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InternalMed_Harrison. eIncludes the recently described Alkhurma/Alkhumra variant of Kyasanur Forest disease virus. fAlso known as Ganjam virus. gAlso known as Brezová virus, Cvilín virus, Kharagysh virus, Koliba virus, or Lipovník virus. hAlso known as Čalovo virus or Chittoor virus. iAlso known as Palma virus. j The final virus name has not yet been decided. Alternatives used in the literature are Huaiyangshan virus (HYSV) and Henan fever virus (HNFV). kAlso known as Astra virus and Batken virus.


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InternalMed_Harrison. The distributions of arthropod-borne and rodent-borne viruses are restricted by the areas inhabited by their reservoir hosts and/or vectors. Consequently, a patient’s geographic origin or travel history can provide important clues in the differential diagnosis. Table 233-2 lists the approximate geographic distribution of most arthropod-borne and rodent-borne infections. Many of these diseases can be acquired in either rural or urban settings; these diseases include yellow fever, dengue (previously called dengue fever), severe dengue (previously called dengue hemorrhagic fever and dengue shock syndrome), chikungunya virus disease, hemorrhagic fever with renal syndrome caused by Seoul virus, sandfly fever caused by sandfly fever Naples and Sicilian viruses, and Oropouche virus disease.


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InternalMed_Harrison. In patients with suspected viral infection, a recognized history of mosquito bite has little diagnostic significance, but a history of tick bite is more diagnostically useful. Exposure to rodents is sometimes reported by persons infected with arenaviruses or hantaviruses. Laboratory diagnosis is required in all cases, although epidemics occasionally provide enough clinical and epidemiologic clues for a presumptive etiologic diagnosis. For most arthropod-borne and rodent-borne viruses, acute-phase serum samples (collected within 3 or 4 days of onset) have yielded isolates. Paired serum samples have been used to demonstrate rising antibody titers. Intensive efforts to develop rapid tests for viral hemorrhagic fevers have resulted in reliable antigen-detection enzyme-linked immunosorbent assays (ELISAs), IgM-capture ELISAs, and multiplex polymerase chain reaction (PCR) assays. These tests can provide a diagnosis based on a single serum sample within a few hours and are particularly


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InternalMed_Harrison. assays (ELISAs), IgM-capture ELISAs, and multiplex polymerase chain reaction (PCR) assays. These tests can provide a diagnosis based on a single serum sample within a few hours and are particularly useful in patients with severe disease. More sensitive reverse-transcription PCR (RT-PCR) assays may yield diagnoses based on samples without detectable antigen and may also provide useful genetic information about the etiologic agent.


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InternalMed_Harrison. Hantavirus infections differ from other viral infections discussed here in that severe acute disease is immunopathologic; patients present with serum IgM that serves as the basis for a sensitive and specific test. At diagnosis, patients with encephalitides generally are no longer viremic or antigenemic and usually do not have virions in cerebrospinal fluid (CSF). In this situation, the value of serologic methods for IgM determination and RT-PCR is high. IgM-capture ELISA is increasingly being used for the simultaneous testing of serum and CSF. IgG ELISA or classic serology is useful in the evaluation of past exposure to viruses, many of which circulate in areas with minimal medical infrastructures and sometimes cause only mild or subclinical infection.


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InternalMed_Harrison. The spectrum of possible human responses to infection with arthropod-or rodent-borne viruses is wide, and knowledge of the outcome of most of these infections is limited. People infected with these viruses may not develop signs of illness. If viral disease is recognized, it can usually be grouped into one of five broad categories: arthritis and rash, encephalitis, fever and myalgia, pulmonary disease, or viral hemorrhagic fever (VHF) (Table 233-3). These categories often overlap. For example, infections with West Nile and Venezuelan equine Type of Diseasea Type of Diseasea


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InternalMed_Harrison. Type of Diseasea Type of Diseasea Europe Lymphocytic (Avalon) and Bhanja virus Dengue/severe Dhori and Eyach, — Chikungunya choriomeningitis/ infections; California dengue; tick-Thogoto virus Kemerovo, infections hemorrhagic fever with renal rhagic fever; syndrome; Inkoo virus infec-(Usutu virus infection; sandfly fever/Pappataci tion); West Nile fever/phlebotomus fever; virus infection Uukuniemi virus infection aQuotation marks indicate common usage in the absence of International Classification of Disease version 10 (ICD-10) recognition. Diseases not acknowledged by the ICD-10 are designated as “virus infection.” Disease names are placed in parentheses when cases are either extremely rare or controversial. aVirus names are placed in parentheses when human infections are either extremely rare or controversial.


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InternalMed_Harrison. encephalitis viruses are discussed here as encephalitides, but during epidemics many patients present with much milder febrile syndromes. Similarly, Rift Valley fever virus is best known as a cause of VHF, but the attack rates for febrile disease are far higher, and encephalitis and blindness occasionally occur as well. Lymphocytic choriomeningitis virus is classified here as a cause of fever and myalgia because this syndrome is the most common disease manifestation; even when central nervous system (CNS) disease evolves during infection with this virus, neural manifestations are usually mild and are preceded by fever and myalgia. Infection with any dengue virus type (1, 2, 3, or 4) is considered as a cause of fever and myalgia because this syndrome is by far the most common manifestation worldwide. However, severe dengue is a VHF with a complicated pathogenesis that is of tremendous importance in pediatric practice in certain areas of the world. Unfortunately, most of the known


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InternalMed_Harrison. worldwide. However, severe dengue is a VHF with a complicated pathogenesis that is of tremendous importance in pediatric practice in certain areas of the world. Unfortunately, most of the known arthropodor rodent-borne viral diseases have not been studied in detail with modern medical approaches; thus available data may be incomplete or biased. The reader must be aware that data on geographic distribution are often fuzzy: the literature frequently is not clear as to whether the data pertain to the distribution of a particular virus or the areas where human disease has been observed. In addition, the designations for viruses and viral diseases have changed multiple times over decades. Here, virus and taxon names are in line with the latest reports of the International Committee on Taxonomy of Viruses, and disease names are largely in accordance with the World Health Organization’s International Classification of Disease version 10 (ICD-10) and more recent updates.


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InternalMed_Harrison. Arthritides are common accompaniments of several viral diseases, such as hepatitis B, parvovirus B19 infection, and rubella, and occasionally accompany infection due to adenoviruses, enteroviruses, herpesviruses, and mumps virus. Two ungrouped bunyaviruses, Gan Gan virus and Trubanaman virus, and the flavivirus Kokobera virus have been associated with single cases of polyarthritic disease. Arthropod-borne alphaviruses are also common causes of arthritides—usually acute febrile diseases accompanied by the development of a maculopapular rash. Rheumatic involvement includes arthralgia alone, periarticular swelling, and (less commonly) joint effusions. Most alphavirus infections are less severe and have fewer articular manifestations in children than in adults. In temperate climates, these ailments are summer diseases. No specific therapies or licensed vaccines exist. The most important alphavirus arthritides are Barmah Forest virus infection, chikungunya virus disease, Ross River


InternalMed_Harrison

InternalMed_Harrison. ailments are summer diseases. No specific therapies or licensed vaccines exist. The most important alphavirus arthritides are Barmah Forest virus infection, chikungunya virus disease, Ross River disease, and Sindbis virus infection. A large (>2 million cases), albeit isolated, epidemic was caused by o’nyong nyong virus in 1959–1961 (o’nyong nyong fever). Mayaro, Semliki Forest, and Una viruses have caused isolated cases or limited and infrequent epidemics (30 to several hundred cases per year) in the past. Signs and symptoms of infections with these viruses often are similar to those observed with chikungunya virus disease.


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InternalMed_Harrison. Chikungunya Virus Disease Disease caused by chikungunya virus is endemic in rural areas of Africa. Intermittent epidemics take place in towns and cities of both Africa and Asia. Aedes aegypti mosquitoes are the usual vectors for the disease in urban areas. In 2004, a massive epidemic began in the Indian Ocean region (in particular on the islands of Réunion and Mauritius) and was most likely spread by travelers; Aedes albopictus was identified as the major vector of chikungunya virus during that epidemic. Between 2013 and 2014, several thousand chikungunya virus infections were reported (and several tens of thousands of cases were suspected) from Caribbean islands. The virus was imported to Italy, France, and the United States by travelers from the Caribbean. Chikungunya virus poses a threat to the continental United States as suitable vector mosquitoes are present in the southern states. The disease is most common among adults, in whom the clinical presentation may be dramatic. The


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InternalMed_Harrison. to the continental United States as suitable vector mosquitoes are present in the southern states. The disease is most common among adults, in whom the clinical presentation may be dramatic. The abrupt onset of chikungunya virus disease follows an incubation period of 2–10 days. Fever (often severe) with a saddleback pattern and severe arthralgia are accompanied by chills and constitutional symptoms and signs, such as abdominal pain, anorexia, conjunctival injection, headache, nausea, and photophobia. Migratory polyarthritis mainly affects the small 1313 joints of the ankles, feet, hands, and wrists, but the larger joints are not necessarily spared. Rash may appear at the outset or several days into the illness; its development often coincides with defervescence, which occurs around day 2 or 3 of the disease. The rash is most intense on the trunk and limbs and may desquamate. Young children develop less prominent signs and are therefore less frequently hospitalized. Children also


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InternalMed_Harrison. 2 or 3 of the disease. The rash is most intense on the trunk and limbs and may desquamate. Young children develop less prominent signs and are therefore less frequently hospitalized. Children also often develop a bullous rather than a maculopapular/ petechial rash. Maternal–fetal transmission has been reported and in some cases has led to fetal death. Recovery may require weeks, and some elderly patients may continue to experience joint pain, recurrent effusions, or stiffness for several years. This persistence of signs and symptoms may be especially common in HLA-B27-positive patients. In addition to arthritis, petechiae are occasionally seen and epistaxis is not uncommon, but chikungunya virus should not be considered a VHF agent. A few patients develop leukopenia. Elevated concentrations of aspartate aminotransferase (AST) and C-reactive protein have been described, as have mildly decreased platelet counts. Treatment of chikungunya virus disease relies on nonsteroidal


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InternalMed_Harrison. concentrations of aspartate aminotransferase (AST) and C-reactive protein have been described, as have mildly decreased platelet counts. Treatment of chikungunya virus disease relies on nonsteroidal anti-inflammatory drugs and sometimes chloroquine for refractory arthritis.


