Emerging viruses

INTRODUCTION — 

Most emerging viruses originate in animals and are vector-borne or zoonotic diseases. Issues related to Bourbon virus, Heartland virus, Keystone virus, Oropouche virus, Chapare virus, variegated squirrel bornavirus, and Alongshan virus are reviewed here.

Issues related to other emerging viruses, such as Ebola virus, Zika virus, and chikungunya virus, are discussed separately. (See "Clinical manifestations and diagnosis of Ebola disease" and "Zika virus infection: An overview" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

NORTH AMERICA

Bourbon virus disease — Bourbon virus is a member of the genus Thogotovirus in the family Orthomyxovirus. It was first described in 2014 as a cause of infection in a resident of Bourbon county in eastern Kansas; it has also been observed in Missouri [1-3].

The patient was a male over 50 years of age who developed fever, chills, weakness, anorexia, headache, myalgias, arthralgias, nausea, and diarrhea. He had a recent history of several tick bites and had recently removed an engorged tick. Physical examination was notable for fever, a diffuse maculopapular rash on his chest, abdomen, and back, and nontender left axillary adenopathy. Laboratory studies demonstrated leukopenia, thrombocytopenia, and an elevated aspartate aminotransferase level. The patient was treated with doxycycline for presumed tickborne illness with no clinical response. His pulmonary, hepatic, and renal function deteriorated, and he died 11 days after onset of illness [2].

Extensive diagnostic testing for known tickborne pathogens was negative. Results of plaque reduction neutralization testing for Heartland virus at the United States Centers for Disease Control and Prevention on blood collected on day 9 of illness suggested the presence of an unrecognized virus [2]. Electron microscopic study demonstrated viral particles consistent with viruses in the Orthomyxovirus family. Genome sequencing, real-time reverse-transcription polymerase chain reaction (RT-PCR) testing, and phylogenetic analysis revealed a novel virus most closely related to two other viruses in the Thogotovirus genus that have been found only in the Eastern hemisphere [2].

The differential diagnosis of Bourbon virus disease includes Lyme disease, Southern tick-associated rash illness, ehrlichiosis, anaplasmosis, Rocky Mountain spotted fever, Heartland virus infection, leptospirosis, and influenza.

Studies to identify the host and vector are underway. Evidence is mounting that the lone star tick (A. americanum) is a vector of Bourbon virus to humans [4,5]. In a survey of serum and plasma samples from wildlife and domestic animals in Missouri, Bourbon virus neutralizing antibodies were detected in 86 percent of white-tailed deer and 50 percent of racoons [6].

Heartland virus disease — Heartland virus is a member of the genus Bandavirus, family Phenuviridae [7]; it was previously a member of the genus Phlebovirus in the family Bunyavirus [8].

Heartland virus has been isolated from leukocytes, and virions can be visualized in infected cells by electron microscopy [8,9]. Viral antigens have been identified by immunohistochemical staining in large mononuclear cells in bone marrow aspirates [8]. Viral antigens have also been detected in postmortem spleen and mediastinal and mesenteric lymph nodes, and the virus has been detected in a postmortem blood sample by RT-PCR and isolation in cell culture [10]. In one report of a fatal case, immunohistochemical studies were positive in brain, liver, pancreas, heart, lung, large and small bowel, kidney, testes, bone marrow, lymph nodes, spleen, and muscle; viral ribonucleic acid (RNA) was also identified in liver, gallbladder, pancreas, and spleen by RT-PCR and sequencing [11].

Epidemiology — Heartland virus was first reported in 2012 in two individuals from Missouri. Since then, sporadic cases have been reported in the midwestern and southeastern United States [8,10,12-15]. Additionally, a confirmed case acquired in New York has been reported [16].

Reported cases have all occurred among men over 50 years of age who reported spending several hours outside each day. Onset of illness occurred between May and September, and most patients had a history of a tick bite within two weeks prior to symptoms [8,10,12].

The overall incidence of Heartland virus infection is unknown since the diagnosis is often not pursued. A seroprevalence study of asymptomatic blood donors from 10 counties in northwestern Missouri demonstrated Heartland virus antibodies in 0.9 percent (95% CI 0.4-4.2 percent), suggesting the possibility of a significant number of undiagnosed infections [17].

