i. Bunyaviridae

California , Hantavirus Pulmonary Syndrome, Hantavirus Hemorrhagic Fever With Renal 166 Syndrome, and Bunyavirus Hemorrhagic Fevers Raphael Dolin

SHORT VIEW SUMMARY

Definition Major Causes of Human Diseases Diagnostic tests are typically performed in } is a large order of RNA (See Table 166.1) reference laboratories. consisting of 10 families and more than 350 } California encephalitis group: Therapy named species. They are enveloped, } La Crosse (LACV) } Treatment is primarily supportive because specific single-stranded RNA viruses with a segmented Jamestown Canyon virus (JCV) } antiviral therapy is not available. has genome. Bunyavirales members can be found virus (RVFV) } been studied in some bunyavirus , and worldwide and are able to infect invertebrates, Crimean-Congo hemorrhagic fever virus (CCHFV) } data from in vitro and in vivo models hold vertebrates, and plants. Hantaviruses } promise. Ribavirin has shown clinical benefit in Hemorrhagic fever with renal syndrome Epidemiology } HFRS and in CCHF. However, comprehensive (HFRS) } Bunyaviruses are significant human pathogens clinical trials have not been conducted. } Hantavirus pulmonary syndrome with the ability to cause severe disease, } Severe fever with thrombocytopenia syndrome Prevention ranging from febrile illness, encephalitis, and virus (SFTSV) } No specific preventive measures are available, hepatitis to hemorrhagic fever. but experimental for some With exception of hantaviruses, bunyaviruses Diagnosis } bunyaviruses have been developed and are are transmitted by hematophagous arthropods, In most cases the diagnosis is based on } undergoing study. Individual protective including ticks, mosquitoes, and phlebotomine serologic investigation of acute and early measures, such as arthropod repellents and flies. convalescent sera. Early diagnosis can be insecticide-impregnated bed nets, Hantaviruses are maintained in nature through based on reverse-transcriptase polymerase } are recommended in endemic areas. persistent of rodents. chain reaction assays of samples.

Bunyaviruses are an extraordinarily diverse and numerous group of viruses whose taxonomic complexity has led to a recently reorganized Structure,Structure, RReplication, and classification yb the International Committee on Taxonomy of Viruses Antigenic Relationships (ICTV). In 2017 the ICTV reclassified the family Bunyaviridae to that Bunyavirales members are spherical, enveloped RNA viruses, 80 to 120 nm of an order, Bunyavirales, that comprises 10 families: Arenaviridae, in diameter and that display surface glycoproteins of 5 to 10 nm.3 The RNA Cruliviridae, Fimoviridae, Hantaviridae, Mypoviridae, Nairoviridae, is of negative sense or ambisense, and codes for six or fewer proteins. The Peribunyaviridae, Phasmaviridae, Phenuiviridae, and Wupedeviridae. genome consists of two to six segments, although the majority of bunya- The families comprise 35 genera, with more than 350 named viruses viruses studied have a trisegmented genome (Fig. 166.1).3–5 The large RNA identified as ps ecies.1,2 Classification into separate families and species segment (L) encodes an RNA-dependent RNA polymerase; the medium is based on genomic, structural, biochemical, and antigenic chracteristics,3 segment (M) encodes viral glycoprotein precursors, which are cleaved by although limited data are available for a number of these viruses. The the host protease to yield mature glycoproteins, Gn and Gc, that are involved distribution of these viruses is via arthropod-vertebrate cycles or by in receptor binding and endomembrane fusion. The small genome segment chronic infection of vertebrates, which lead to epidemiologic patterns (S) encodes the nucleocapsid proteins.3–5 The molecular weights of the that are ecologically determined and can be focal or diffuse depending proteins and RNAs vary by genus. In general, the Gn or Gc proteins, or on climatic variables. Table 166.1 presents salient features of infections both, are targets for neutralizing .3 The nucleocapsid protein is caused by Bunyavirales viruses, including vectors, transmission, epide- believed to be the most important source of immunologic relationships miology, and clinical expression. Details of these infections are discussed observed within and across families and genera. In general, the fluorescent further as follows. test is the most cross-reactive, with hemagglutination inhibition 2169 2170 (HI), and although the neutralization tests provide greater specificity, the Virus replication occurs in the cytoplasm, and virions mature by latter is of greatest use in distinguishing individual viruses. Enzyme-linked budding from the Golgi complex and endoplasmic reticulum into vesicles. immunosorbent assays () increasingly are used for diagnosis of Some bunyaviruses are exceptions, such as Rift Valley fever virus (RVFV), s acute or resolving (immunoglobulin [Ig]M) or retrospective (IgG) infections which buds through the outer cell membrane of hepatocytes, and Sin 3 ent (see later). Nombre virus (SNV), which matures at the cytoplasmic membrane. g

ic A EPIDEMIOLOGY g EcologyEcology andand DistributionDist With the exception of hantaviruses, all bunyaviruses are transmitted tiolo E by arthropods (mosquitoes, ticks, and sand flies). Hantaviruses are S transmitted through feces from rodent species, such as deer mice or the striped field mouse.

