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, 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 virus 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 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 reverse-transcription polymerase chain reaction (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 RNA was also identified in liver, gallbladder, pancreas, and spleen by RT-PCR and sequencing [11].

Epidemiology — Heartland virus was initially described in 2012; subsequently, a small number of human cases have been reported in Missouri, Illinois, Oklahoma, Tennessee, and Arkansas [8,10,12-15]. The cases all occurred among men over 50 years of age who reported spending several hours outside each day, and most patients had a history of tick bite within two weeks prior to symptoms. Onset of illness occurred between May and September [8,10,12].

As of January, 2021, more than 50 cases have been identified, including cases in six additional states (Kansas, Indiana, Iowa, Kentucky, North Carolina, and Georgia) [16]. A study of asymptomatic blood donors conducted in 10 counties in northwestern Missouri demonstrated a seroprevalence of 0.9 percent (95% CI 0.4-4.2 percent) suggesting that asymptomatic infection may occur [17].

Transmission — Transmission of Heartland virus is likely tickborne. The virus has been detected via polymerase chain reaction and culture among nymphs of the lone star tick (Amblyomma americanum), which is found in a broad geographic area extending from Texas to Maine (figure 1 and figure 2) [18]. Thus far all reported cases have been from states where this tick is found [16]. The vertebrate host has not been definitively identified; neutralizing antibodies to Heartland virus have been observed in raccoons, deer, horses, moose, coyotes, dogs, and opossums [19,20].

Human-to-human transmission has not been observed. Person-to-person transmission by contact with infected blood or secretions could occur as has been reported in the related severe fever with thrombocytopenia syndrome (SFTS) virus infection [21,22]. (See "Severe fever with thrombocytopenia syndrome virus".)

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 thrombocytopenia 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 and insect bites: Repellents and other measures", section on 'Ticks'.)

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]. Oropouche virus disease was first described in 1961 in Vega de Oropouche, Trinidad [31]. The first 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, and French Guiana [30,32-38].

Oropouche virus disease is transmitted by biting midges (Culicoides paraensis); in rural areas, the transmission cycle may involve midges as well as nonhuman primates, sloths, birds, and mosquitoes [30,32,33,39]. In urban areas, Oropouche virus transmission can occur between viremic individuals and biting midges [32].

C. paraensis has been observed to breed in piles of rotting banana stumps and cacao husks; farmers with exposure to bananas and cacao appear to be at increased risk for transmission [39,40]. The risk of Oropouche virus transmission appears to be greatest during the rainy season [41].

C. paraensis has been identified in a number of states east of the Mississippi River [42]. Human-to-human transmission by C. paraensis could potentially occur. However, the potential for the establishment of a rural transmission cycle in the United States if the virus were introduced seems extremely low given the absence of the ecologic conditions observed in epidemic settings.

The incubation period for Oropouche virus disease is typically 4 to 8 days (range 3 to 12 days) [43]. The illness is characterized by abrupt onset of fever, chills, headache, myalgias, arthralgias, retro-orbital pain, photophobia, and rash [31,34]. Laboratory findings include leukopenia and neutropenia. Symptoms usually last 4 to 5 days, but recurrence up to 10 days following initial recovery has been observed [32]. Further data are needed on the frequency of asymptomatic infection. Immunity following infection is likely lifelong [33].

Hemorrhagic manifestations (petechiae, epistaxis, and gingival bleeding) were reported in 16 percent of patients in one series [34]. Meningoencephalitis has been described in a small number of cases [44,45].

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 via detection of viral RNA in blood via reverse-transcription polymerase chain reaction testing. Detection of the virus in saliva and urine from an infected patient has been reported [46]. Viremia is usually present during the first two days of illness [32].

The differential diagnosis of Oropouche virus disease includes dengue, yellow fever, chikungunya and Zika virus infections, malaria, leptospirosis, ehrlichiosis, and influenza.

Treatment of Oropouche virus disease is supportive; no drugs or vaccines are available. Preventive measures include use of mesh screens and other interventions to prevent insect bites. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

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 [47]. 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 [48].

Fatal encephalitis was observed among three breeders of variegated squirrels in Germany between 2011 and 2013 [47]. 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 [47].

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 [47].

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 [49]. 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) [50]. 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 [51,52]. 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 [47]. 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 [53].

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 [54]. Diagnostic evaluation (including reverse-transcription polymerase chain reaction, 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 [54].

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 [55,56]. Serologic evidence of ALSV infection has been identified in sheep and cattle in Inner Mongolia [57].

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 [58]. 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.

SUMMARY

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

●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 RT-PCR performed by the 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 reverse-transcriptase polymerase chain reaction (RT-PCR) by the United States Centers for Disease Control and Prevention (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.)

●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). 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 exposure. (See 'Oropouche virus disease' above.)

●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.)

●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.)