Transmission — Evidence suggests that Heartland virus is transmitted to humans via bites from the lone star tick (Amblyomma americanum). Human-to-human transmission has not been observed.

All human cases thus far have been within the lone star tick's broad geographic habitat, which extends from Texas to Maine (figure 1 and figure 2) [18,19]. Nymphal lone star ticks in their natural habitat have been shown, by polymerase chain reaction (PCR) and culture, to carry Heartland virus.

Another tick, the Asian longhorned tick (Haemaphysalis longicornis), has been shown under experimental laboratory-based settings to be capable of carrying and transmitting Heartland virus [20]. Although this highly invasive tick is emerging in many states in the United States, no Heartland virus has been detected in these ticks in their natural habitat. More details about the Asian longhorned tick can be found elsewhere. (See "Severe fever with thrombocytopenia syndrome virus", section on 'Geographic distribution and lifecycle of H. longicornis ticks'.)

Antibody studies in animals suggest that nonhuman mammals can also become infected with Heartland virus, including raccoons, deer, horses, moose, coyotes, dogs, and opossums [21,22].

Clinical manifestations — Clinical manifestations of Heartland virus infection include fever, fatigue, anorexia, headache, confusion, dry cough, nausea, diarrhea, and myalgias and/or arthralgias [8]. Fatigue and short-term memory loss lasting weeks to months may occur [8].

One case report from Missouri described a patient with manifestations of hemophagocytic lymphohistiocytosis [23]. Another case report from Missouri described a heart transplant patient who recovered following a reduction in his immunosuppressive medication [24].

Death has been reported in association with Heartland virus infection [10]. In one case, the infection was widely disseminated and resulted in multisystem organ failure [11].

Laboratory findings include leukopenia, thrombocytopenia, and elevated hepatic aminotransferases.

Diagnosis — The diagnosis of Heartland virus should be suspected in patients with nonspecific symptoms (fever, anorexia, headache, confusion, nausea, and myalgias and/or arthralgias) and history of tick bite in areas where the virus and/or appropriate tick have been found.

Suspected cases should be reported promptly to state health departments and/or the United States Centers for Disease Control and Prevention, where protocols exist for serologic studies (enzyme-linked immunosorbent assay and plaque reduction neutralization tests) on acute and convalescent sera, RT-PCR, and cell culture.

Differential diagnosis — The differential diagnosis of Heartland virus infection includes [10]:

●Ehrlichiosis and anaplasmosis – Clinical manifestations of ehrlichiosis and anaplasmosis include fever, chills, malaise, myalgia, and headache; laboratory manifestations include leukopenia, thrombocytopenia, and elevated serum aminotransferase levels. The diagnosis is established via indirect fluorescent antibody test. (See "Human ehrlichiosis and anaplasmosis".)

●Severe fever with thrombocytopenia syndrome (SFTS) – Clinical manifestations of SFTS include a prodrome of fever, headache, myalgia, arthralgia, dizziness, and malaise, followed by hemorrhage, thrombocytopenia, elevated liver enzymes, and central nervous system manifestations such as confusion. The diagnosis is established via PCR or antibody detection. (See "Severe fever with thrombocytopenia syndrome virus".)

●West Nile virus infection – Clinical manifestations of West Nile virus infection include fever, headache, fatigue, anorexia, nausea, and myalgia. Neuroinvasive disease occurs in less than 1 percent of cases. The diagnosis is established by antibody testing or PCR. (See "Clinical manifestations and diagnosis of West Nile virus infection".)

●Spotted fever Rickettsia – Clinical manifestations of spotted fever Rickettsia include fever, headache, and intense myalgias, often in association with a rash or localized eschar. The diagnosis can be made via serology, PCR, or immunologic detection of rickettsiae in tissue. (See "Other spotted fever group rickettsial infections".)

●Leptospirosis – Clinical manifestations of leptospirosis include fever, rigors, myalgias, headache, and conjunctival suffusion. The diagnosis is established via serology. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Influenza – Clinical manifestations of influenza include fever, headache, myalgia, and malaise together with manifestations of respiratory tract illness. The diagnosis is established via immunofluorescence, rapid antigen immunoassay, or PCR. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●Thrombotic thrombocytopenic purpura (TTP) – The clinical presentation of TTP consists of severe microangiopathic hemolytic anemia and thrombocytopenia. The diagnosis is established via ADAMTS13 protein deficiency (See "Diagnosis of immune TTP".)