L Gn protein California Encephalitis Viruses M Among the California encephalitis (CE) virus group, La Crosse virus Gc protein (LACV) is the most medically significant virus, causing an average of 6 Lipid envelope 79 cases per year, predominantly in children younger than 15 years. Its principal vector is triseriatus, a forest-dwelling, tree-hole–breed- L protein ing mosquito of the north-central and northeastern regions of the RNP N protein country. LACV is maintained in this mosquito via transovarial transmis- ectious Diseases and Their f sion supplemented by intraspecific venereal transmission and amplifica- In FIG. 166.1 Bunyavirus structure. The three genome segments (L, M, tion during summer by mosquitoes feeding on viremic chipmunks, I and S) are encapsidated by nucleocapsid protein to form ribonucleoprotein 7,8 complexes (RNPs), and together with the viral L protein (RNA-dependent squirrels, foxes, and woodchucks. RNA polymerase) are packaged within a host cell-derived lipid envelope Female mosquitoes infected by any of these mechanisms are capable

Part II modified by insertion of the viral glycoproteins Gn and Gc. (Modified from of transmitting virus via a bite. The virus survives during the winter in Elliot RM, Schmaljohn CS. Bunyaviridae. In: Knipe DM, Howley PM, eds. mosquito eggs.9 LACV and human encephalitis were first recognized Fields Virology. Philadelphia: Lippincott Williams & Wilkins; 2013:1245.) in the upper Mississippi and Ohio River valleys. Most cases have

TABLE 166.1 Some Characteristics of Severe Diseases Caused by Bunyavirales DISEASE PATTERN GENUS AND TRANSMISSION AND ANNUAL MAJOR CLINICAL DISEASE VIRUSES VECTOR TO HUMANS INCIDENCE FEATURES California encephalitis Aedes triseriatus Mosquito bite Summer-fall; northern , La Crosse Transovarial transmission; United States: 60–130 , cerebral Jamestown Canyon amplification by cases edema chipmunks Rift Valley fever Phlebovirus Aedes mcintoshi Mosquito bite; aerosol Endemic in rainy season Acute febrile illness with Rift Valley fever Transovarial transmission; or contact with fresh sub-Saharan Africa: occasional retinitis, horizontal transmission carcasses, domestic hundreds of cases; hemorrhagic fever, or in other arthropods animals occasional encephalitis associated with exceptional rainfall Crimean-Congo Orthonairovirus Hyalomma ticks Tick bite, contact with Spring-summer; regions of Severe hemorrhagic fever hemorrhagic fever Crimean-Congo Amplified by hares, blood of humans or former Soviet Union, Hemorrhagic Fever domestic animals domestic animals Middle East, Africa: 50–200 cases Hemorrhagic fever Chronic infection of Aerosols from rodent Endemic and ; Fever, shock, bleeding, with renal syndrome Hantaan striped field mouse, excreta season depends on local renal failure Dobrava yellow-necked mouse, conditions. Asia, Seoul rat, or bank vole Europe: 100,000 cases Puumala Hantavirus pulmonary Orthohantavirus Chronic infection of deer Aerosols from rodent Discovered in 1993; Fever, shock, pulmonary syndrome Sin Nombre mouse and other excreta dozens of cases edema Bayou rodents annually in North and Black Creek Canal South America Tropical Fever Orthobunyavirus Biting midge By biting midges Epidemic and sporadic Acute febrile illness with Oropouche Culicoides paraensis disease in tropical areas occasional hemorrhagic of Brazil, Peru, and complications Panama Sand fly fever Phlebovirus Phlebotomus perniciosus, Mosquito bite Circum-Mediterranean Fever, , myalgia, Toscana Phlebotomus papatasi distribution in Southern meningitis Sand fly fever Europe Severe fever with Phlebovirus Haemaphysalis longicornis, Tick bites, close Central and eastern Fever, multiorgan thrombocytopenia SFTS Ixodes nipponensis, person-to-person China, South Korea, dysfunction, bleeding syndrome (SFTS) Amblyomma contact western Japan diathesis testudinarium Heartland virus disease Phlebovirus Tick-borne Probably tick-borne Midwestern and southern Fever, headache, cough, Heartland Lone Star tick United States: confusion, myalgia, Amblyomma americanum 30 cases since 2012 multiorgan dissemination, thrombocytopenia 2171 been reported from Wisconsin, Minnesota, Iowa, Indiana, Ohio, and Another hantavirus, Seoul virus (SEOV), is found worldwide in Rattus Illinois.10,11 However, recognition of the disease in West Virginia and norvegicus. Although the virus is found wherever the reservoir sewer Georgia10 has led to an understanding that viral transmission occurs rat occurs, disease has rarely, if ever, been identified in the United States. Cha throughout the eastern United States; during 2003–07 West Virginia Bank voles, Clethrionomys glareolus, are the reservoir-vectors of 12 had the greatest number of cases (95) in the United States. Studies Puumala virus, the cause of a milder form of HFRS termed nephropathia p in Tennessee suggest recent extension into that state.11 Other vectors epidemica in Scandinavia, the western former Soviet Union, and Europe. ter 166 are not of major importance except focally. The Asian mosquito Aedes These small rodents are found in forests and agricultural hedgerows, albopictus is an efficient vector and is capable of horizontal and vertical have highly fluctuating populations, and disperse into rural and suburban transmission in the laboratory.13 Its strongly anthropophilic biting habits gardens and dwellings, particularly in the fall and winter of years when California Encephaliti and its documented extension into areas where LACV is endemic raise their populations reach peaks.32,33 concern, particularly because the virus has been isolated from field Many native North and South American rodents (family Muridae, collections of A. albopictus.14 subfamily Sigmodontinae) host phylogenetically distinct hantaviruses Other CE viruses have distinct ecologic cycles based on an element associated with HPS.34 HPS is a disease of the Americas and is probably of transovarial transmission in mosquitoes, and human disease is more important in South America than in North America. The most uncommon and usually, but not always, mild.15,16 important North American hantavirus is SNV. The reservoir of SNV is s the deer mouse, Peromyscus maniculatus, a species that is widespread , Hantavirus Pulmonary Syndrome, Hantavirus Hemorrhagic Fever With Renal Syndrome, and Bunyavirus Hemorrhagic Fever Rift Valley Fever in the United States and readily enters homes and other structures. On RVFV is maintained in sub-Saharan Africa via transovarial transmission the East Coast, the closely related New York virus causes chronic infection in certain floodwater-breeding Aedes mosquitoes, notably Aedes mcin- of the white-footed mouse, Peromyscus leucopus. Somewhat more distantly toshi.17 Infected eggs can remain dormant but viable in soil for years related viruses are Bayou and Black Creek Canal viruses found in the while awaiting heavy rains for subsequent hatching. Other mosquitoes southern United States and Florida, respectively, and are associated are important during epizootics and epidemics; large domestic ungulates, with a degree of renal failure in their clinical picture. The most important such as sheep or cattle, serve as amplifiers because they experience high South American virus is Andes virus, which is a common cause of viremia during infection.18 In 1977 the virus was introduced into Egypt, disease in Argentina and Chile and is the only hantavirus that has producing widespread epidemic disease in humans and domestic animals; caused person-to-person transmission.34 it reappeared in the 1990s. After an extensive epidemic in Kenya in 1997–98, it was introduced into the Arabian peninsula, where it also Transmission to Humans caused epidemic disease in animals and humans.19,20 Heavy rainfall in California Encephalitis Virus Group East Africa resulted in a major recurring epidemic in 2006–07.21 It is LACV transmission occurs through the bite of female mosquitoes that likely that other receptive areas, such as North America, might experience have viral infection of their salivary glands. Human infection occurs the same fate if an introduction should occur.22 mainly during the summer and early fall in persons entering forested areas for recreation or those living near forests. Members of A. triseriatus Crimean-Congo Hemorrhagic Fever (eastern tree-hole mosquito) range a considerable distance from forest Crimean-Congo hemorrhagic fever virus (CCHFV) is transmitted by across open terrain in search of a blood meal and breed effectively in ticks. It was first described in Russian soldiers in theC rimea in 1944 some manufactured containers, such as abandoned tires, bringing the and named Crimean fever. Subsequently, an identical virus was isolated mosquito range closer to human habitation.35 Jamestown Canyon virus from an ill child in the Congo in 1956 and was named Congo virus. has also been isolated from multiple mosquito species and various After the viruses were shown to be identical, they were renamed mammals (see later). Crimean-Congo hemorrhagic fever virus.23–25 The principal vectors belong to the genus Hyalomma. Immature stages feed on hares, Rift Valley Fever hedgehogs, and ground-feeding birds, whereas adults parasitize large RVF in Africa has two main modes of transmission. It is recognized as wild and domestic animals. This virus is widely distributed in south- a disease of farmers, veterinarians, and abattoir workers who have close western Russia, the Balkans, the Middle East, central Asia, western contact with blood shed from sick domestic livestock or fresh carcasses China, and Africa, and between 1998 and 2013, CCHF was reported containing a high concentration of virus.18 Another major route of most frequently in Turkey, Russia, Iran, Pakistan, and Afghanistan.26,27 transmission to humans is from mosquito bites, particularly during The incidence of CCHF appears to be increasing, and possible causes epidemics. Infrequent years of heavy precipitation trigger the dormant include alterations in agricultural and domestic animal practices and transovarially infected eggs, and other secondary vectors widely dis- climate changes.28 seminate virus.18,22 Hantaviruses Crimean-Congo Hemorrhagic Fever Hantaviruses cause two forms of severe acute illness: hemorrhagic fever CCHFV infects humans principally by the bite of adult Hyalomma with renal syndrome (HFRS), caused by hantaviruses of the Old World, ticks. Milkers and shepherds are frequent victims. Asymptomatically and hantavirus cardiopulmonary syndrome (HCPS), also known as viremic sheep and cattle have been implicated in transmission to abattoir hantavirus pulmonary syndrome (HPS), caused by hantaviruses of the workers, even outside known endemic areas,36 and it is also hazardous New World. These ga ents are fundamentally parasites of wild rodents to crush infected ticks. Highly infectious blood from patients also has 29 and insectivores. As such, hantaviruses are the exception to the general caused several alarming nosocomial outbreaks with fatalities in medical s rule that bunyaviruses are arthropod-borne viruses. Although many personnel, particularly when the correct diagnosis of the index case rodent species worldwide have been shown to be infected, each of the was not suspected.37–39 These have followed direct contact with