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InternalMed_Harrison. Barmah Forest Virus Infection and Ross River Disease Barmah Forest virus and Ross River virus cause diseases that are indistinguishable on clinical grounds alone (hence the previously common disease designation epidemic polyarthritis for both infections). Ross River virus has caused epidemics in Australia, Papua New Guinea, and the South Pacific since the beginning of the twentieth century and continues to be responsible for ~4800 cases of disease in rural and suburban areas annually. In 1979–1980, the virus swept through the Pacific Islands, causing more than 500,000 infections. Ross River virus is predominantly transmitted by Aedes normanensis, Aedes vigilax, and Culex annulirostris. Wallabies and rodents are probably the main vertebrate hosts. Barmah Forest virus infections have been on the rise in recent years. In 2005– 2006, roughly 2000 cases were recorded in Australia. Barmah Forest virus is transmitted by both Aedes and Culex mosquitoes and has been isolated from biting


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InternalMed_Harrison. been on the rise in recent years. In 2005– 2006, roughly 2000 cases were recorded in Australia. Barmah Forest virus is transmitted by both Aedes and Culex mosquitoes and has been isolated from biting midges. The vertebrate hosts remain to be deter mined, but serologic studies implicate horses and possums.


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InternalMed_Harrison. Of the human Barmah Forest and Ross River virus infections surveyed, 55–75% were asymptomatic; however, these viral diseases can be debilitating. The incubation period is 7–9 days; the onset of illness is sudden, and disease is usually ushered in by disabling symmetrical joint pain. A nonitchy, diffuse, maculopapular rash (more common in Barmah Forest virus infection) generally develops coincidentally or follows shortly, but in some patients it can precede joint pains by several days. Constitutional symptoms such as low-grade fever, asthenia, headache, myalgia, and nausea are not prominent or are absent in many patients. Most patients are incapacitated for considerable periods (≥6 months) by joint involvement, which interferes with grasping, sleeping, and walking. Ankle, interphalangeal, knee, metacarpophalangeal, and wrist joints are most often involved, although elbows, shoulders, and toes may also be affected. Periarticular swelling and tenosynovitis are common, and one-third of


InternalMed_Harrison

InternalMed_Harrison. knee, metacarpophalangeal, and wrist joints are most often involved, although elbows, shoulders, and toes may also be affected. Periarticular swelling and tenosynovitis are common, and one-third of patients have true arthritis (more common in Ross River disease). Myalgia and nuchal stiffness may accompany joint pains. Only half of all patients with arthritis can resume normal activities within 4 weeks, and 10% still must limit their activity after 3 months. Occasional patients are symptomatic for 1–3 years but without progressive arthropathy.


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InternalMed_Harrison. In the diagnosis of either infection, clinical laboratory values are normal or variable. Tests for rheumatoid factor and antinuclear antibodies are negative, and the erythrocyte sedimentation rate is acutely elevated. Joint fluid contains 1000–60,000 mononuclear cells/μL, and viral antigen can usually be detected in macrophages. IgM antibodies are valuable in the diagnosis of this infection, although such antibodies occasionally persist for years. Isolation of the virus from blood after mosquito inoculation or growth of the virus in cell culture is possible early in the illness. Because of the great economic impact of annual epidemics in Australia, an inactivated Ross River virus vaccine is under development. Nonsteroidal anti-inflammatory drugs such as naproxen or acetylsalicylic acid are effective for treatment.


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InternalMed_Harrison. 1314 Sindbis Virus Infection Sindbis virus is transmitted among birds by infected mosquitoes. Infections with northern European or southern African variants are particularly likely in rural environments. After an incubation period of <1 week, Sindbis virus infection begins with rash and arthralgia. Constitutional clinical signs are not marked, and fever is modest or lacking altogether. The rash, which lasts ~1 week, begins on the trunk, spreads to the extremities, and evolves from macules to papules that often vesiculate. The arthritis is multiarticular, migratory, and incapacitating, with resolution of the acute phase in a few days; the ankles, elbows, knees, phalangeal joints, wrists, and—to a much lesser extent—proximal and axial joints are involved. Persistence of joint pain and occasionally of arthritis is a major problem and may continue for months or even years despite lack of deformities.


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InternalMed_Harrison. Zika Virus Infection Zika virus is an emerging pathogen that is transmitted among nonhuman primates and humans by Aedes mosquitoes. Human infections are usually benign and are most likely misdiagnosed as dengue or influenza. Zika virus infection is characterized by influenza-like clinical signs, including fever, headaches, and malaise. A maculopapular rash, conjunctivitis, myalgia, and arthralgia usually accompany or follow those manifestations. Zika virus infection was first documented in Africa in 1947 and was later recognized in southeastern and southern Asia. In recent years, the number of Zika virus infections reported from Micronesia and Polynesia has increased steadily.


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InternalMed_Harrison. The major encephalitis viruses are found in the families Bunyaviridae, Flaviviridae, Rhabdoviridae, and Togaviridae. However, individual agents of other families, including Dhori virus and thogotovirus (Orthomyxoviridae) as well as Banna virus (Reoviridae), have been known to cause isolated cases of encephalitis as well. Arboviral encephalitides are seasonal diseases, commonly occurring in the warmer months. Their incidence varies markedly with time and place, depending on ecologic factors. The causative viruses differ substantially in terms of case–infection ratio (i.e., the ratio of clinical to sub-clinical infections), lethality rate, and residual disease. Humans are not important amplifiers of these viruses.


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InternalMed_Harrison. All the viral encephalitides discussed in this section have a similar pathogenesis. An infected arthropod ingests blood from a human and thereby initiates infection. The initial viremia is thought to originate from the lymphoid system. Viremia leads to multifocal entry into the CNS, presumably through infection of olfactory neuroepithelium, with passage through the cribriform plate; “Trojan horse” entry with infected macrophages; or infection of brain capillaries. During the viremic phase, there may be little or no recognizable disease except in tick-borne flavivirus encephalitides, which may manifest with clearly delineated phases of fever and systemic illness.


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InternalMed_Harrison. CNS lesions arise partly from direct neuronal infection and subsequent damage and partly from edema, inflammation, and other indirect effects. The usual pathologic features of arboviral encephalitides are focal necroses of neurons, inflammatory glial nodules, and perivascular lymphoid cuffing. Involved areas display the “luxury perfusion” phenomenon, with normal or increased total blood flow and low oxygen extraction. The typical patient presents with a prodrome of nonspecific constitutional signs and symptoms, including fever, abdominal pain, sore throat, and respiratory signs. Headache, meningeal signs, photophobia, and vomiting follow quickly. The severity of human infection varies from an absence of signs/symptoms to febrile headache, aseptic meningitis, and full-blown encephalitis. The proportions and severity of these manifestations vary with the infecting virus. Involvement of deeper brain structures in less severe cases may be signaled by lethargy, somnolence, and intellectual


InternalMed_Harrison

InternalMed_Harrison. proportions and severity of these manifestations vary with the infecting virus. Involvement of deeper brain structures in less severe cases may be signaled by lethargy, somnolence, and intellectual deficit (as disclosed by the mental status examination). More severely affected patients are obviously disoriented and may become comatose. Tremors, loss of abdominal reflexes, cranial nerve palsies, hemiparesis, monoparesis, difficulty swallowing, limb-girdle syndrome, and frontal lobe signs are all common. Spinal and motor neuron diseases are documented after West Nile and Japanese encephalitis virus infections. Seizures and focal signs may be evident early or may appear during the course of the disease. Some patients present with an abrupt onset of fever, convulsions, and other signs of CNS involvement. The acute encephalitis usually lasts from a few days to as long as 2–3 weeks. The infections may be fatal, or recovery may be slow, with weeks or months required for the return of maximal


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InternalMed_Harrison. The acute encephalitis usually lasts from a few days to as long as 2–3 weeks. The infections may be fatal, or recovery may be slow, with weeks or months required for the return of maximal recoupable function, or incomplete, with persisting long-term deficits. Difficulty concentrating, fatigability, tremors, and personality changes are common during recovery.


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InternalMed_Harrison. The diagnosis of arboviral encephalitides depends on the careful evaluation of a febrile patient with CNS disease and the performance of laboratory studies to determine etiology. Clinicians should (1) consider empirical acyclovir treatment for herpesvirus meningoencephalitis and antibiotic treatment for bacterial meningitis until test results are received; (2) exclude intoxination and metabolic or oncologic causes, including paraneoplastic syndromes, hyperammonemia, liver failure, and anti-NMDA receptor encephalitis; and (3) rule out a brain abscess or a stroke. Leptospirosis, neurosyphilis, Lyme disease, cat-scratch disease, and more recently described viral encephalitides (e.g., Nipah virus infection) should be considered if epidemiologically relevant. CSF examination usually shows a modest increase in leukocyte counts—in the tens or hundreds or perhaps a few thousand. Early in the process, a significant proportion of these leukocytes may be polymorphonuclear, but mononuclear cells


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InternalMed_Harrison. increase in leukocyte counts—in the tens or hundreds or perhaps a few thousand. Early in the process, a significant proportion of these leukocytes may be polymorphonuclear, but mononuclear cells are usually predominant later. CSF glucose concentrations are generally normal. There are exceptions to this pattern of findings: in eastern equine encephalitis, for example, polymorphonuclear leukocytes may predominate during the first 72 h of disease and hypoglycorrhachia may be detected. In lymphocytic choriomeningitis/meningoencephalitis, lymphocyte counts may be in the thousands, and the glucose concentration may be diminished. A humoral immune response is usually detectable at or near the onset of disease. Both serum (acuteor convalescent-phase) and CSF should be examined for IgM antibodies and viruses by plaque-reduction neutralization assay and/or (RT)-PCR. Virus generally cannot be isolated from blood or CSF, although Japanese encephalitis virus has been recovered from CSF of patients


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InternalMed_Harrison. viruses by plaque-reduction neutralization assay and/or (RT)-PCR. Virus generally cannot be isolated from blood or CSF, although Japanese encephalitis virus has been recovered from CSF of patients with severe disease. RT-PCR analysis of CSF may yield positive results. Viral antigen is present in brain tissue, although its distribution may be focal. Electroencephalography usually shows diffuse abnormalities and is not directly helpful.