●Hematologic malignancy – Patients with hematologic malignancy present with symptoms related to complications of cytopenia, including fatigue, infection, and/or hemorrhagic manifestations. The diagnosis is established via bone marrow examination. (See related topics.)

Treatment and prevention — Treatment is supportive. There is no specific antiviral therapy and no vaccine for prevention.

Prevention involves avoidance of tick exposure, use of insect repellants, and prompt removal of attached ticks. (See "Prevention of arthropod bites: Repellents and other measures".)

Keystone virus disease — Keystone virus (genus Orthobunyavirus, family Peribunyaviridae) is a member of the orthobunyavirus California serogroup. The virus was first isolated from a pool of Aedes atlanticus mosquitoes collected during ecological studies conducted in the Tampa Bay area of Florida during 1963 to 1964 [25]. The virus has been found in A. atlanticus mosquitoes and wildlife including squirrels, raccoons, and white tail deer in regions extending from Maryland to eastern Texas [26,27] within the range of A. atlanticus [28].

A 2018 case report describes the first human isolate of Keystone virus from a previously healthy 16-year-old male in north-central Florida with a history of multiple mosquito bites followed by onset of subjective low-grade fever and a diffuse erythematous papular rash on the trunk, arm, and face, accompanied by mild fatigue and ankle discomfort. The rash resolved over two days [29].

RT-PCR of the patient's urine followed by sequencing demonstrated L genome sequences with 98 to 99 percent identity with three other Keystone L sequences. The virus was subsequently grown in Vero E6 cells inoculated with the patient's urine [29], suggesting that the illness resulted from Keystone virus infection and that infection with this virus should be considered in the differential diagnosis of febrile rash illness in this geographic region when tests for other agents are negative [29]. Laboratory tests for Keystone virus are not commercially available; testing for Keystone virus would require the assistance of a research or reference laboratory.

CENTRAL AND SOUTH AMERICA

Oropouche virus disease — Oropouche virus is a member of the genus Orthobunyavirus in the family Bunyavirus; four genotypes have been identified [30].

Epidemiology — Oropouche virus disease was first described in 1961 in Vega de Oropouche, Trinidad [31]. The first known epidemic occurred in Belem, Brazil, in 1961 [32]. Subsequently, the virus has been associated with large epidemics and sporadic disease in tropical areas of Brazil, Peru, Panama, Haiti, Colombia, Bolivia, Ecuador, and French Guiana [30,32-39].

In 2024, Brazil reported an ongoing outbreak with over 5000 infections in the first half of the year [40,41]. Additional cases were also reported in Bolivia, Colombia, and Peru. In May of 2024, the first case was described in Cuba, and numerous cases have been reported in the United States among travelers from Cuba [39]. As of August of 2024, no cases of transmission within the United States had been detected [42].

Traditionally, farmers with exposure to bananas and cacao appeared to be at the highest risk for transmission, and the risk of transmission was greatest in rural areas during the rainy season [43-45]. During the 2024 outbreak, significant transmission in urban areas of Brazil was detected [41].

Transmission

●Arthropod-borne - Oropouche virus disease is transmitted by biting midges (Culicoides paraensis); in rural areas, the transmission cycle may also involve nonhuman primates, sloths, birds, and mosquitoes [30,32,33,43]. In urban areas, Oropouche virus transmission can occur between viremic humans and biting midges, and mosquitoes (Culex quinquefasciatus) may also play a role [32,39,41,42].

The biting midge, C. paraensis, has been observed to breed in piles of rotting banana stumps and cacao husks [43-45]. It is small in size and is also called a "no see-um" in some locales. This midge has been identified in a number of states east of the Mississippi River [46]. However, the potential for the establishment of a rural transmission cycle in the United States if the virus were introduced seems low, given the absence of the ecologic conditions observed in epidemic settings.

●Maternal-fetal transmission – Fetal abnormalities and pregnancy loss have occurred among infants born to pregnant patients with Oropouche virus infection, suggesting a risk for vertical transmission.