blood presently recognized viral species has a single major rodent host species. and body fluids40,41 and with aerosol generating procedures.42 This species becomes chronically infected despite an immune response that eliminates viremia, and its members excrete virus in urine and Hantaviruses saliva for weeks or months.30,31 Mechanisms of intraspecific transmission Aerosols of virus-contaminated rodent urine or perhaps feces are thought depend largely on horizontal transmission between sexually mature to represent the principal vehicle for the transmission of hantaviruses; animals.31 Hantaan virus (HTNV) is the cause of HFRS in Korea, China, disease has also followed the bite of infected rodents because saliva and eastern Russia and is carried by the striped field mouse,A podemus contains virus, although this appears to be much less frequent.43,44 agrarius. A. agrarius is found in or near cultivars of humans; rodent Infections from Apodemus or Clethrionomys are acquired principally breeding seasons and human agricultural practices result in fall and by persons visiting or working in forests and on farms. Depending on spring disease peaks.32,33 Dobrava virus, associated with Aedes flavicollis, the circumstances, the incidence may be highest in summer or in fall is the major cause of severe HFRS in the Balkans, and related viruses and early winter. Disease is maximal in “high-rodent” years, when cause similarly severe disease in other areas of the former Soviet Union. suburban residents may be exposed to disposing of infected rodents.32–34,45 2172 Deer mice are numerous and readily enter human dwellings and melena, epistaxis, hematuria, and hemoptysis.57 Clinical manifestations outbuildings, particularly when mouse populations are high or in in the prehemorrhagic period include fever, malaise, myalgia, dizziness, autumn when food and cover are scarce. Abundant rodent populations and, in some patients, , , and lasting for an s led to a large number of cases in the southwestern United States in the average of about 3 days. The hemorrhagic phase usually begins on days ent summer of 1993 and resulted in the first discovery of the virus. Most 3 to 5 after the onset of illness and is usually short, lasting on average g hantavirus epidemic years have been associated with increased rodent 2 to 3 days. Cerebral hemorrhage, gingival bleeding, and bleeding from 33,34 ic A populations. the nose, vagina, uterus, or urinary tract may occur, as well as internal g bleeding in abdominal muscles. Cerebral hemorrhage and massive liver CLINICAL MANIFESTATIONS necrosis indicate a poor prognosis. Hepatomegaly and splenomegaly tiolo E CaliforniaCalifornia EnEncephalitiscephalitis VirVirusus GGroup may occur in up to 40% of the patients. Death generally occurs Infection of humans by CE viruses is most commonly asymptomatic. on days 5 to 14 of illness and is attributed to hemorrhages, hemorrhagic After an of 3 to 7 days, however, individuals may pneumonia, or cardiovascular disturbances. Lethal cases typically do experience mild febrile illness, encephalitis, or meningoencephalitis. not develop an antibody response. The mortality rate has been reported Greater than 90% of acute central nervous system (CNS) disease caused to average around 30% but may range from about 5% to greater by LACV occurs in children younger than 15 years; males are affected than 80%.58 more often than females, and the mortality in acute CNS disease is about 1%.1,10,46–48 LACV infection has caused encephalitis in an Hantaviruses immunocompromised adult with a presentation resembling herpes Hemorrhagic Fever With Renal Syndrome simplex encephalitis.47 Clinically and pathologically, CE is difficult to The hallmarks of clinical infection by HTN, Dobrava, SEO, and Puumala distinguish from other acute viral infections of the CNS. It can range viruses and other Eurasian hantaviruses are fever, thrombocytopenia, ectious Diseases and Their f in severity from mild aseptic meningitis to a severe disease mimicking and acute renal insufficiency, pathologically typical of acute interstitial In herpes simplex encephalitis. Computed tomographic scans are abnormal nephritis. The incubation period, typically 2 weeks, may vary from 5 I in a minority of cases, magnetic resonance imaging is sometimes positive, to 42 days. In the severe form of HFRS exemplified by HTNV infection and either can yield focal images.10 The electroencephalogram is abnormal or Dobrava virus in Europe, patients who survive full-blown disease

Part II in two-thirds of patients, often with focal findings that include periodic progress through febrile (toxic), hypotensive, oliguric, and polyuric lateralizing epileptiform discharges (PLEDs) that lead to a suspicion of clinical stages and may require weeks or months to recover from general herpes simplex encephalitis.48 PLEDs often localize to the temporal asthenia.59–61 lobe and are associated with more severe disease (e.g., convulsions, In the toxic phase patients complain of headache, abdominal and intubation, prolonged intensive care unit stay) as well as sequelae (e.g., lower back pain, dizziness, and often blurred vision.56–59 Conjunctival epilepsy, cognitive and memory deficits).49 Fever, headache, nausea, injection and petechiae occur over the upper trunk and soft palate. An and vomiting are present in most patients. Lethargy, aphasia, incoordina- erythematous flush that blanches on pressure is characteristically seen tion, and focal motor abnormalities, even , may be present, on the torso and face. Leukocyte levels are normal or more likely elevated, but the outstanding serious finding is convulsions, which