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InternalMed_Harrison. Experience with medical imaging is still evolving. Both computed tomography (CT) and magnetic resonance imaging (MRI) scans may be normal except for evidence of preexisting conditions or occasional diffuse edema. Imaging is generally nonspecific in that most patients do not present with pathognomonic lesions, but it can be used to rule out other suspected causes of disease. It is important to remember that imaging may yield negative results if done early in the disease course but later may detect lesions. For example, eastern equine encephalitis (focal abnormalities) and severe Japanese encephalitis (hemorrhagic bilateral thalamic lesions) have caused lesions detectable by medical imaging.


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InternalMed_Harrison. Comatose patients may require management of intracranial pressure elevations, inappropriate secretion of antidiuretic hormone, respiratory failure, or seizures. Specific therapies for these viral encephalitides are not available. The only practical preventive measures are vector management and personal protection against the arthropod transmitting the virus. For Japanese encephalitis or tick-borne viral encephalitis, vaccination should be considered in certain circumstances (see relevant sections below).


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InternalMed_Harrison. Bunyaviruses: California (Meningo)encephalitis The isolation of California encephalitis virus established California serogroup orthobunyaviruses as causes of encephalitides. However, California encephalitis virus has been implicated in only a very few cases of encephalitis, whereas its close relative, La Crosse virus, is the major cause of encephalitis in this serogroup (~70 cases per year in the United States). California (meningo)encephalitis due to La Crosse virus infection is most commonly reported from the upper Midwest of the United States but is also found in other areas of the central and eastern parts of the country, most often in West Virginia, Tennessee, North Carolina, and Georgia. The serogroup includes 13 other viruses, some of which (e.g., Inkoo, Jamestown Canyon, Lumbo, snowshoe hare, and Tahyña viruses) also cause human disease. Transovarial transmission is a strong component of transmission of the California serogroup viruses in Aedes and Ochlerotatus mosquitoes. The


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InternalMed_Harrison. hare, and Tahyña viruses) also cause human disease. Transovarial transmission is a strong component of transmission of the California serogroup viruses in Aedes and Ochlerotatus mosquitoes. The mosquito vector of La Crosse virus is Ochlerotatus triseriatus. In addition to transovarial transmission, acquisition through feeding on viremic chipmunks and other mammals as well as venereal transmission can result in infection of this mosquito. O. triseriatus breeds in sites such as tree holes and abandoned tires and bites during daylight hours. The habits of this mosquito correlate with the risk factors for human cases: recreation in forested areas, residence at a forest’s edge, and the presence of water-containing abandoned tires around the home. Intensive environmental modification based on these findings has reduced the incidence of disease in a highly endemic area in the U.S. Midwest.


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InternalMed_Harrison. Most humans are infected from July through September. The Asian tiger mosquito (A. albopictus) efficiently transmits La Crosse virus to mice and also transmits the agent transovarially in the laboratory; this aggressive anthropophilic mosquito has the capacity to urbanize, and its possible impact on transmission of virus to humans is of concern. The prevalence of antibody to La Crosse virus in humans is ≥20% in endemic areas, a figure indicating that infection is common but often asymptomatic. CNS disease has been recognized primarily in children <15 years of age.


InternalMed_Harrison

InternalMed_Harrison. The illness from La Crosse virus varies from aseptic meningitis accompanied by confusion to severe and occasionally fatal encephalitis (lethality rate, <0.5%). The incubation period is ~3–7 days. Although there may be prodromal symptoms/signs, the onset of CNS disease is sudden, with fever, headache, and lethargy often joined by nausea and vomiting, convulsions (in one-half of patients), and coma (in one-third of patients). Focal seizures, hemiparesis, tremor, aphasia, chorea, Babinski signs, and other evidence of significant neurologic dysfunction are common, but residual disease is not. Approximately 10% of patients have recurrent seizures in the succeeding months. Other serious sequelae of La Crosse virus infection are rare, although a decrease in scholastic standing in children has been reported and mild personality change has occasionally been suggested.


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InternalMed_Harrison. The blood leukocyte count is commonly elevated in patients with La Crosse virus infection, sometimes reaching 20,000/μL, and is usually accompanied by a left shift. CSF leukocyte counts are typically 30–500/μL with a mononuclear cell predominance (although 25–90% of cells are polymorphonuclear in some patients). The blood protein concentration is normal or slightly increased, and the glucose concentration is normal. Specific virologic diagnosis based on IgM-capture assays of serum and CSF is efficient. The only human anatomic site from which virus has been isolated is the brain. Treatment is supportive over a 1to 2-week acute phase during which status epilepticus, cerebral edema, and inappropriate secretion of antidiuretic hormone are important concerns. A phase 2B clinical trial of IV ribavirin in children with La Crosse virus infection was discontinued during dose escalation because of adverse effects.


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InternalMed_Harrison. Jamestown Canyon virus has been implicated in several cases of encephalitis in adults, usually with a significant respiratory illness at onset. Human infection with this virus has been documented in New York, Wisconsin, Ohio, Michigan, Ontario, and other areas of North America where the vector mosquito, Aedes stimulans, feeds on its main host, the white-tailed deer. Tahyña virus can be found in central Europe, Russia, China, and Africa. The virus is a prominent cause of febrile disease but can also cause pharyngitis, pulmonary syndromes, aseptic meningitis, or meningoencephalitis.


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InternalMed_Harrison. Flaviviruses The most important flavivirus encephalitides are Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, and West Nile virus infection. Australian encephalitis (Murray Valley encephalitis) and Rocio virus infection resemble Japanese encephalitis but are documented only occasionally in Australia and Brazil, respectively. Powassan virus has caused ~50 cases of often-severe disease (lethality rate, ~10%), frequently occurring among children in eastern Canada and the United States. Usutu virus has caused only individual cases of human infection, but such infections may be underdiagnosed.


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InternalMed_Harrison. japanese encepHalitis Japanese encephalitis is the most important viral encephalitis in Asia. Each year 35,000–50,000 cases and more than 15,000 deaths are reported. Japanese encephalitis virus is found 1315 throughout Asia, including far eastern Russia, Japan, China, India, Pakistan, and southeastern Asia, and causes occasional epidemics on western Pacific islands. The virus has been detected in the Torres Strait islands, and five human encephalitis cases have been identified on the nearby Australian mainland. The virus is particularly common in areas where irrigated rice fields attract the natural avian vertebrate hosts and provide abundant breeding sites for mosquitoes such as Culex tritaeniorhynchus, which transmit the virus to humans. Additional amplification by pigs, which suffer abortion, and horses, which develop encephalitis, may be significant as well. Vaccination of these additional amplifying hosts may reduce the transmission of the virus.


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InternalMed_Harrison. Clinical signs of Japanese encephalitis emerge after an incubation period of 5–15 days and range from an unspecific febrile presentation (nausea, vomiting, diarrhea, cough) to aseptic meningitis, meningoencephalitis, acute flaccid paralysis, and severe encephalitis. Common findings are cerebellar signs, cranial nerve palsies, and cognitive and speech impairments. A Parkinsonian presentation and seizures are typical in severe cases. Effective vaccines are available. Vaccination is indicated for summer travelers to rural Asia, where the risk of acquiring Japanese encephalitis is considered to be about 1 per 5000 to 1 per 20,000 travelers per week if travel duration exceeds 3 weeks. Usually two intramuscular doses of the vaccine are given 28 days apart, with the second dose administered at least 1 week prior to travel.


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InternalMed_Harrison. st. loUis encepHalitis St. Louis encephalitis virus is transmitted between mosquitoes and birds. This virus causes a low-level endemic infection among rural residents of the western and central United States, where Culex tarsalis is the vector (see “Western Equine Encephalitis,” below). The more urbanized mosquitoes Culex pipiens and Culex quinquefasciatus have been responsible for epidemics resulting in hundreds or even thousands of cases in cities of the central and eastern United States. Most cases occur in June through October. The urban mosquitoes breed in accumulations of stagnant water and sewage with high organic content and readily feed on humans in and around houses at dusk. The elimination of open sewers and trash-filled drainage systems is expensive and may not be possible, but screening of houses and implementation of personal protective measures may be an effective approach to the prevention of infection. The rural mosquito vector is most active at dusk and outdoors; its


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InternalMed_Harrison. screening of houses and implementation of personal protective measures may be an effective approach to the prevention of infection. The rural mosquito vector is most active at dusk and outdoors; its bites can be avoided by modification of activities and use of repellents.


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InternalMed_Harrison. Disease severity increases with age. St. Louis encephalitis virus infections that result in aseptic meningitis or mild encephalitis are concentrated among children and young adults, while severe and fatal cases primarily affect the elderly. Infection rates are similar in all age groups; thus the greater susceptibility of older persons to disease is a biologic consequence of aging. St. Louis encephalitis has an abrupt onset after an incubation period of 4–21 days, sometimes following a prodrome, and begins with fever, lethargy, confusion, and headache. In addition, nuchal rigidity, hypotonia, hyperreflexia, myoclonus, and tremors are common. Severe cases can include cranial nerve palsies, hemiparesis, and seizures. Patients often report dysuria and may have viral antigen in urine as well as pyuria. The overall rate of lethality is generally ~7% but may reach 20% among patients >60 years of age. Recovery is slow. Emotional lability, difficulties with concentration and memory, asthenia,


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InternalMed_Harrison. pyuria. The overall rate of lethality is generally ~7% but may reach 20% among patients >60 years of age. Recovery is slow. Emotional lability, difficulties with concentration and memory, asthenia, and tremors are commonly prolonged in older convalescent patients. The CSF of patients with St. Louis encephalitis usually contains tens to hundreds of leukocytes, with a lymphocytic predominance and a left shift. The CSF glucose concentration is normal in these patients.