●Sexual transmission – Replication-competent Oropouche virus has been detected in semen, suggesting a risk for sexual transmission [47].

●Blood or laboratory exposure – Replication-competent Oropouche virus has been detected in whole blood and serum, suggesting a risk for transmission via these routes [47].

Clinical manifestations

●Incubation period – The incubation period for Oropouche virus disease is typically 3 to 10 days (range 3 to 12 days) [39,48].

●Symptoms and signs – Approximately 60 percent of infected individuals develop symptoms [39]. Symptoms and signs include abrupt onset of fever, chills, headache, myalgias, arthralgias, retro-orbital pain, photophobia, and maculopapular rash [31,34,39]. Conjunctival infection and gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, abdominal pain) may also occur. Initial symptoms usually last four to five days [35].

Symptoms can recur up to 10 days following initial recovery [32]. Such recurrences have been reported in up to 70 percent of infected individuals and do not represent newly acquired infections [42]. Immunity following infection is likely lifelong [33].

Hemorrhagic manifestations (eg, petechiae, epistaxis, gingival bleeding, melena, menorrhagia) can occur and were reported in 16 percent of patients in one series [34,42]. Meningitis or meningoencephalitis have been described in a small number of cases; more data on the magnitude of this risk are needed [42,49,50].

The case fatality rate among infected individuals appears to be low. In the 2024 outbreak, two deaths were reported among over 8000 infected individuals [39,42].

●Complications  

•Adverse pregnancy outcomes – Fetal death or congenital abnormalities, including microcephaly, have been reported among infants born to pregnant patients with Oropouche infection [39,42,51,52]. In the 2024 outbreak, five cases of vertical transmission with these outcomes were reported out of over 8000 identified infections [39,42].

•Guillain-Barre syndrome – Guillain-Barre syndrome has been described in association with Oropouche virus infection [53]. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

●Laboratory findings – Laboratory findings may include leukopenia, lymphopenia, elevated C-reactive protein, and mildly elevated liver enzymes [39]. Patients with invasive neurologic disease may have pleocytosis and elevated protein in cerebrospinal fluid (CSF).

Diagnosis — Oropouche virus infection should be considered in any individual with compatible symptoms who has been exposed to areas of known outbreaks or infections. Other infections with similar symptomatology and geographic prevalence (eg, dengue, Zika, Chikungunya, influenza, malaria) should also be considered [39]. (See 'Differential diagnosis' below.)

The diagnosis of Oropouche virus disease is established via detection of antibody (using enzyme-linked immunosorbent assay or plaque reduction neutralization testing on acute and convalescent sera) or detection of viral RNA in blood via reverse-transcription polymerase chain reaction testing (RT-PCR). In the United States, such tests may be obtained by contacting local and state public health agencies [39]. Detection of the virus in saliva and urine from an infected patient has been reported [54]. Viremia is usually present during the first two days of illness [32].

Differential diagnosis — The differential diagnosis of Oropouche virus disease includes dengue, yellow fever, chikungunya and Zika virus, malaria, leptospirosis, ehrlichiosis, rickettsial infections, and coronavirus disease 2019 (COVID-19). Common viral infections (influenza, adenovirus, parvovirus, enterovirus, measles) should also be considered [39].

Many areas with Oropouche transmission also have ongoing transmission of infections such as malaria, as well as dengue, Zika, and chikungunya viruses [41]. Because of similar symptoms, distinguishing these infections usually requires laboratory testing.

Treatment — Treatment of Oropouche virus disease is supportive; no drugs are available [39]. Nonsteroidal anti-inflammatory agents (NSAIDs) should be avoided to reduce the risk of bleeding.

Ruling out other potential serious or treatable infections (eg, malaria) is important because specific treatment regimens for these infections can improve outcomes.

For pregnant people with Oropouche infection, serial monitoring with fetal ultrasound during pregnancy (every four weeks) and careful evaluation of newborns has been suggested by the United States Centers for Disease Control and Prevention (CDC) [51].

Prevention — There is no available vaccine for prevention of Oropouche virus.