occur in about often exceeding 20,000/mm3. The differential count shows a left shift, one-half of cases. The cerebrospinal fluid (CSF) generally shows a modest immature myeloid cells, and atypical lymphocytes as well, confirming pleocytosis (<100 white blood cells [WBCs]/mm3) that occasionally is the decreased thrombocyte count. At the end of the febrile period (4–7 largely granulocytic and exhibits a normal or slightly increased protein days), many patients experience severe clinical shock. Those surviving concentration. Peripheral leukocytosis in excess of 15,000 WBCs/mm3 then endure varied grades of renal insufficiency that can include anuria, is not uncommon. Although most patients make uneventful recoveries, oliguria, mucosal bleeding diathesis, electrolyte and acid-base abnormali- abnormal electroencephalographic findings 1 to 5 years later are present ties, hypertension, and pneumonitis complicated by . in 75%, emotional lability is persistent in 10%, and epilepsy is a chronic After 3 to 10 days, polyuria begins with attendant stresses on the fluid problem in 6% to 10% of all diagnosed cases. Frank neurologic deficit and electrolyte balance. The fatality rate in severe HFRS caused by is uncommon but does occur.46 Thus the residua of LAC encephalitis Hantaan or Dobrava viruses averages about 5%: one-third during the may be more serious than is generally appreciated. A possible congenital shock phases and two-thirds (cerebrovascular accidents and pulmonary infection with LACV has been reported, without apparent abnormalities edema) during the renal phases of illness. to the neonate. LACV infection during pregnancy has been associated Pathogenic hantaviruses enter endothelial cells via β3 integrins, with teratogenic effects in rabbits,g erbils, and sheep.50–52 which can result in disruption of cell-to-cell adhesion and in permeability alterations. This may result in an acute capillary leak syndrome, which Rift Valley Fever accounts for varied clinical manifestations that are seen in hantavirus- RVFV infection in humans causes undifferentiated febrile disease in associated diseases,62,63 including hemodynamic changes. The renal the great majority of instances. The incubation period lasts 2 to 6 days lesions, predominantly in medullary tubules, may be related to both and is followed by fever and malaise, often accompanied by headache, systemic and intrarenal hemodynamic factors and to the influence of photophobia, and back and joint pain.53,54 Perhaps 10% of patients immunopathologically released kinins and cytokines.64 Bradykinin has experience macular and perimacular retinitis, and vasculitis that may been implicated in this regard,65,66 and complement activation has been cause a permanent loss of vision. In as much as 1% of infections, ful- noted, involving both classical and alternative pathways.67,68 Complement minant disease with hemorrhage, jaundice, and hepatitis may develop components C3 and C5 appear to be linked to observed disorders of at the end of a 3- to 6-day febrile episode, with high mortality.55 Other coagulation and fibrinolysis cascades.69 infections (<1%) lead to severe, frequently fatal, encephalitis directly The milder form of HFRS caused by Puumala virus, often referred related to viral invasion of the CNS. to as nephropathia epidemica, is rarely hemorrhagic and is fatal in less than 1% of clinical cases. and renal dysfunction may Crimean-Congo Hemorrhagic Fever be manifestations. Up to 90% of Puumala virus infections are asymp- CCHF is generally a mild febrile illness but one that may progress to tomatic. Proteinuria, creatinine elevation, and leukocytosis are common severe and fatal hemorrhagic disease.56 CCHF has a distinct course of but are much less severe than in HTNV infection.70,71 infection in humans with four differentp hases: incubation, prehemor- SEOV also causes a mild to moderately severe HFRS in Eurasia, rhagic, hemorrhagic, and convalescence period. After infection via tick with more prominent hepatic involvement than classic HFRS.59,72 bite, the incubation period is usually short, ranging on average between 1 and 5 days. The incubation period after contact with infected blood Hantavirus Pulmonary Syndrome or tissues is usually 5 to 6 days, with a documented maximum of 13 HPS begins with a febrile prodrome, followed by a severe increase in days.57 The first evidence of disease is usually a flushing of the face and pulmonary vascular permeability and shock.64,73,74 If hypoxia is managed the pharynx and a rash that progresses to petechiae, ecchymoses, and shock is not fatal, the vascular leak reverses in a few days and hemorrhage of mucous membranes and conjunctiva, hematemesis, recovery is virtually complete, although renal and other sequelae have 2173 been suggested.75 The firsty s mptoms are fever of sudden onset and useful in diagnosis, particularly in severe cases. The RT-PCR assay generalized myalgia. This prodrome resembles the initial phases of HFRS provides additional sensitivity with no loss of specificity. Antibodies and may also be accompanied by abdominal pain and gastrointestinal detectable by a variety of methods generally appear within 5 to 14 days Cha (GI) disturbances.73 About 4 to 5 days later (range, 1–10 days) the of onset and coincide with clinical improvement. ELISA detection of 18,36,37,82 patient presents with respiratory symptoms, which usually consist of IgM antibodies is a reliable, definitive method. Because of the p modest cough and dyspnea. Examination may be unrevealing, but in aerosol hazard to laboratory personnel, acute samples must be handled ter 166 general fever, tachycardia, and