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InternalMed_Harrison. tick-borne viral encepHalitis Tick-borne encephalitis viruses are currently subdivided into four groups: the western/European subtype (previously called central European encephalitis virus), the (Ural-) Siberian subtype (previously called Russian spring-summer encephalitis virus), the Far Eastern subtype, and the louping ill subtype (previously called louping ill virus or, in Japan, Negishi virus). Small mammals and grouse, deer, and sheep are the vertebrate amplifiers for these viruses, which are transmitted by ticks. The risk of infection varies by geographic area and can be highly localized within a given area; human 1316 infections usually follow either outdoor activities resulting in tick bites or consumption of raw (unpasteurized) milk from infected goats or, less commonly, from other infected animals (cows, sheep). Milk seems to represent the main transmission route for louping ill viruses, which cause disease only very rarely. The western/European subtype viruses are


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InternalMed_Harrison. from other infected animals (cows, sheep). Milk seems to represent the main transmission route for louping ill viruses, which cause disease only very rarely. The western/European subtype viruses are transmitted mainly by Ixodes ricinus from Scandinavia to the Ural Mountains. (Ural-)Siberian viruses are transmitted predominantly by Ixodes persulcatus from Europe across the Ural Mountains to the Pacific Ocean; louping ill viruses seem to be confined primarily to Great Britain. Several thousand infections with tick-borne encephalitis virus are recorded each year among people of all ages. Human tick-borne viral encephalitis occurs between April and October, with a peak in June and July. Western/European viruses classically caused bimodal disease. After an incubation period of 7–14 days, the illness begins with a fever– myalgia phase (arthralgia, fever, headaches, myalgia, nausea) that lasts for 2–4 days and is thought to correlate with viremia. A subsequent remission for several days is


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InternalMed_Harrison. illness begins with a fever– myalgia phase (arthralgia, fever, headaches, myalgia, nausea) that lasts for 2–4 days and is thought to correlate with viremia. A subsequent remission for several days is followed by the recurrence of fever and the onset of meningeal signs. The CNS phase (7–10 days before onset of improvement) varies from mild aseptic meningitis, which is more common among younger patients, to severe (meningo-)encephalitis with coma, seizures, tremors, and motor signs. Spinal and medullary involvement can lead to typical limb-girdle paralysis and respiratory paralysis. Most patients with western/European virus infections recover (lethality rate, 1%), and only a minority of patients have significant deficits. However, the lethality rate from (Ural-)Siberian virus infections reaches 7–8%. Infections with Far Eastern viruses generally run a more abrupt course. The encephalitic syndrome caused by these viruses sometimes begins without a remission from the fever–myalgia phase


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InternalMed_Harrison. 7–8%. Infections with Far Eastern viruses generally run a more abrupt course. The encephalitic syndrome caused by these viruses sometimes begins without a remission from the fever–myalgia phase and has more severe manifestations than the western/European syndrome. The lethality rate is high (20–40%), and major sequelae—most notably, lower motor neuron paralyses of the proximal muscles of the extremities, trunk, and neck—are common, developing in approximately one-half of patients. Thrombocytopenia sometimes develops during the initial febrile illness, resembling the early hemorrhagic phase of some other tick-borne flavivirus infections, such as Kyasanur Forest disease. In the early stage of the illness, virus may be isolated from the blood. In the CNS phase, IgM antibodies are detectable in serum and/or CSF. Diagnosis of tick-borne viral encephalitis primarily relies on serology and detection of viral genomes by RT-PCR. There is no specific therapy for infection. However, effective


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InternalMed_Harrison. in serum and/or CSF. Diagnosis of tick-borne viral encephalitis primarily relies on serology and detection of viral genomes by RT-PCR. There is no specific therapy for infection. However, effective alum-adjuvanted, formalin-inactivated virus vaccines are produced in Austria, Germany, and Russia in chicken embryo cells (FSME-Immun® and Encepur®). Two doses of the Austrian vaccine separated by an interval of 1–3 months appear to be effective in the field, and antibody responses are similar when vaccine is given on days 0 and 14. Because rare cases of postvaccination Guillain-Barré syndrome have been reported, vaccination should be reserved for persons likely to experience rural exposure in an endemic area during the season of transmission. Cross-neutralization for the western/European and Far Eastern variants has been established, but there are no published field studies on cross-protection among formalin-inactivated vaccines. Because 0.2–4% of ticks in endemic areas may be infected,


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InternalMed_Harrison. Far Eastern variants has been established, but there are no published field studies on cross-protection among formalin-inactivated vaccines. Because 0.2–4% of ticks in endemic areas may be infected, the use of immunoglobulin prophylaxis of tick-borne viral encephalitis has been raised. Prompt administration of high-titered specific antibody preparations should probably be undertaken, although no controlled data are available to prove the efficacy of this measure. Immunoglobulins should be considered because of the risk of antibody-mediated enhancement of infection or antigen–antibody complex deposition in tissues.


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InternalMed_Harrison. west nile virUs infection West Nile virus is now the primary cause of arboviral encephalitis in the United States. In 2012, 2873 cases of neuroinvasive disease (e.g., meningitis, encephalitis, acute flaccid paralysis), with 270 deaths, and 2801 cases of non-neuroinvasive infection were reported. West Nile virus was initially described as being transmitted among wild birds by Culex mosquitoes in Africa, Asia, and southern Europe. In addition, the virus has been implicated in severe and fatal hepatic necrosis in Africa. West Nile virus was introduced into New York City in 1999 and subsequently spread to other areas of the northeastern United States, causing die-offs among crows, exotic zoo birds, and other birds. The virus has continued to spread and is now found in almost all states as well as in Canada, Mexico, South America, and the Caribbean islands. C. pipiens remains the major vector in the northeastern United States, but several other Culex species and A. albopictus are also


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InternalMed_Harrison. well as in Canada, Mexico, South America, and the Caribbean islands. C. pipiens remains the major vector in the northeastern United States, but several other Culex species and A. albopictus are also involved. Jays compete with crows and other corvids as amplifiers and lethal targets in other areas of the country.


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InternalMed_Harrison. West Nile virus is a common cause of febrile disease without CNS involvement (incubation period, 3–14 days), but it occasionally causes aseptic meningitis and severe encephalitis, particularly among the elderly. The fever–myalgia syndrome caused by West Nile virus differs from that caused by other viruses in terms of the frequent—rather than occasional—appearance of a maculopapular rash concentrated on the trunk (especially in children) and the development of lymphadenopathy. Back pain, fatigue, headache, myalgia, retroorbital pain, sore throat, nausea and vomiting, and arthralgia (but not arthritis) are common accompaniments that may persist for several weeks. Encephalitis, sequelae, and death are all more common among elderly, diabetic, and hypertensive patients and among patients with previous CNS insults. In addition to the more severe motor and cognitive sequelae, milder findings may include tremor, slight abnormalities in motor skills, and loss of executive functions. Intense


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InternalMed_Harrison. previous CNS insults. In addition to the more severe motor and cognitive sequelae, milder findings may include tremor, slight abnormalities in motor skills, and loss of executive functions. Intense clinical interest and the availability of laboratory diagnostic methods have made it possible to define a number of unusual clinical features. Such features include chorioretinitis, flaccid paralysis with histologic lesions resembling poliomyelitis, and initial presentation with fever and focal neurologic deficits in the absence of diffuse encephalitis. Immunosuppressed patients may have fulminant courses or develop persistent CNS infection. Virus transmission through both transplantation and blood transfusion has necessitated screening of blood and organ donors by nucleic acid–based tests. Occasionally, pregnant women infect their fetuses with West Nile virus.


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InternalMed_Harrison. Rhabdoviruses: Chandipura Virus Infection Chandipura virus seems to be an emerging and increasingly important human virus in India, where it is transmitted among hedgehogs by mosquitoes and sandflies. In humans, the disease begins as an influenza-like illness, with fever, headache, abdominal pain, nausea, and vomiting; these manifestations are followed by neurologic impairment and infection-related or autoimmune-mediated encephalitis. Chandipura virus infection is characterized by high lethality in children. Several hundred cases of infection are recorded in India every year. Infections with other arthropod-borne rhabdoviruses (Isfahan, Piry, vesicular stomatitis Indiana, vesicular stomatitis New Jersey) may imitate the early febrile stage of Chandipura virus infection.


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InternalMed_Harrison. Togaviruses • eastern eQUine encepHalitis This disease is encountered primarily in swampy foci along the eastern coast of the United States, with a few inland foci as far removed as Michigan. Infected humans present for medical care from June through October. During this period, the bird–Culiseta mosquito cycle spills over into other mosquitoes such as Aedes sollicitans or Aedes vexans, which are more likely to feed on mammals. There is concern over the potential role of the introduced anthropophilic mosquito species A. albopictus, which has been found to be infected with eastern equine encephalitis virus and is an effective experimental vector in the laboratory. Horses are a common target for the virus. Contact with unvaccinated horses may be associated with human disease, but horses probably do not play a significant role in amplification of the virus.


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InternalMed_Harrison. Eastern equine encephalitis is one of the most destructive of the arboviral diseases, with a sudden onset after an incubation period of ~5–10 days, rapid progression, 50–75% lethality, and frequent sequelae in survivors. This severity is reflected in the extensive necrotic lesions and polymorphonuclear infiltrates found at postmortem examination of the brain. Acute polymorphonuclear CSF pleocytosis, often occurring during the first 1–3 days of disease, is another indication of severity. In addition, leukocytosis with a left shift is a common feature. A formalin-inactivated vaccine has been used to protect laboratory workers but is not generally available or applicable.


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InternalMed_Harrison. venezUelan eQUine encepHalitis Venezuelan equine encephalitis viruses are separated into epizootic viruses (subtypes IA/B and IC) and enzootic viruses (subtypes ID, IE, and IF). Closely related enzootic viruses are Everglades virus, Mucambo virus, and Tonate virus. Enzootic viruses are found primarily in humid tropical-forest habitats and are maintained between culicoid mosquitoes and rodents. These viruses cause human disease but are not pathogenic for horses and do not cause epizootics. Enzootic viruses are common causes of acute febrile disease. Everglades virus has caused encephalitis in humans in Florida. Extrapolation from the rate of genetic change suggests that Everglades virus may have been introduced into Florida <200 years ago. Everglades virus is most closely related to the ID subtype viruses that appear to have given evolutionary rise to the epizootic variants active in South America.


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InternalMed_Harrison. Epizootic viruses have an unknown natural cycle but periodically cause extensive epizootics/epidemics in equids and humans in the Americas. These epizootics/epidemics are the result of high-level viremia in horses and mules, which transmit the infection to several types of mosquitoes. Infected mosquitoes in turn infect humans and perpetuate virus transmission. Humans also have high-level viremia, but their role in virus transmission is unclear. Epizootics of Venezuelan equine fever occurred repeatedly in South America at intervals of ≤10 years from the 1930s until 1969, when a massive epizootic spread throughout Central America and Mexico, reaching southern Texas in 1971. Genetic sequencing suggested that the virus from that outbreak originated from residual “un-inactivated” IA/B subtype virus in veterinary vaccines. The outbreak was terminated in Texas with a live attenuated vaccine (TC-83) originally developed for human use by the


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InternalMed_Harrison. U.S. Army; the epizootic virus was then used for further production of inactivated veterinary vaccines. No further epizootic disease was identified until 1995, when additional epizootics took place in Colombia, Venezuela, and Mexico. The viruses involved in these epizootics as well as previously epizootic IC viruses are close phylogenetic relatives of known enzootic ID viruses. This finding suggests that active evolution and selection of epizootic viruses are under way in South America.


