South Africa strains. Despite these differences, only one serotype exists.

For 2019, the CDC reported 115 travel-associated US cases in 26 states (with the largest number of reports from California, New Jersey, and Ohio) (eFigure 32–4). The territory of Puerto Rico reports the only current locally acquired cases, with 2 cases as of December 5, 2019. Chikungunya virus prevalence is ubiquitous in endemic countries in Africa, the Americas, Asia, and Europe.

Among naïve populations, attack rates are often as high as 50%. On Saint Martin, 39% of infections were asymptomatic. Vertical transmission is documented if the mother is viremic during parturition, and transmission does not appear to occur throughout pregnancy as it does with Zika virus. Infectious virus was isolated from saliva, although transmission from oral secretions is not observed among humans. Endemicity of A aegypti in the Americas and the introduction of A albopictus into Europe and the New World raise concern for further extension of the epidemic. Case reports show that chikungunya virus may coinfect patients with yellow fever virus, plasmodia, Zika virus, and dengue virus.

Clinical Findings

A. Symptoms and Signs

After an incubation period of 1–12 days (estimated median 3), there is abrupt onset of fever; headache; intestinal complaints, including diarrhea, vomiting, or abdominal pain; myalgias; and arthralgias/arthritis affecting small, large, and axial joints. The simultaneous involvement of more than 10 joints and the presence of tenosynovitis (especially in the wrist) are characteristic. The stooped posture of patients gives the disease its name. Joint symptoms persist for 4 months in 33% and linger for years in about 10%. A centrally distributed pigmented or pruritic maculopapular rash is reported in 10–40% of patients; it can be bullous with sloughing in children. Mucosal disease occurs in about 15%. Facial edema and localized petechiae are reported. Neurologic complications, including encephalitis, myelopathy, peripheral neuropathy, Guillain-Barré syndrome, myeloneuropathy, and myopathy, are usually found in persons younger than 5 or older than 49 years. Encephalitis occurred in 8.6 per 100,000 persons infected in La Réunion during 2005–2006 with 17% mortality and increased risk of encephalitis among those older than 65 years. Hemorrhagic fever–like presentations are unusual. Coinfection with other respiratory viruses and with dengue is common. Some of the neuropathology may be immune-mediated, and these cases are usually in those over age 20 and associated with longer latencies and better outcomes. Death is rare and usually related to underlying comorbidities. The differential diagnosis includes other tropical febrile diseases, such as malaria, leishmaniasis, or dengue.

B. Laboratory Findings

Diagnosis is made epidemiologically and clinically. Mild leukopenia occurs as does thrombocytopenia, which is seldom severe. Elevated inflammatory markers do not correlate well with the severity of arthritis. Radiographs of affected joints are normal during the acute phase. Bone lesions are visible in some patients with chronic symptoms.

Serologic confirmation requires elevated IgM titers or fourfold increase in convalescent IgG levels using an ELISA. RT-PCR and ELISA are commercially available; no ELISA kit is FDA-cleared. Culture techniques (viral isolation in insect or mammalian cell lines or by inoculation of mosquitoes or mice) require BSL 3 (biosafety level 3) containment. Directions on submitting specimens for testing may be obtained from the CDC Arboviral Diseases Branch, 970-221-6400. Suspected cases in the United States should be promptly reported to public health authorities. Zika virus, a flavivirus that has similar presentation to chikungunya including rash, fatigue, headache, and joint swelling and pain, is transmitted by the same mosquito species.

Complications & Prognosis

Common complications of chikungunya fever are long-term weakness, asthenia, myalgia, arthralgia, and arthritis, noted to be present in 25–66.5% of cases at 1 year. Risk factors for long-term arthralgias include the existence of such symptoms at 4 months after onset of disease and age over 35 years. Persons with preexisting arthritis are also at increased risk for prolonged symptoms after chikungunya infection with polyarthralgias occasionally lasting for years. Nasal skin necrosis is rarely reported. The Guillain-Barré syndrome is also reported. Comorbid conditions, including hypertension, diabetes, and cardiac diseases, may contribute to severe outcomes; although in some series, patients with significant neurologic complications do not show comorbidities. Severe outcomes and higher mortality are reported among more recent Brazilian cases.

Treatment & Prevention

Treatment is supportive with NSAIDs and corticosteroids. Chloroquine and methotrexate may be useful for managing refractory arthritis. Chronic disease may require disease modifying antirheumatic drugs, such as the reports from La Réunion where methotrexate was associated with a positive response. Sofosbuvir, mefenamic acid (an NSAID), and ribavirin inhibited viral replication in vitro and prevented pathologic changes in infected mice. Berberine, abamectin, and ivermectin may have some activity against chikungunya as well. No licensed vaccine exists, although at least 18 vaccines are in trials including inactivated and live attenuated vaccines. A measles-vectored chikungunya virus vaccine (MV-CHIK) is the most advanced vaccine candidate and is currently in phase 2 clinical trials. At this time, prevention relies on avoidance of mosquito vectors. Transplantation of tissue from immigrants or from travelers to known endemic areas should be discouraged. Prophylaxis with specific chikungunya immunoglobulins may be useful for immunosuppressed persons.

General Considerations

Colorado tick fever is a reportable biphasic, febrile illness caused by a reovirus infection transmitted by Dermacentor andersoni tick bite. About five cases occur annually, largely among men over age 40. The disease is limited to the western United States and Canada and is most prevalent during the tick season (March to November), typically at 4,000–10,000 feet above sea level in grassy areas. There is a discrete history of tick bite or exposure in 90% of cases. Most recently, in the summer of 2018, four cases of Colorado tick fever were reported in Oregon (three of which had definite tick exposure). The virus infects the marrow erythrocyte precursors, leading to viremia lasting the life span of the infected red cells. Blood transfusions can be a vehicle of transmission. Despite frequent exposure among national park and forest employees to ticks and reported bites, Colorado tick fever rarely develops in these persons.

Clinical Findings

A. Symptoms and Signs

The incubation period is 3–6 days, rarely as long as 19 days. The onset is usually abrupt with a high fever. Severe myalgia, headache, photophobia, anorexia, nausea and vomiting, and generalized weakness are prominent. Physical findings are limited to an occasional faint rash. The acute symptoms resolve within a week. Remission is followed in 50% of cases by recurrent fever and a full recrudescence lasting 2–4 days. In an occasional case, there may be three bouts of fever.

The differential diagnosis includes influenza, Rocky Mountain spotted fever, numerous other viral infections, and, in the right setting, relapsing fevers.

B. Laboratory Findings

Leukopenia with a shift to the left and atypical lymphocytes occurs, reaching a nadir 5–6 days after the onset of illness. Thrombocytopenia may occur. An RT-PCR assay may be used to detect early viremia. Detection of IgM by capture ELISA or plaque reduction neutralization is possible after 2 weeks from symptom onset and is the most frequently used diagnostic tool.

Complications

Aseptic meningitis (particularly in children), encephalitis, and hemorrhagic fever occur rarely. Malaise may last weeks to months. Fatalities are very uncommon. Rarely, spontaneous abortion or multiple congenital anomalies may complicate Colorado tick fever infection acquired during pregnancy.

Treatment

No specific treatment is available. Ribavirin has shown efficacy in an animal model. Antipyretics are used, although salicylates should be avoided due to potential bleeding with the thrombocytopenia seen in patients with Colorado tick fever.

Prognosis

The disease is usually self-limited and benign.

Prevention

Tick avoidance is the best prevention. The tick season is primarily from March to November, and the ticks mostly live at high altitudes (over 7000 feet) in sagebrush.