tachypnea are present, perhaps with with care, and attempts to isolate these two agents should be restricted mild hypotension. Laboratory abnormalities commonly found at this to facilities with maximal containment. time or developing within 1 to 2 days thereafter are an elevated hema- California Encephaliti tocrit; leukocytosis, left shift, or both; abnormal (atypical) lymphocytes Hantaviruses and immature myeloid cells on smear; mild thrombocytopenia; a Virtually all hantavirus patients have both IgM and IgG ELISA antibodies prolonged activated partial thromboplastin time; and mildly elevated present when admitted to the hospital.60 Hantaviruses can be recovered aspartate aminotransferase or lactate dehydrogenase (LDH) levels. Mild only with difficulty in cell culture or animal hosts,31 but the agent can increases in serum creatinine levels and proteinuria occur in some be detected in blood or tissues by RT-PCR or in tissues by immuno- cases,34 but the severe renal lesions seen in HFRS are not a regular histochemical staining.76,79,83

64,76 s feature of this syndrome. Respiratory involvement can progress from , Hantavirus Pulmonary Syndrome, Hantavirus Hemorrhagic Fever With Renal Syndrome, and Bunyavirus Hemorrhagic Fever mild desaturation and interstitial pulmonary edema to florid pulmonary THERAPY edema with respiratory failure in a matter of hours.74,77 HPS should be TherapyTherapy w iwithth th the antiviral drug Ribavirin, a guanosine analogue, has suspected when an otherwise healthy adult develops unexplained been shown to be effective in the treatment of HFRS in a double-blind pulmonary edema or is suspected of adult respiratory distress syndrome placebo-controlled study in China using the intravenous dosing regimen without one of the known causes of this syndrome being present; established for (see Chapter 167). Intensive monitoring and thrombocytopenia or a decreasing platelet count is a particularly useful frequent dialysis, even without ribavirin, result in very low mortality. finding early in the course.74 Extracorporeal membrane oxygenation An open-label trial of ribavirin failed to show any efficacy in HPS may improve survival but has never been tested in a controlled trial.78 patients, perhaps because death typically occurs within 24 to 48 hours The histopathologic findings of interstitial infiltrates of T lymphocytes of hospitalization.75 and alveolar pulmonary edema without marked necrosis or polymorpho- Studies in vitro and in laboratory animals suggest that ribavirin also nuclear leukocyte involvement, plus the rapid resolution of the lesion, might be effective in the treatment of severe RVF and CCHF, and suggest that the major abnormality may be the induction of a functional observational clinical experience with the drug in CCHF supports its vascular permeability increase via an immunopathologic mechanism.76,79 use.84,85 However, a recent Cochrane Database review states that there is “insufficient evidence to show whether ribavirin is effective in treating DIAGNOSIS CCHF” and that appropriately designed clinical trials are necessary. 86,87 A widewide varietyvariety of laboratory tests have been developed to establish a Ribavirin also has activity in vitro against LACV, and treatment of one diagnosis of infections with bunyaviruses. The applicability and availability unusual case of LACV infection diagnosed with brain biopsy has been of laboratory tests vary with the ecology and pathobiology of individual reported.88 bunyaviruses. Serologic diagnosis is most frequently used for many The possible effectiveness of treatment with immune plasma was bunyavirus infections, and most patients will have serum immunologic examined in HPS in 29 confirmed cases in Chile (2008–12). The case evidence of infection once they present clinically. The presence of fatality rate was 4 per 29 (14%) in cases treated with convalescent plasma, virus-specific IgM may provide evidence for a recent infection but is compared with 18 per 66 (27%) in HPS cases who were not treated generally less specific than a rise in IgG titers in acute and convalescent with plasma at the same study sites (P = .15).89 Further studies are serum specimens. required to investigate this observation. Virus detection by conventional tissue culture techniques is difficult Effective supportive care is important in all of the severe bunyavirus for most bunyaviruses. However, viral detection by highly sensitive and diseases. Careful management of , cerebral edema, and seizures specific molecular techniques for viral detection have now been developed is critical in CE patients; there is danger in too vigorous use of pheno- for many bunyaviruses. barbital in children with status epilepticus.10,48,88 Early management of Availability of and expertise with individual bunyavirus laboratory hantavirus patients should avoid excessive administration of fluids in tests vary with geographic locale and frequency of infections encountered. these febrile, hemoconcentrated, hypotensive patients. Vascular leak Readers are urged to consult local public health authorities if questions leads to extravasation into retroperitoneal tissues (HFRS) or lung (HPS); arise. cardiotonic drugs should be used early because of the hemodynamic Laboratory diagnosis for individual groups of bunyaviruses are profile of decreased cardiac output and increased systemic vascular described later. resistance.64 Patients with severe HFRS may require hemodialysis or peritoneal dialysis during the oliguric phase, and plasma protein or California Encephalitis whole blood, or both, may be useful in treating hemorrhage or shock, The diagnosis