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InternalMed_Harrison. During epizootics, extensive human infection is the rule, with clinical disease in 10–60% of infected individuals. Most infections result in notable acute febrile disease, while relatively few infections (5–15%) result in neurologic disease. A low rate of CNS invasion is supported by the absence of encephalitis among the many infections resulting from exposure to aerosols in the laboratory setting or from vaccination accidents. The most recent large epizootic of Venezuelan equine fever occurred in Colombia and Venezuela in 1995; of the more than 85,000 clinical cases, 4% (with a higher proportion among children than adults) included neurologic symptoms/signs, and 300 cases ended in death.


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InternalMed_Harrison. The prevention of epizootic Venezuelan equine fever depends on vaccination of horses with the attenuated TC-83 vaccine or with an inactivated vaccine prepared from that variant. Enzootic viruses are genetically and antigenically different from epizootic viruses, and protection against the former with vaccines prepared from the latter is relatively ineffective. Humans can be protected by immunization with similar vaccines prepared from Everglades virus, Mucambo virus, and Venezuelan equine encephalitis virus, but the use of the vaccines is restricted to laboratory personnel because of reactogenicity, possible fetal pathogenicity, and limited availability.


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InternalMed_Harrison. western eQUine encepHalitis The primary maintenance cycle of western equine encephalitis virus in the United States is between C. tarsalis and birds, principally sparrows and finches. Equids and humans become infected, and both suffer encephalitis without amplifying the virus in nature. St. Louis encephalitis virus is transmitted in a similar cycle in the same regions harboring western equine encephalitis virus; disease caused by the former occurs about a month earlier than that caused by the latter (July through October). Large epidemics of western equine encephalitis occurred in the western and central United States and Canada during the 1930s through 1950s, but in recent years the disease has been uncommon. From 1964 through 2010, only 640 cases were reported in the United States. This decline in incidence may reflect in part the integrated approach to mosquito management that has been employed in irrigation projects and the increasing use of 1317 agricultural pesticides. The


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InternalMed_Harrison. This decline in incidence may reflect in part the integrated approach to mosquito management that has been employed in irrigation projects and the increasing use of 1317 agricultural pesticides. The decreased incidence of western equine encephalitis almost certainly reflects the increased tendency for humans to be indoors behind closed windows at dusk—the peak biting period by the major vector.


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InternalMed_Harrison. After an incubation period of ~5–10 days, western equine encephalitis virus causes a typical diffuse viral encephalitis, with an increased attack rate and increased morbidity among the young, particularly children <2 years old. In addition, the lethality rate is high among the young and the very elderly (3–7% overall). One-third of individuals who have convulsions during the acute illness have subsequent seizure activity. Infants <1 year old—particularly those in the first months of life—are at serious risk of motor and intellectual damage. Twice as many males as females develop clinical encephalitis after 5–9 years of age. This difference in incidence may be related to greater outdoor exposure of boys to the vector but may also be due in part to biologic differences. A formalin-inactivated vaccine has been used to protect laboratory workers but is not generally available.


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InternalMed_Harrison. The fever and myalgia syndrome is most commonly associated with zoonotic virus infection. Many of the numerous viruses listed in Table 233-1 probably cause at least a few cases of this syndrome, but only some of these viruses have prominent associations with the syndrome and are of biomedical importance. The fever and myalgia syndrome typically begins with the abrupt onset of fever, chills, intense myalgia, and malaise. Patients may also report joint or muscle pains, but true arthritis is not found. Anorexia is characteristic and may be accompanied by nausea or even vomiting. Headache is common and may be severe, with photophobia and retroorbital pain. Physical findings are minimal and are usually confined to conjunctival injection with pain on palpation of muscles or the epigastrium. The duration of symptoms/signs is quite variable (generally 2–5 days), with a biphasic course in some instances. The spectrum of disease varies from sub-clinical to temporarily incapacitating. Less


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InternalMed_Harrison. The duration of symptoms/signs is quite variable (generally 2–5 days), with a biphasic course in some instances. The spectrum of disease varies from sub-clinical to temporarily incapacitating. Less constant findings include a nonpruritic maculopapular rash. Epistaxis may occur but does not necessarily indicate a bleeding diathesis. A minority of the patients may develop aseptic meningitis. This diagnosis is difficult to make in remote areas, given patients’ photophobia and myalgia as well as the lack of opportunity to examine the CSF. Although pharyngitis or radiographic evidence of pulmonary infiltrates is found in some patients, the agents causing this syndrome are not primary respiratory pathogens.


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InternalMed_Harrison. The differential diagnosis includes anicteric leptospirosis, rickettsial diseases, and the early stages of other syndromes discussed in this chapter. The fever and myalgia syndrome is often described as “influenza-like,” but the usual absence of cough and coryza makes influenza an unlikely confounder except at the earliest stages. Treatment is supportive, but acetylsalicylic acid is avoided because of the potential for exacerbated bleeding or Reye’s syndrome. Complete recovery is the general outcome for people with this syndrome, although prolonged asthenia and nonspecific symptoms have been described in some patients, particularly after infection with lymphocytic choriomeningitis virus or dengue virus types 1–4.


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InternalMed_Harrison. Efforts at prevention of viral infection are best based on vector control, which, however, may be expensive or impossible. For mosquito control, destruction of breeding sites is generally the most economically and environmentally sound approach. Emerging containment technologies include the release of genetically modified mosquitoes and the spread of Wolbachia bacteria to limit mosquito multiplication rates. Depending on the vector and its habits, other possible approaches include the use of screens or other barriers (e.g., permethrin-impregnated bed nets) to prevent the vector from entering dwellings, judicious application of arthropod repellents such as N,N,-diethyltoluamide (DEET) to the skin, wearing of long-sleeved and ideally permethrin-impregnated clothing, and avoidance of the vectors’ habitats and times of peak activity.


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InternalMed_Harrison. Arenaviruses Lymphocytic choriomeningitis/meningoencephalitis is the only human arenavirus infection resulting predominantly in fever 1318 and myalgia. Lymphocytic choriomeningitis virus is transmitted to humans from the common house mouse (Mus musculus) by aerosols of excreta and secreta. The virus is maintained in the mouse mainly by vertical transmission from infected dams. The vertically infected mouse remains viremic and sheds virus for life, with high concentrations of virus in all tissues. Infected colonies of pet hamsters also can serve as a link to humans. Infections among scientists and animal caretakers can occur because the virus is widely used in immunology laboratories as a model of T cell function and can silently infect cell cultures and passaged tumor lines. In addition, patients may have a history of residence in rodent-infested housing or other exposure to rodents. An antibody prevalence of ~5–10% has been reported among adults from Argentina, Germany, and the


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InternalMed_Harrison. patients may have a history of residence in rodent-infested housing or other exposure to rodents. An antibody prevalence of ~5–10% has been reported among adults from Argentina, Germany, and the United States. Lymphocytic choriomeningitis/meningoencephalitis differs from the general syndrome of fever and myalgia in that the onset is gradual. Conditions occasionally associated with the disease are orchitis, transient alopecia, arthritis, pharyngitis, cough, and maculopapular rash. An estimated one-fourth of patients (or fewer) experience a febrile phase of 3–6 days. After a brief remission, many develop renewed fever accompanied by severe headache, nausea and vomiting, and meningeal signs lasting for ~1 week (the CNS phase). These patients virtually always recover fully, as do the rare patients with clear-cut signs of encephalitis. Recovery may be delayed by transient hydrocephalus. During the initial febrile phase, leukopenia and thrombocytopenia are common, and virus can usually be


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InternalMed_Harrison. with clear-cut signs of encephalitis. Recovery may be delayed by transient hydrocephalus. During the initial febrile phase, leukopenia and thrombocytopenia are common, and virus can usually be isolated from blood. During the CNS phase, the virus may be found in the CSF, and antibodies are present in the blood. The pathogenesis of lymphocytic choriomeningitis/meningoencephalitis is thought to resemble that following direct intracranial inoculation of the virus into adult mice. The onset of the immune response leads to T cell–mediated immunopathologic meningitis. During the meningeal phase, CSF mononuclear-cell counts range from the hundreds to the low thousands per microliter, and hypoglycorrhachia is found in one-third of patients. IgM-capture ELISA, immunochemistry, and RT-PCR are used in the diagnosis of lymphocytic choriomeningitis/meningoencephalitis. IgM-capture ELISA of serum and CSF usually yields positive results; RT-PCR assays have been developed for probing CSF. Because


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InternalMed_Harrison. in the diagnosis of lymphocytic choriomeningitis/meningoencephalitis. IgM-capture ELISA of serum and CSF usually yields positive results; RT-PCR assays have been developed for probing CSF. Because patients who have fulminant infections transmitted by recent organ transplantation do not mount an immune response, immunohistochemistry or RT-PCR is required for diagnosis. Infection should be suspected in acutely ill febrile patients with marked leukopenia and thrombocytopenia. In patients with aseptic meningitis, any of the following suggests lymphocytic choriomeningitis/meningoencephalitis: a well-marked febrile prodrome, adult age, occurrence in the autumn, low CSF glucose levels, or CSF mononuclear-cell counts of >1000/μL. In pregnant women, infection may lead to fetal invasion with consequent congenital hydrocephalus and chorioretinitis. Because the maternal infection may be mild, causing only a short febrile illness, antibodies to the virus should be sought in both the mother and the


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InternalMed_Harrison. congenital hydrocephalus and chorioretinitis. Because the maternal infection may be mild, causing only a short febrile illness, antibodies to the virus should be sought in both the mother and the fetus under suspicious circumstances, particularly in TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and HIV)–negative neonatal hydrocephalus.


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InternalMed_Harrison. Bunyaviruses Numerous bunyaviruses cause fever and myalgia. Many of these viruses cause individual infections and usually do not result in epidemics—e.g., the viruses of the orthobunyavirus Anopheles A serogroup (e.g., Tacaiuma virus), Bwamba serogroup (Bwamba virus, Pongola virus), Guama serogroup (Catu virus, Guama virus), Nyando serogroup (Nyando virus), and Wyeomyia serogroup (Wyeomyia virus); the unclassified bunyavirus Tataguine virus; the phlebovirus Bhanja complex (Bhanja virus, Heartland virus) and Candiru complex (Alenquer, Candiru, Escharate, Maldonado, Morumbi, and Serra Norte viruses); the hantavirus Choclo virus; and the Dugbe and Nairobi sheep disease nairoviruses. In the relevant orthobunyaviral Bunyamwera serogroup (Bunyamwera, Batai, Cache Valley, Fort Sherman, Germiston, Guaroa, Ilesha, Ngari, Shokwe, and Xingu viruses), Ngari virus recently has been implicated in a large epidemic in Africa.