Individuals exposed to areas where Oropouche virus is known to spread can take personal measures to prevent acquiring infection from biting midges and mosquitoes. Such measures include use of insect repellants, wearing clothing that covers the skin (eg, long-sleeve shirts, pants), and use of mosquito nets and mesh screens. However, biting midges may be small enough to pass through fine mesh mosquito nets and may be resistant to common insect repellants; more data are necessary to determine susceptibility to specific insect repellants [41]. (See "Prevention of arthropod bites: Repellents and other measures".)

Individuals, especially pregnant people, may want to avoid travel to regions with ongoing transmission. Travelers returning from such regions should continue to avoid biting midge and mosquito exposures for three weeks after return, to prevent importation and spread of the virus in unaffected regions [39,42].

Chapare hemorrhagic fever — Chapare virus is a member of the genus Mammarenavirus in the family Arenaviridae. Mammarenaviruses include other agents (Junin, Machupo, Guanarito, and Sabia viruses) that also cause viral hemorrhagic fevers throughout South America [55].

●Epidemiology – Chapare virus was first reported to cause human disease in 2003 in Bolivia [56]. No other confirmed cases were reported until 2019 when Bolivia experienced a cluster of five cases and subsequently identified an additional four cases in 2019 and 2020 [57].

The incidence of Mammarenavirus infections in South America is unknown because of the clinical similarity between Chapare hemorrhagic fever and other locally endemic infections and the lack of available diagnostic tests.

●Transmission – The virus appears to spread to humans via environmental exposure or person-to-person transmission [57].

Environmental transmission is presumed to be from direct exposure to infected rodents or their excreta. Testing of local small mammals in Bolivia identified the virus in small-eared pygmy rice rats (Oligoryzomys microtis), rodents that are highly prevalent in the affected regions [57]. In one area, 29 percent of rodents were positive by polymerase chain reaction (PCR).

●Risk factors – Although definitive studies evaluating risk factors have not been published, confirmed cases have all occurred in agricultural workers in an affected area or in household or health care contacts of infected individuals [56,57]. All reported cases occurred in individuals who were previously healthy.

●Clinical manifestations – The clinical features described below are based on 10 cases for which clinical data are available [56,57].

The incubation period for the infection ranged from 9 to 16 days among patients with known dates of exposure [57].

Initial symptoms were similar among infected individuals [56,57]. Common clinical features included fever, headache, myalgia, arthralgia, and nausea with or without emesis. Abdominal pain, retro-orbital pain, lumbar pain, and diarrhea were also reported. Of nine cases for which initial symptoms were reported, six had either gingival hemorrhage or epistaxis at the time of presentation.

Although clinical information is incomplete, hemorrhagic shock appears to have occurred in at least 5 of 10 reported cases [56,57]. Hemorrhage initially manifested as gingival hemorrhage or epistaxis. Those who had worsening hemorrhage developed vaginal, gastrointestinal, intracerebral, urinary and/or injection site bleeding as well as petechiae and ecchymoses.

Neurologic symptoms and signs were not uncommon in reported cases including seizures, confusion, agitation, hemiparesis, and lower extremity paralysis thought to be due to viral myopathy or Guillain-Barré syndrome [57].

Of 10 reported cases, death occurred in five. Death occurred 9 to 22 days after of onset of illness [57]. Among survivors, prolonged hospitalization and recovery were common.

●Laboratory findings – Limited data are available: of five individuals with reported laboratory results, all had leukopenia, anemia, thrombocytopenia, elevated aminotransferases, and abnormal coagulation tests (elevated prothrombin time and/or activated partial thromboplastin time) [57].

●Diagnosis – The diagnosis of Chapare virus infection should be suspected in patients from known affected areas who present with an acute febrile illness of unclear etiology and have risk factors for environmental or nosocomial/household exposure, especially if hemorrhagic features are present and testing for more common pathogens is negative.

Definitive diagnosis is hampered by lack of widespread availability of diagnostic tests. Cases have been diagnosed using various techniques including next-generation sequencing, viral cultures, RT-PCR, and serologic tests [57].

Among confirmed cases, viral RNA was detected in blood, urine, nasopharyngeal and oropharyngeal samples, bronchial lavage fluid, conjunctival specimens, and semen [57]. In survivors, viral RNA was detected up to 170 days after symptom-onset and infectious virus was detected in one semen sample 86 days after symptom-onset.