of CE is by serologic means because virus is usually not or both, in this and other hemorrhagic fevers. Heparin is not recom- present in blood or secretions by the time patients present with the mended for the treatment of presumptive or incipient disseminated clinical phase of CNS disease. The diagnosis can be rapidly and specifically intravascular coagulation in HFRS. Patients with mild HFRS due to achieved with ELISAs for antiviral IgM antibodies in blood and CSF, Puumala virus rarely require dialysis. s which are usually, but not always, positive at the time of admission.10,80 A licensed indirect fluorescent antibody test is available for IgG and PREVENTION IgM antibodies to LACV and may be useful in the diagnosis.11 An HI PreventionPrevention of bunyavirusbunyav diseases currently is accomplished primarily assay is also available and may be more sensitive but may require by personal means (e.g., avoidance of rodent contact, use of mosquito neutralization assays for confirmation.81 and tick repellents), and perhaps, in the case of LACV, by the elimination Viruses may also be detected by reverse-transcriptase polymerase of manufactured containers leading to mosquito breeding, together chain reaction (RT-PCR) and multiplex nucleotide sequencing.3 Virus with aerial spraying of slow-release insecticides over forested areas of isolation can be attempted by intracerebral inoculation of suckling mice known high A. triseriatus reproduction.90 or tissue culture in Vero cells.3 A variety of vaccines against a number of bunyaviruses have been developed and studied, but none have received widespread usage. Riff Valley Fever and Congo-Crimea Immunization of livestock against RVFV is carried out with formalin Hemorrhagic Fever Viruses inactivated and live-attenuated vaccines in parts of Africa.91,92 An RVFV and CCHFV are readily recovered from the blood of acutely ill inactivated suckling mouse–derived against CCHFV has been patients in cell cultures or suckling mice. Antigen-detection ELISA is developed in Eastern Europe,93 and CCHFV glycoprotein vaccines are 2174 also under study.94 Several inactivated virus vaccines have been developed S and L segments were derived from Bunyamwera virus, and M segments against SEOV and HTNV in Asia,95 and DNA gene–based vaccines were derived from Batai virus. Thus this virus should be considered in against hantaviruses are also under study.3 other epidemics and is a cautionary example s of the emergence of novel pathogens through viral .117 ent OTHER BUNYAVIRALES OF CONCERN g JamestownJamestown CanyonCanyon VVirusirus Severe Fever With Thrombocytopenia ic A Jamestown Canyon virus (JCV) is a member of the CE group of bun- Syndrome Virus g yaviruses that have been a likely unrecognized cause of infections and A new member of the Phlebovirus genus was isolated in China (Hubei CNS disease in North America.96,97 JCV was first identified in Jamestown and Henan provinces) from patients who presented with fever, throm- tiolo E Canyon, Colorado in 196198 and has been recovered from various bocytopenia, leukocytopenia, and multiorgan dysfunction and named mosquito species: Aedes, Coquillettidia, Culex, and Culiseta. Burgeoning severe fever with thrombocytopenia syndrome virus (SFTSV).118 The populations of whitetail deer have been suspected as a vertebrate amplifier. clinical symptoms were initially considered to resemble those of human Serologic surveys in humans and animals indicate that JCV is widespread granulocytic anaplasmosis.119 The majority of affected patients were through North America. A recent analysis of 31 laboratory-confirmed farmers living in wooded and hilly areas, and they were working in the infections of JCV indicated that most infections occurred in spring to fields before onset of clinical signs of disease. SFTSV RNA has been early fall and involved all age groups.96 Clinically recognized infections detected in ticks of the Ixodidae (Haemaphysalis longicornis, Ixodes present as an undifferentiated febrile illness, meningitis, or meningo- nipponensis, Amblyomma testudinarium) that were collected from encephalitis. Approximately half of identified infections required domestic animals where patients lived. Initially, no epidemiologic hospitalization, and deaths have not been reported to date.96 The rate evidence of human-to-human transmission of SFTSV was detected.118 of asymptomatic infections with JCV is not known.97 However, subsequent publications indicated that the virus can be ectious Diseases and Their f Partial cross-reactions exist between LACV and JCV IgM responses transmitted from person-to-person through close personal contact with In and may require plaque neutralization or RT-PCR tests to differentiate the index patient without known exposure to suspected animals or I between infections with these. vectors.120–122 Nosocomial transmission in hospital settings has also been reported.123