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InternalMed_Harrison. ortHobUnyavirUs groUp c serogroUp Apeú, Caraparú, Itaquí, Madrid, Marituba, Murutucú, Nepuyo, Oriboca, Ossa, Restan, and Zungarococha viruses are among the most common causes of arboviral infection in humans entering South American jungles. These viruses cause acute febrile disease and are transmitted by mosquitoes in neotropical forests. ortHobUnyavirUs simbU serogroUp Oropouche virus is transmitted in Central and South America by a biting midge, Culicoides paraensis, which often breeds to high density in cacao husks and other vegetable detritus found in towns and cities. Explosive epidemics involving thousands of patients have been reported from several towns in Brazil and Peru. Rash and aseptic meningitis have been detected in a number of patients. Iquitos virus, a recently discovered reassortant and close relative of Oropouche virus, causes disease that is easily mistaken for Oropouche virus disease; its overall epidemiologic significance remains to be determined.


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InternalMed_Harrison. pHlebovirUs sandfly fever serogroUp A previous designation for sandfly fever, “3-day fever,” instructively describes the brief debilitating course associated with this essentially benign infection. There is neither a rash nor CNS involvement, and complete recovery is the rule. Sandfly fever is caused by at least six distinct phleboviruses of the phlebovirus sandfly fever serocomplex (Chagres virus, sandfly fever Cyprus virus, sandfly fever Naples virus, sandfly fever Sicilian virus, sandfly fever Turkey virus, and Toscana virus). Sandfly fever Naples virus, sandfly fever Sicilian virus, and Toscana viruses are the most important human pathogens of this group. Phlebotomus sandflies transmit the viruses, probably among small mammals, and infect humans by bites. Female sandflies may be infected by the oral route as they take a blood meal and may transmit the virus to offspring when they lay their eggs after a second blood meal. This prominent transovarial transmission confounds virus


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InternalMed_Harrison. by the oral route as they take a blood meal and may transmit the virus to offspring when they lay their eggs after a second blood meal. This prominent transovarial transmission confounds virus control.


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InternalMed_Harrison. Sandfly fever is found in the circum-Mediterranean area, extending to the east through the Balkans into parts of China as well as into western Asia. Chagres virus is endemic in Panama. Sandflies are found in both rural and urban settings and are known for their short flight ranges and their small sizes; the latter enables them to penetrate standard mosquito screens and netting. Epidemics have been described in the wake of natural disasters and wars. After World War II, extensive spraying in parts of Europe to control malaria greatly reduced sandfly populations and sandfly fever Naples virus transmission; the incidence of sandfly fever continues to be low.


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InternalMed_Harrison. A common pattern of disease in endemic areas consists of high attack rates among travelers and military personnel and little or no disease in the local population, who are protected after childhood infection. Toscana virus infection is common during the summer among rural residents and vacationers, particularly in Italy, Spain, and Portugal; a number of cases have been identified in travelers returning to Germany and Scandinavia. The disease may manifest as an uncomplicated febrile illness but is often associated with aseptic meningitis, with virus isolated from the CSF.


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InternalMed_Harrison. Punta Toro virus is a phlebovirus that is not part of the sandfly fever serocomplex but that, like the members of this complex, is transmitted by sandflies. Punta Toro virus causes a sandfly fever–like disease in the Latin American tropical forest, where the vectors rest on tree buttresses. Epidemics have not been reported, but antibody prevalence among inhabitants of villages in endemic areas indicates a cumulative lifetime exposure rate of >50%.


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InternalMed_Harrison. Flaviviruses The most clinically important flaviviruses that cause the fever and myalgia syndrome are dengue viruses 1–4. In fact, dengue is probably the most important arthropod-borne viral disease worldwide, with 50–100 million infections occurring per year. Year-round transmission of dengue viruses 1–4 occurs between latitudes of 25°N and 25°S, but seasonal forays of the viruses into the United States and Europe have been documented. All four viruses have A. aegypti as their principal vector. Through increasing spread of mosquitoes throughout the tropics and subtropics and international travel of infected humans, large areas of the world have become vulnerable to the introduction of dengue viruses. Thus, dengue and severe dengue (see “Viral Hemorrhagic Fevers,” below) are becoming increasingly common. For instance, conditions favorable to dengue virus 1–4 transmission via A. aegypti exist in Hawaii and the southern United States. The range of a lesser dengue virus vector, A.


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InternalMed_Harrison. increasingly common. For instance, conditions favorable to dengue virus 1–4 transmission via A. aegypti exist in Hawaii and the southern United States. The range of a lesser dengue virus vector, A. albopictus, now extends from Asia to the United States, the Indian Ocean, parts of Europe, and Hawaii.


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InternalMed_Harrison. A. aegypti typically breeds near human habitation, using relatively fresh water from sources such as water jars, vases, discarded containers, coconut husks, and old tires. The mosquito usually inhabits dwellings and bites during the day. Bursts of dengue cases are to be expected in the southern United States, particularly along the Mexican border, where containers of water may be infested with A. aegypti. Closed habitations with air-conditioning may inhibit transmission of many arboviruses, including dengue viruses 1–4.


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InternalMed_Harrison. Dengue begins after an incubation period averaging 4–7 days, when the typical patient experiences the sudden onset of fever, frontal headache, retroorbital pain, and back pain along with severe myalgias. These symptoms gave rise to the colloquial designation of dengue as “break-bone fever.” Often a transient macular rash appears on the first day, as do adenopathy, palatal vesicles, and scleral injection. The illness may last a week, with additional symptoms and clinical signs usually including anorexia, nausea or vomiting, and marked cutaneous hypersensitivity. Near the time of defervescence on days 3–5, a maculopapular rash begins on the trunk and spreads to the extremities and the face. Epistaxis and scattered petechiae are often noted in uncomplicated dengue, and preexisting gastrointestinal lesions may bleed during the acute illness.


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InternalMed_Harrison. Laboratory findings of dengue include leukopenia, thrombocytopenia, and, in many cases, elevations of serum aminotransferase concentrations. The diagnosis is made by IgM ELISA or paired serology during recovery or by antigen-detection ELISA or RT-PCR during the acute phase. Virus is readily isolated from blood in the acute phase if mosquito inoculation or mosquito cell culture is used.


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InternalMed_Harrison. Reoviruses Several orbiviruses (Lebombo, Kemerovo, Orungo, and Tribeč viruses) and coltiviruses (Colorado tick fever, Eyach, and Salmon River viruses) can cause fever and myalgia in humans. With the exception of Lebombo and Orungo viruses, all of these viruses are transmitted by ticks. The most important reoviral arthropod-borne disease is Colorado tick fever. Several hundred patients with this disease are reported annually in the United States. The infection is acquired between March and November through the bite of an infected ixodid tick, the Rocky Mountain wood tick (Dermacentor andersoni), in mountainous western regions at altitudes of 1200–3000 m. Small mammals serve as amplifying hosts. The most common presentation is fever and myalgia; meningoencephalitis is not uncommon, and hemorrhagic disease, pericarditis, myocarditis, orchitis, and pulmonary presentations have also been reported. Rash develops in a minority of patients. Leukopenia and thrombocytopenia are also noted. The


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InternalMed_Harrison. disease, pericarditis, myocarditis, orchitis, and pulmonary presentations have also been reported. Rash develops in a minority of patients. Leukopenia and thrombocytopenia are also noted. The disease usually lasts 7–10 days and is often biphasic. The most important differential diagnostic considerations since the beginning of the twentieth century have been Rocky Mountain spotted fever (although Colorado tick fever is much more common in Colorado) and tularemia. Colorado tick fever virus replicates for several weeks in erythropoietic cells and can be found in erythrocytes. This feature, detected in erythroid smears stained by immunofluorescence, can be diagnostically helpful and is important during screening of blood donors.


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InternalMed_Harrison. Hantavirus pulmonary syndrome (HPS) was first described in 1993, but retrospective identification of cases by immunohistochemistry (1978) and serology (1959) support the idea that HPS is a recently discovered rather than a truly new disease. The causative agents are hantaviruses of a distinct phylogenetic lineage that is associated with the cricetid rodent subfamily Sigmodontinae. Sin Nombre virus, which chronically infects North American deer mice (Peromyscus maniculatus), is the most important agent of HPS in the United States. Several other related viruses (Anajatuba, Andes, Araraquara, Araucária, Bayou, Bermejo, Black Creek Canal, Blue River, Castelo dos Sonhos, El Moro Canyon, Juquitiba, Laguna Negra, Lechiguanas, Maciel, Monongahela, Muleshoe, New York, Orán, Paranoá, Pergamino, Río Mamoré, and Tunari) cause the disease in North and South America, 1319 but Andes virus is unusual in that it has been implicated in human-tohuman transmission. HPS particularly affects rural


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InternalMed_Harrison. Río Mamoré, and Tunari) cause the disease in North and South America, 1319 but Andes virus is unusual in that it has been implicated in human-tohuman transmission. HPS particularly affects rural residents living in dwellings permeable to rodent entry or working in occupations that pose a risk of rodent exposure. Each type of rodent has its own particular habits; in the case of deer mice, these behaviors include living in and around human habitation.


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InternalMed_Harrison. HPS begins with a prodrome of ~3–4 days (range, 1–11 days) comprising fever, malaise, myalgia, and—in many cases—gastrointestinal disturbances such as abdominal pain, nausea, and vomiting. Dizziness is common and vertigo occasional. Severe prodromal symptoms/ signs may bring some patients to medical attention, but most cases are recognized as the pulmonary phase begins. Typical signs are slightly lowered blood pressure, tachycardia, tachypnea, mild hypoxemia, thrombocytopenia, and early radiographic signs of pulmonary edema. Physical findings in the chest are often surprisingly scant. The conjunctival and cutaneous signs of vascular involvement seen in hantavirus VHFs (see below) are uncommon. During the next few hours, decompensation may progress rapidly to severe hypoxemia and respiratory failure.