●Differential diagnosis – Differential diagnosis for the early phase of illness is broad and includes infections endemic to the affected areas; in Bolivia, such infections include malaria, Chikungunya virus, Zika virus, and leptospirosis in addition to other local hemorrhagic fevers such as dengue virus, hantavirus, yellow fever virus, and Machupo virus.

●Clinical management – In reported cases, no antiviral therapy was used, and there are no studies evaluating antiviral agents for this infection [57]. Treatment consists of supportive care.

●Infection control – Of 10 reported cases, three have been described in health care workers via nosocomial transmission [57]. Early and careful attention to infection control in health care settings is warranted when this illness is suspected.

EUROPE

Variegated squirrel bornavirus encephalitis — Variegated squirrel bornavirus 1 (VSBV-1) is a bornavirus species associated with encephalitis among individuals in contact with variegated squirrels [58]. Variegated squirrels are tree squirrels found in Central America that are sometimes kept as exotic pets. VSBV-1 has also been detected in exotic squirrels in Germany and the Netherlands [59].

Fatal encephalitis was observed among three breeders of variegated squirrels in Germany between 2011 and 2013 [58]. The patients were males 62 to 72 years old and were mutual friends who had shared their variegated squirrel breeding pairs on multiple occasions; all had underlying comorbidities [58].

The illnesses were characterized by fever, chills, confusion, unsteady gait, and psychomotor slowing with progression to coma. All three patients developed bilateral crural vein thrombosis and aspiration pneumonia; two developed pulmonary emboli [58].

Magnetic resonance imaging of the brain demonstrated hyperintense lesions in temporal, parietal, and cortical areas in two patients and dilated ventricles with meningeal contrast enhancement in the third patient. Abnormal electroencephalogram findings were observed in all three patients.

An occupation-associated fatal limbic encephalitis case has been reported in an animal caretaker who worked in a zoo in Germany [60]. An evaluation of 103 encephalitis cases of unknown etiology identified four fatal cases with serologic evidence of bornavirus infection (one with VSVBV-1 in a person with occupational contact with exotic squirrels and three with Borna disease virus 1 living in virus endemic areas) [61]. Accumulated evidence suggests that wildlife trade of exotic squirrels poses a potential risk of spillover infection to owners of exotic pet squirrels and to zoo animal caretakers [62,63]. Infected animals are typically asymptomatic.

The differential diagnosis of variegated squirrel bornavirus encephalitis includes herpes simplex encephalitis, herpes B encephalitis, rabies, tickborne encephalitis, Toxoplasma encephalitis, neurosyphilis, and brain abscess.

Laboratory investigation using a metagenomic approach revealed VSBV-1 RNA in brain specimens from all three patients and from a healthy squirrel owned by one of the patients [58]. Bornavirus-specific immunoglobulin G in high titer was observed in serum and spinal fluid from one of the patients.

Treatment of variegated squirrel bornavirus encephalitis is supportive; no drugs or vaccines are available. Avoidance of scratches and bites by variegated squirrels is warranted [64].

ASIA

Alongshan virus disease — Alongshan virus (ALSV; family Flaviviridae) was first isolated in 2017, in a 42-year-old female farmer from the town of Alongshan, China who developed an acute febrile illness manifested by headache, fatigue, and nausea, accompanied by cough, sore throat, and a history of tick bites [65]. Diagnostic evaluation (including reverse-transcription polymerase chain reaction [RT-PCR], cell-culture assays, and genomic sequencing) identified a previously unrecognized segmented RNA virus belonging to the jingmenvirus group of the family Flaviviridae. After several passages, a virus (diameter of 80 to 100 nm) was visualized by transmission electron microscopy in Vero cells manifesting cytopathic effect after four days of incubation [65].

Screening of other hospitalized patients from Inner Mongolia and Heilongjiang with fever, headache, and history of tick bites identified the virus in 86 patients. Serologic assays performed on all 19 patients for whom paired specimens were available demonstrated seroconversion. Serum specimens obtained from 100 healthy individuals in the region were all negative for the virus and for ALSV antibodies.