Part II Oropouche Virus SFTSV appears to be most closely related to the Bhanja serogroup Oropouche virus has been associated with epidemics and sporadic cases among members of the Phlebovirus genus.124 SFTSV has been detected of febrile illness in tropical areas of Brazil, Panama, and Peru.99–101 It is in central and eastern China, rural areas of South Korea, and Western transmitted by biting midges (Culicoides paraensis). In rural areas Japan.125,126 transmission may also involve nonhuman primates, , birds, and SFTS has an incubation period of 7 to 14 days and begins with a febrile mosquitoes. In urban areas Oropouche virus can be transmitted between illness, malaise, headache, GI disturbances, myalgias, and arthralgias. viremic individuals and biting midges.101–104 The risk of transmission During the second week of illness, multiorgan dysfunction can develop, appears to be highest during the rainy season, during which breeding with renal dysfunction, myocarditis, and CNS involvement.127–130 Bleeding of midges is increased.105 C. paraensis has been identified in states east manifestations, including disseminated intravascular coagulation and of the Mississippi River, but the likelihood of establishment of ecologic mucosal hemorrhage, can ensue. Disease manifestations may begin factors for virus transmission in the United States is low. to resolve over 1 to 2 weeks, but cases can continue to worsen, and The incubation period of disease in human ranges from 3 to 12 overall case fatality rates have been estimated to be 6% to 21%.129,131,132 days.99,100,106 Infection results in an abrupt onset of fever, chills, headache, Laboratory abnormalities include leukopenia, thrombocytopenia, elevated myalgia, and often vomiting and arthralgia. Aseptic meningitis has liver function tests, and elevated LDH and creatine phosphokinase levels. been reported in some cases. Symptoms last for 4 to 5 days and are The pathogenesis of SFTS appears to be related to high viral loads, usually self-limiting. However, prolonged asthenia and arthralgia can which results in a systemic inflammatory response. Marked upregulation occur, and recurrences 10 days after recovery have been observed.101 of multiple cytokines has been correlated with disease severity.133–135 Laboratory diagnosis during the first week of illness can be made Toscana Virus by detection of SFTSV in blood by RT-PCR134 or by loop-mediated The classic sand fly fevers (Sicilian and Naples viruses) are acute febrile isothermal amplification.135 illnesses with headache and myalgias and were common in the broad Therapy consists of general medical support and measures to treat European and Asian range of their vector, Phlebotomus papatasi, until bleeding diathesis. Ribavirin has in vitro activity against SFTSV and dichlorophenyltrichloroethane (DDT) campaigns against malaria virtually has been used to treat patients with SFTS in China, without apparent eliminated this sand fly in much of Europe. Another sand fly, Phlebotomus effectiveness.136 Favipiravir has been shown to be effective in vitro and perniciosus, spreads the related but distinct Toscana virus, which appears in a mouse model against SFTSV (also see Chapter 45). to be a common cause of infections in Tuscany and areas of Southern Europe.107–110 High seroprevalence rates to Toscana virus in endemic Heartland Virus areas suggest that most infections are asymptomatic or are of minimal Heartland virus is a newly recognized pathogenic bunyavirus in the symptomatology. However, Toscana virus can cause febrile disease, Phlebovirus genus, first reported from two cases in Missouri in 2012.137 aseptic meningitis, or mild encephalitis. Overall prognosis is good, As of 2017 30 cases have been reported to the Centers for Disease although severe cases have been reported. CNS infections are common Control and Prevention, all from the midwestern and southern United in the circum-Mediterranean distribution of the vector in Europe, from States.137,139 Transmission appears likely to be tick-borne, and Heartland Cyprus to Portugal and Spain, and are often causes of disease in returning virus has been detected by PCR and culture in nymphs of the Lone travelers.107,111,112 Diagnosis can usually be made serologically by detection Star tick (Amblyomma americanum), which can be found in the United of virus-specific gI M by ELISA and immunofluorescence assays, or by States from Texas to Maine.140 Neutralizing antibodies to Heartland virus neutralizing antibody rises.113 virus have been found in a wide variety of vertebrate life, including opossums, dogs, raccoons, deer, moose, horses, and coyotes,141,142 but Ngari Virus the major vertebrate host has not been identified. Human-to-human During the 1997–98 RVF outbreak in Kenya, two viruses belonging to transmission has not been reported, although such has been observed the Orthobunyavirus genus were isolated from putative hemorrhagic in infection by a related Phlebovirus (SFTSV) (see earlier). fever cases, and RT-PCR was positive in 12 sera. The virus was found Clinical manifestations of Heartland virus–associated disease consist to have the S and L RNA segments of Bunyamwera virus, but the M of fever, headache, GI disturbances, dry cough, confusion, myalgias, segment was derived from another bunyavirus, subsequently identified and arthralgias.138 Fatigue and memory loss lasting weeks to months has as Ngari virus.114 Subsequent complete genomic sequencing of Ngari been described.138 Widespread dissemination143 and fatal cases have been virus indicated that Ngari virus was a naturally occurring reassortant reported.144,145 Laboratory findings include leukopenia, thrombocytopenia, between two , Bunyamwera and Batai viruses.115,116 and elevated liver enzymes.143,146 A fatal case of Heartland virus infections 2175 with hemophagocytic lymphohistiocytosis in an immunocompromised ACKNOWLEDGMENT patient has been described.147 ThisThis c hchapterapter i sis based based o non a nandd up updated from chapters on Bunyaviridae Laboratory diagnosis of Heartland virus infection can be made by written by C.J. Peters and D.A. Bente for the previous editions of Principles Cha virus detection by RT-PCR or tissue culture, or serologically by ELISA and Practice of Infectious Diseases. 148 or plaque reduction neutralization tests. p ter 166

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