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InternalMed_Harrison. The HPS differential diagnosis includes abdominal surgical conditions and pyelonephritis as well as rickettsial disease, sepsis, meningococcemia, plague, tularemia, influenza, and relapsing fever. A specific diagnosis is best made by IgM antibody testing of acute-phase serum, which has yielded positive results even in the prodrome. Tests using a Sin Nombre virus antigen detect antibodies to the related HPS-causing hantaviruses. Occasionally, heterotypic viruses will react only in the IgG ELISA, but such a finding is highly suspicious given the very low seroprevalence of these viruses in normal populations. RT-PCR is usually positive when used to test blood clots obtained in the first 7–9 days of illness and when used to test tissues; this assay is useful in identifying the infecting virus in areas outside the home range of deer mice and in atypical cases.


InternalMed_Harrison

InternalMed_Harrison. During the prodrome, the differential diagnosis of HPS is difficult, but by the time of presentation or within 24 h thereafter, a number of diagnostically helpful clinical features become apparent. Cough usually is not present at the outset. Interstitial edema is evident on a chest x-ray. Later, bilateral alveolar edema with a central distribution develops in the setting of a normal-sized heart; occasionally, the edema is initially unilateral. Pleural effusions are often seen. Thrombocytopenia, circulating atypical lymphocytes, and a left shift (often with leukocytosis) are almost always evident; thrombocytopenia is a particularly important early clue. Hemoconcentration, hypoalbuminemia, and proteinuria should also be sought for diagnosis. Although thrombocytopenia virtually always develops and prolongation of the partial thromboplastin time is the rule, clinical evidence for coagulopathy or laboratory indications of disseminated intravascular coagulation (DIC) are found in only a


InternalMed_Harrison

InternalMed_Harrison. and prolongation of the partial thromboplastin time is the rule, clinical evidence for coagulopathy or laboratory indications of disseminated intravascular coagulation (DIC) are found in only a minority of severely ill patients. Patients with severe illness also have acidosis and elevated serum lactate concentrations. Mildly increased values in renal function tests are common, but patients with severe HPS often have markedly elevated serum creatinine concentrations. Some New World hantaviruses other than Sin Nombre virus (e.g., Andes virus) have been associated with more kidney involvement, but few such cases have been studied.


InternalMed_Harrison

InternalMed_Harrison. Management of HPS during the first few hours after presentation is critical. The goal is to prevent severe hypoxemia by oxygen therapy, with intubation and intensive respiratory management if needed. During this period, hypotension and shock with increasing hematocrit invite aggressive fluid administration, but this intervention should be undertaken with great caution. Because of low cardiac output with myocardial depression and increased pulmonary vascular permeability, shock should be managed expectantly with pressors and modest infusion of fluid guided by pulmonary capillary wedge pressure. Mild cases can be managed by frequent monitoring and oxygen administration without intubation. Many patients require intubation to manage hypoxemia and developing shock. Extracorporeal membrane oxygenation is instituted in severe cases, ideally before the onset of shock. The procedure is indicated in patients who have a cardiac index of 2.3 L/min/m2 or an arterial oxygen tension/fractional


InternalMed_Harrison

InternalMed_Harrison. oxygenation is instituted in severe cases, ideally before the onset of shock. The procedure is indicated in patients who have a cardiac index of 2.3 L/min/m2 or an arterial oxygen tension/fractional inspired oxygen (PaO2/FiO2) ratio of 1320 <50 and who are unresponsive to conventional support. Lethality rates remain at ~30–40% even with good management, but most patients surviving the first 48 h of hospitalization are extubated and discharged within a few days with no apparent long-term residua. The antiviral drug ribavirin inhibits hantaviruses in vitro but did not have a marked effect on patients treated in an open-label study.


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InternalMed_Harrison. VHF is a constellation of findings based on vascular instability and decreased vascular integrity. An assault, direct or indirect, on the microvasculature leads to increased permeability and (particularly when platelet function is decreased) to actual disruption and local hemorrhage (a positive tourniquet sign). Blood pressure is decreased, and in severe cases shock supervenes. Cutaneous flushing and conjunctival suffusion are examples of common, observable abnormalities in the control of local circulation. Hemorrhage occurs infrequently. In most patients, hemorrhage is an indication of widespread vascular damage rather than a life-threatening loss of blood volume. In some VHFs, specific organs may be particularly impaired. For instance, the kidneys are primary targets in hemorrhagic fever with renal syndrome (HFRS), and the liver is a primary target in yellow fever and filovirus diseases. However, in all of these diseases, generalized circulatory disturbance is critically important.


InternalMed_Harrison

InternalMed_Harrison. with renal syndrome (HFRS), and the liver is a primary target in yellow fever and filovirus diseases. However, in all of these diseases, generalized circulatory disturbance is critically important. The pathogenesis of VHF is poorly understood and varies among the viruses regularly implicated in the syndrome. In some viral infections, direct damage to the vascular system or even to parenchymal cells of target organs is an important factor; in other viral infections, soluble mediators are thought to play a major role in the development of hemorrhage or fluid redistribution.


InternalMed_Harrison

InternalMed_Harrison. The acute phase in most cases of VHF is associated with ongoing virus replication and viremia. VHFs begin with fever and myalgia, usually of abrupt onset. (Arenavirus infections are the exceptions as they often develop gradually.) Within a few days, the patient presents for medical attention because of increasing prostration that is often accompanied by abdominal or chest pain, anorexia, dizziness, severe headache, hyperesthesia, photophobia, and nausea or vomiting and other gastrointestinal disturbances. Initial examination often reveals only an acutely ill patient with conjunctival suffusion, tenderness to palpation of muscles or abdomen, and borderline hypotension or postural hypotension, perhaps with tachycardia. Petechiae (often best visualized in the axillae), flushing of the head and thorax, periorbital edema, and proteinuria are common. AST concentrations are usually elevated at presentation or within a day or two thereafter. Hemoconcentration from vascular leakage, which is


InternalMed_Harrison

InternalMed_Harrison. and thorax, periorbital edema, and proteinuria are common. AST concentrations are usually elevated at presentation or within a day or two thereafter. Hemoconcentration from vascular leakage, which is usually evident, is most marked in HFRS and in severe dengue. The seriously ill patient progresses to more severe clinical signs and develops shock and other findings typical of the causative virus. Shock, multifocal bleeding, and CNS involvement (encephalopathy, coma, seizures) are all poor prognostic signs.


InternalMed_Harrison

InternalMed_Harrison. One of the major diagnostic clues to VHF is travel to an endemic area within the incubation period for a given syndrome. Except in infections with Seoul, dengue, and yellow fever viruses, which have urban hosts/vectors, travel to a rural setting is especially suggestive of a diagnosis of VHF. In addition, several diseases considered in the differential diagnosis—falciparum malaria, shigellosis, typhoid fever, leptospirosis, relapsing fever, and rickettsial diseases—are treatable and potentially lethal.


InternalMed_Harrison

InternalMed_Harrison. Early recognition of VHF is important because of the need for virus-specific therapy and supportive measures. Such measures include prompt, atraumatic hospitalization; judicious fluid therapy that takes into account the patient’s increased capillary permeability; administration of cardiotonic drugs; use of pressors to maintain blood pressure at levels that will support renal perfusion; treatment of the relatively common secondary bacterial (and the more rare fungal) infections; replacement of clotting factors and platelets as indicated; and the usual precautionary measures used in the treatment of patients with hemorrhagic diatheses. DIC should be treated only if clear laboratory evidence of its existence is found and if laboratory monitoring of therapy is feasible; there is no proven benefit of such therapy. The available evidence suggests that VHF patients have decreased cardiac output and will respond poorly to fluid loading as it is often practiced in the treatment of shock


InternalMed_Harrison

InternalMed_Harrison. benefit of such therapy. The available evidence suggests that VHF patients have decreased cardiac output and will respond poorly to fluid loading as it is often practiced in the treatment of shock associated with bacterial sepsis. Specific therapy is available for several of the VHFs. Strict barrier nursing and other precautions against infection of medical staff and visitors are indicated when VHFs are encountered except when the illness is due to dengue viruses, hantaviruses, Rift Valley fever virus, or yellow fever virus.


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InternalMed_Harrison. Novel VHF-causing agents are still being discovered. Besides the viruses listed below, the latest addition may be the unclassified rhabdovirus Bas-Congo virus, which has been associated with three cases of VHF in the Democratic Republic of the Congo. However, Koch’s postulates have not yet been fulfilled to prove cause and effect. Arenaviruses The most important arenaviruses causing VHF are Junín virus, Lassa virus, and Machupo virus. Chapare, Guanarito, Lujo, and Sabiá viruses have caused limited and/or infrequent outbreaks or individual cases.


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InternalMed_Harrison. jUnín/argentinian and macHUpo/bolivian HemorrHagic fevers These severe diseases (with fetal lethality rates reaching 15–30%) are caused by Junín virus and Machupo virus, respectively. Their clinical presentations are similar, but their epidemiology differs because of the distribution and behavior of the viruses’ rodent reservoirs. Junín/ Argentinian hemorrhagic fever has thus far been recorded only in rural areas of Argentina, whereas Machupo/Bolivian hemorrhagic fever seems to be confined to rural Bolivia. Infection with the causative agents almost always results in disease, and all ages and both sexes are affected. Person-to-person or nosocomial transmission is rare but has occurred. The transmission of Junín/Argentinian hemorrhagic fever from convalescing men to their wives suggests the need for counseling of patients with arenavirus hemorrhagic fever concerning the avoidance of intimate contacts for several weeks after recovery. Compared with the pattern in Lassa fever (see


InternalMed_Harrison

InternalMed_Harrison. the need for counseling of patients with arenavirus hemorrhagic fever concerning the avoidance of intimate contacts for several weeks after recovery. Compared with the pattern in Lassa fever (see below), thrombocytopenia—often marked—is the rule, hemorrhage is common, and CNS dysfunction (e.g., marked confusion, tremors of the upper extremities and tongue, and cerebellar signs) is much more common in disease caused by Junín virus and Machupo virus. Some cases follow a predominantly neurologic course, with a poor prognosis.