Most of the infected patients had fever, headache, and fatigue; 35 percent were comatose and 26 percent had a rash or petechiae; 95 percent has a history of tick bite prior to onset of illness. The typical incubation period was 3 to 7 days (range 1 to 10 days). Infections occurred most frequently between May and July; 73 percent of infections occurred in males, and nearly all infected individuals were farmers or forestry workers. Patients were treated empirically with ribavirin and benzylpenicillin sodium for 3 to 5 days. Hospital stays were typically 10 to 14 days. No person-to-person transmission was observed, and no deaths occurred.

Possible modes of transmission include ticks and mosquitoes. ALSV RNA was detected in mosquitoes and Ixodes persulcatus ticks collected in wooded and hilly areas where patients were bitten. This tick is widely distributed in Asia and eastern Europe; common hosts include many mammals (eg, sheep, cattle, horses, dogs, rabbits, and humans). ALSV infection has also been detected in Ixodes persulcatus ticks in Russia and Ixodes ricinus ticks in Finland [66,67]. Serologic evidence of ALSV infection has been identified in sheep and cattle in Inner Mongolia [68].

ALSV infection should be suspected in individuals with a compatible illness and a history of tick bite who reside in or have traveled to Inner Mongolia or northeastern China [69]. Laboratory tests are not commercially available; testing for would require the assistance of a research or reference laboratory.

The differential diagnosis of ALSV infection includes tickborne encephalitis, severe fever with thrombocytopenia syndrome, human anaplasmosis, rickettsial disease, and leptospirosis.

Wetland virus disease — Wetland virus is a member of the genus Orthonairovirus in the family Nairoviridae. Orthonairoviruses include other agents (eg, Crimean-Congo virus) that also cause febrile illnesses in parts of Asia and Africa [70].

●Epidemiology – Wetland virus was first discovered as a cause of human disease in 2019 in a single hospitalized patient in China [70]. Subsequent regional surveillance identified 16 additional hospitalized patients with the infection in northeastern China.

Serologic testing of asymptomatic forest rangers in the same locale revealed evidence of past infection in two percent [70].

●Transmission – The virus appears to spread to humans via tick bites. The virus has been isolated from multiple species of ticks in northeastern China, and infected patients all reported tick exposure or bites [70]. Animal models have shown transmission from infected ticks to uninfected mice, and evidence of prior infection has been detected in sheep, horses, pigs, and other animals in the region.

●Clinical manifestations – The clinical features described below are based on 17 cases for which clinical data are available [70].

Symptoms and signs are nonspecific and include the following [70]:

•Fever (94 percent)

•Dizziness (65 percent)

•Headache (53 percent)

•Nausea, vomiting, and/or diarrhea (53 percent had at least one of these symptoms)

•Myalgia (29 percent)

•Lymphadenopathy (24 percent)

•Petechiae (24 percent)

•Arthritis (18 percent)

•Back pain (12 percent)

Coma was reported in one patient, and no deaths were reported. Median hospital stay was eight days (range 4 to 15 days).

●Laboratory findings – The most frequent laboratory abnormality was lymphopenia, which occurred in 65 percent of patients. Other findings included leukopenia; thrombocytopenia; and elevated levels of fibrinogen, D-dimer, C-reactive protein, liver aminotransferases, lactate dehydrogenase, creatinine kinase, creatinine, and uric acid [70].

The lone patient with coma had cerebrospinal fluid (CSF) sampling that revealed a CSF white blood cell count of 105 cells per mL (90 percent lymphocytes) and a total protein of 1446 mg/L.

●Diagnosis – Diagnosis was made via serologic testing, including acute and convalescent samples [70]. However, definitive diagnosis is hampered by lack of widespread availability of diagnostic tests.

Patients suspected of having Wetland virus should also be tested for other pathogens that cause similar clinical manifestations, especially tickborne infection for patients with tick exposures. This may include severe fever with thrombocytopenia syndrome and rickettsial spotted fevers [70]. (See "Severe fever with thrombocytopenia syndrome virus" and "Other spotted fever group rickettsial infections".)

In surveillance studies of patients with documented Wetland virus infection, coinfection with other tickborne pathogens has been detected, including spotted fever rickettsia and Borrelia burgdorferi sensu lato [70].