InternalMed_Harrison

InternalMed_Harrison. The clinical laboratory is helpful in diagnosis since thrombocytopenia, leukopenia, and proteinuria are typical findings. Junín/ Argentinian hemorrhagic fever is readily treated with convalescent-phase plasma given within the first 8 days of illness. In the absence of passive antibody therapy, IV ribavirin in the dose recommended for Lassa fever is likely to be effective in all the South American VHFs caused by arenaviruses. A safe, effective, live attenuated vaccine exists for Junín/Argentinian hemorrhagic fever. After vaccination of more than 250,000 high-risk persons in the endemic area, the incidence of this VHF decreased markedly. In experimental animals, this vaccine is cross-protective against Machupo/Bolivian hemorrhagic fever.


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InternalMed_Harrison. lassa fever Lassa virus is known to cause endemic and epidemic disease in Nigeria, Sierra Leone, Guinea, and Liberia, although it is probably more widely distributed in western Africa. In countries where Lassa virus is endemic, Lassa fever can be a prominent cause of febrile disease. For example, in one hospital in Sierra Leone, laboratory-confirmed Lassa fever is consistently responsible for one-fifth of admissions to the medical wards. In western Africa alone, probably tens of thousands of Lassa virus infections occur annually. Lassa virus can be transmitted by close person-to-person contact. The virus is often present in urine during convalescence and is suspected to be present in seminal fluid early in recovery. Nosocomial spread has occurred but is uncommon if proper sterile parenteral techniques are used. All ages and both sexes are affected; the incidence of disease is highest in the dry season, but transmission takes place year-round.


InternalMed_Harrison

InternalMed_Harrison. Among the VHF agents, only arenaviruses are typically associated with a gradual onset of illness, which begins after an incubation period of 5–16 days. Hemorrhage is seen in only ~15–30% of Lassa fever patients; a maculopapular rash is often noted in light-skinned patients. Effusions are common, and male-dominant pericarditis may develop late. Maternal lethality is higher than the usual 15–30% and is especially increased during the last trimester. The fetal death rate reaches 90%. Excavation of the uterus may increase survival rates of pregnant women, but data on Lassa fever and pregnancy are still sparse. These figures suggest that interruption of the pregnancy of Lassa virus–infected women should be considered. White blood cell counts are normal or slightly elevated, and platelet counts are normal or somewhat low. Deafness coincides with clinical improvement in ~20% of patients and is permanent and bilateral in some patients. Reinfection may occur but has not been associated with


InternalMed_Harrison

InternalMed_Harrison. are normal or somewhat low. Deafness coincides with clinical improvement in ~20% of patients and is permanent and bilateral in some patients. Reinfection may occur but has not been associated with severe disease.


InternalMed_Harrison

InternalMed_Harrison. High-level viremia or a high serum AST concentration statistically predicts a fatal outcome. Thus, patients with an AST concentration of >150 IU/mL should be treated with IV ribavirin. This antiviral nucleoside analogue appears to be effective in reducing case–fatality rates from those documented among retrospective controls. However, possible side effects, such as reversible anemia (which usually does not require transfusion), dependent hemolytic anemia, and bone marrow suppression, need to be kept in mind. Ribavirin should be given by slow IV infusion in a dose of 32 mg/kg; this dose should be followed by 16 mg/kg every 6 h for 4 days and then by 8 mg/kg every 8 h for 6 days. Inactivated Lassa virus vaccines failed in preclinical studies.


InternalMed_Harrison

InternalMed_Harrison. Bunyaviruses The most important VHF-causing bunyaviruses are Crimean-Congo hemorrhagic fever virus, hantaviruses, Rift Valley fever virus, and “severe fever with thrombocytopenia syndrome virus.” Other bunyaviruses—e.g., the Garissa variant of Ngari virus and Ilesha virus—have caused sporadic VHF outbreaks in Africa.


InternalMed_Harrison

InternalMed_Harrison. crimean-congo HemorrHagic fever (ccHf) This severe VHF has a wide geographic distribution, potentially emerging wherever virus-bearing ticks occur. Because of the propensity of CCHF virus–transmitting ticks to feed on domestic livestock and certain wild mammals, veterinary serosurveys are the most effective mechanism for the monitoring of virus circulation in a particular region. Human infections are acquired via tick bites or during the crushing of infected ticks. Domestic animals do not become ill but do develop viremia. Thus, there is risk of acquiring CCHF during sheep shearing, slaughter, and contact with infected hides or carcasses from recently slaughtered infected animals. Nosocomial epidemics are common and are usually related to extensive blood exposure or needlesticks.


InternalMed_Harrison

InternalMed_Harrison. Although generally similar to other VHFs, CCHF causes extensive liver damage, resulting in jaundice in some patients. Clinical laboratory values indicate DIC and show elevations in concentrations of AST, creatine phosphokinase, and bilirubin. Patients who do not survive generally have more distinct changes than survivors in the concentrations of these markers, even in the early days of illness, and also develop leukocytosis rather than leukopenia. In addition, thrombocytopenia is more marked and develops earlier in patients who do not survive than in survivors. The benefit of IV ribavirin for treatment remains hotly debated, but clinical experience and retrospective comparison of patients with ominous clinical laboratory values suggest that ribavirin may be efficacious. No human or veterinary vaccines are recommended.


InternalMed_Harrison

InternalMed_Harrison. HemorrHagic fever witH renal syndrome HFRS is the most important VHF today, with more than 100,000 cases of severe disease in Asia annually and milder infections numbering in the thousands in Europe. The disease is widely distributed in Eurasia. The major causative viruses are Puumala virus (Europe), Dobrava-Belgrade virus (the Balkans), and Hantaan virus (eastern Asia). Amur/Soochong, Gou, Kurkino, Muju, Saaremaa, Sochi, and Tula viruses also cause HFRS but much less frequently and in more geographically confined areas determined by the distribution of reservoir hosts. Seoul virus is exceptional in that it is associated with brown rats (Rattus norvegicus); therefore, the virus has a worldwide distribution because of the migration of these rodents on ships. Despite the wide distribution of Seoul virus, only mild or moderate HFRS occurs in Asia, and human disease has been difficult to identify in many areas of the world. Most cases of HFRS occur in rural residents or vacationers; the


InternalMed_Harrison

InternalMed_Harrison. of Seoul virus, only mild or moderate HFRS occurs in Asia, and human disease has been difficult to identify in many areas of the world. Most cases of HFRS occur in rural residents or vacationers; the exception is Seoul virus infection, which may be acquired in an urban or rural setting or from contaminated laboratory-rat colonies. Classic Hantaan virus infection in Korea and in rural China is most common in the spring and fall and 1321 is related to rodent density and agricultural practices. Human infection is acquired primarily through aerosols of rodent urine, although virus is also present in rodent saliva and feces. Patients with HFRS are not infectious.


InternalMed_Harrison

InternalMed_Harrison. Severe cases of HFRS evolve in four identifiable stages. The febrile stage lasts 3 or 4 days and is identified by the abrupt onset of fever, headache, severe myalgia, thirst, anorexia, and often nausea and vomiting. Photophobia, retroorbital pain, and pain on ocular movement are common, and the vision may become blurred with ciliary body inflammation. Flushing over the face, the V area of the neck, and the back is characteristic, as are pharyngeal injection, periorbital edema, and conjunctival suffusion. Petechiae often develop in areas of pressure, the conjunctivae, and the axillae. Back pain and tenderness to percussion at the costovertebral angle reflect massive retroperitoneal edema. Laboratory evidence of mild to moderate DIC is present. Other laboratory findings of HFRS include proteinuria and active urinary sediment. The hypotensive stage lasts from a few hours to 48 h and begins with falling blood pressure and sometimes shock. The relative bradycardia typical of the febrile


InternalMed_Harrison

InternalMed_Harrison. and active urinary sediment. The hypotensive stage lasts from a few hours to 48 h and begins with falling blood pressure and sometimes shock. The relative bradycardia typical of the febrile phase is replaced by tachycardia. Kinin activation is marked. The rising hematocrit reflects increasing vascular leakage. Leukocytosis with a left shift develops, and thrombocytopenia continues. Atypical lymphocytes—which in fact are activated CD8+ and, to a lesser extent, CD4+ T cells—circulate. Proteinuria is marked, and the urine’s specific gravity falls to 1.010. Renal circulation is congested and compromised from local and systemic circulatory changes resulting in necrosis of tubules, particularly at the corticomedullary junction, and oliguria. During the oliguric stage, hemorrhagic tendencies continue, probably in large part because of uremic bleeding defects. Oliguria persists for 3–10 days before the return of renal function marks the onset of the polyuric stage (diuresis and


InternalMed_Harrison

InternalMed_Harrison. tendencies continue, probably in large part because of uremic bleeding defects. Oliguria persists for 3–10 days before the return of renal function marks the onset of the polyuric stage (diuresis and hyposthenuria), which carries the danger of dehydration and electrolyte abnormalities.


InternalMed_Harrison

InternalMed_Harrison. Mild cases of HFRS may be much less stereotypical. The presentation may include only fever, gastrointestinal abnormalities, and transient oliguria followed by hyposthenuria. Infections with Puumala virus, the most common cause of HFRS in Europe (nephropathia epidemica), result in a much-attenuated picture but the same general presentation. Bleeding manifestations are found in only 10% of patients, hypotension rather than shock is usually documented, and oliguria is present in only about half of patients. The dominant features may be fever, abdominal pain, proteinuria, mild oliguria, and sometimes blurred vision or glaucoma followed by polyuria and hyposthenuria in recovery. The lethality rate is <1%.


InternalMed_Harrison

InternalMed_Harrison. HFRS should be suspected in patients with rural exposure in an endemic area. Prompt recognition of the disease permits rapid hospitalization and expectant management of shock and renal failure. Useful clinical laboratory parameters include leukocytosis, which may be leukemoid and is associated with a left shift; thrombocytopenia; and proteinuria. HFRS is readily diagnosed by an IgM-capture ELISA that is positive at admission or within 24–48 h thereafter. The isolation of hantaviruses is difficult, but RT-PCR of a blood clot collected early in the clinical course or of tissues obtained postmortem should give positive results. Such testing is usually undertaken if definitive identification of the infecting virus is required.


InternalMed_Harrison

InternalMed_Harrison. Mainstays of therapy are management of shock, reliance on vasopressors, modest crystalloid infusion, IV human serum albumin administration, and treatment of renal failure with prompt dialysis to prevent overhydration that may result in pulmonary edema and to control hypertension that increases the possibility of intracranial hemorrhage. Use of IV ribavirin has reduced lethality and morbidity in severe cases, provided treatment is begun within the first 4 days of illness. Lethality may be as high as 15% but with proper therapy should be <5%. Sequelae have not been definitively established.