●Clinical management – Treatment consists of supportive care. Patients have received ribavirin or immunoglobulin therapy, but the benefit and/or harm from these treatments have not been assessed [70]. Some patients also received antibacterial agents as empiric therapy for possible alternative or concomitant bacterial infection.

SUMMARY AND RECOMMENDATIONS

●Most emerging viruses originate in animals and are categorized as vector-borne or zoonotic diseases. (See 'Introduction' above.)

●North America

•Bourbon virus is a likely tickborne virus associated with nonspecific symptoms and signs (fever, chills, weakness, anorexia, headache, myalgias, arthralgias, nausea, and diarrhea); it has been observed in Kansas and Missouri. The diagnosis may be established via serologic studies and/or reverse-transcriptase polymerase chain reaction (RT-PCR) performed by the United States Centers for Disease Control and Prevention (CDC). There are no specific drugs or vaccines available; prevention consists of avoidance of tick exposure. (See 'Bourbon virus disease' above.)

•Heartland virus is a likely tickborne virus associated with nonspecific symptoms and signs (fever, anorexia, headache, confusion, nausea, and myalgias and/or arthralgias); it has been observed in Missouri, Illinois, Indiana, Iowa, Kansas, Kentucky, North Carolina, Georgia, Oklahoma, Tennessee, and Arkansas. Laboratory findings include leukopenia, thrombocytopenia, and elevated hepatic aminotransferases. The diagnosis may be established via serologic studies and/or real-time RT-PCR by the CDC. Treatment is supportive; prevention consists of avoidance of tick exposure. (See 'Heartland virus disease' above.)

•Keystone virus is a potential emerging human pathogen in United States regions extending from Maryland to eastern Texas. Transmission is likely mosquito-borne; the illness is characterized by low-grade fever and a diffuse erythematous papular rash. (See 'Keystone virus disease' above.)

●Central and South America

•Oropouche virus is a disease transmitted by biting midges associated with nonspecific symptoms and signs (fever, chills, headache, myalgias, arthralgias, retro-orbital pain, photophobia, rash, and neutropenia; hemorrhagic manifestations and meningoencephalitis have been described in some patients). Mosquitoes may also play a role in transmission, and cases of possible vertical transmission have been reported. Oropouche virus disease has been observed in Trinidad, Brazil, Peru, Panama, Haiti, Colombia, and French Guiana. The diagnosis may be established via serologic studies and/or RT-PCR testing. Treatment is supportive; prevention consists of avoidance of midge and mosquito exposure. (See 'Oropouche virus disease' above.)

•Chapare virus is a potential emerging pathogen in Bolivia and causes Chapare hemorrhagic fever. Symptoms include acute febrile illness with headache, myalgia, arthralgia, and other nonspecific symptoms followed, in some cases, by rapid onset of hemorrhagic symptoms and signs that can progress to visceral or intracerebral bleeding and shock. Diagnostic testing is not widely available but has been developed in Bolivia, and treatment is supportive. Nosocomial transmission has been reported, so strict infection control measures should be implemented when this illness is suspected. (See 'Chapare hemorrhagic fever' above.)

●Europe

•Variegated squirrel bornavirus 1 has been observed in association with encephalitis among breeders of variegated squirrels in Germany; variegated squirrels are tree squirrels found in Central America that are sometimes kept as exotic pets. The diagnosis may be established via next-generation sequencing and RT-PCR. There are no specific drugs or vaccines available; prevention consists of avoidance of scratches and bites by variegated squirrels. (See 'Variegated squirrel bornavirus encephalitis' above.)

●Asia

•Alongshan virus is a potential emerging human pathogen in northeastern China. Illness is characterized by fever, headache, fatigue, and a history of tick bite; skin rash and coma may be present. The typical incubation period is three to seven days. The virus has been identified in ticks in Russia and Finland and in sheep and cattle in Inner Mongolia. (See 'Alongshan virus disease' above.)

•Wetland virus is a potential emerging human pathogen in northeastern China. Common symptoms include fever and headache, and laboratory findings are notable for lymphopenia. It appears to spread to humans via tick bites and has been isolated from multiple species of ticks in northeastern China. (See 'Wetland virus disease' above.)