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Harrison’s Manual of Medicine



Infections Caused by Arthropod- and Rodent-Borne Viruses

Viruses Causing Fever and Myalgia

Arboviruses Causing Encephalitis

Alphaviruses Causing Arthritis and Rash

Viruses Causing Hemorrhagic Fevers
Marburg and Ebola Viruses

Rabies virus is an enveloped, bullet-shaped, single-stranded RNA virus belonging to the family Rhabdoviridae. The binding of viral glycoproteins to acetylcholine receptors contributes to neurovirulence.
EPIDEMIOLOGY   Rabies exists in two epidemiologic forms: urban rabies (propagated by unimmunized domesticated dogs and cats) and sylvatic rabies (propagated by skunks, foxes, raccoons, mongooses, wolves, and bats). The virus is transmitted in saliva. Since 1980, 36 human cases of rabies have been diagnosed in the U.S.; 58% of these cases were associated with exposure to bats, while one-third were acquired through dog bites sustained outside the U.S. Most persons with proven rabies in the U.S. report no Hx of animal bite. More than one-third of recent cases have been diagnosed after death. Most cases of postexposure prophylaxis are associated with domesticated animals, such as dogs and cats. Because of delayed diagnosis, postexposure prophylaxis of health care workers and close contacts of cases is common.
CLINICAL MANIFESTATIONS   The incubation period for rabies is variable, probably depending on the amount of virus introduced, the distance of the inoculation site from the CNS, and the host’s defense status. The mean incubation period is 1–2 months, but the range is 7 d to >1 year.
A prodromal period of 1–4 d is marked by fever, headache, malaise, myalgias, increased fatigability, anorexia, nausea and vomiting, sore throat, and nonproductive cough. Paresthesia and/or fasciculations at or near the site of viral inoculation are found in 50–80% of cases in the prodromal stage and constitute the only symptom suggestive of rabies. An encephalitic phase follows, with periods of excessive motor activity, excitation, and agitation. Confusion, combativeness, aberrations of thought, muscle spasms, seizures, focal paralysis, and fever are interspersed with shortening periods of lucidity. Hyperesthesia (excessive sensitivity to light, noise, and touch) is very common. Hydrophobia or aerophobia has been seen in around two-thirds of recent cases and increases the likelihood of antemortem diagnosis. Signs may include hyperthermia, autonomic dysfunction, upper motor neuron paralysis, and vocal cord paralysis. Brainstem dysfunction becomes apparent shortly after the encephalitic phase begins. Manifestations include cranial nerve involvement (diplopia, facial palsies, optic neuritis, and difficulty with deglutition, which, combined with excessive salivation, produces characteristic “foaming at the mouth”); hydrophobia; painful violent involuntary contractions of the diaphragm and of accessory respiratory, pharyngeal, and laryngeal muscles initiated by swallowing liquids (seen in 50% of cases); priapism; and spontaneous ejaculation. The prominence of early brainstem dysfunction distinguishes rabies from other viral encephalitides. The median period of survival after the onset of symptoms is 4 d. With respiratory support, late complications may appear, including inappropriate secretion of vasopressin, diabetes insipidus, cardiac arrhythmias, vascular instability, ARDS, GI bleeding, thrombocytopenia, and paralytic ileus. Recovery is extremely rare.
DIAGNOSIS   The specific diagnosis of rabies can be made by several techniques, including (1) isolation of the virus from saliva, CSF, or brain tissue by mouse inoculation; (2) detection of viral antigen in infected tissue samples, such as corneal impression smears, skin biopsies, or brain biopsies, by fluorescent antibody (FA) staining; (3) documentation of a fourfold rise in neutralizing antibody titer; or (4) detection of rabies virus RNA by PCR. Isolation of virus from saliva, demonstration of viral nucleic acid in saliva, or detection of viral antigen in a nuchal skin biopsy specimen is most sensitive. Brain tissue should be sent for virus culture, FA staining for antigen, histologic and/or electron microscopic examination for Negri bodies, or PCR. Pts receiving postexposure rabies prophylaxis usually have serum and CSF antibody titers of <1:64, whereas in human rabies CSF antibody titers may vary from 1:200 to 1:160,000.

An algorithm for postexposure rabies prophylaxis is shown in Fig. 107-1. Postexposure prophylaxis includes local wound treatment (mechanical and chemical cleansing, administration of tetanus toxoid and antibiotics); passive immunization [human rabies immune globulin (HRIG), 20 U/kg, with the full dose given by local infiltration into the wound and any remaining portion injected IM at a site distant from the vaccination site]; and active immunization [human diploid cell vaccine (HDCV), rabies vaccine adsorbed (RVA), or purified chick embryo vaccine], with five 1-mL doses given IM on days 0, 3, 7, 14, and 28 after exposure. The vaccine should be administered in the deltoid or anterolateral thigh; the gluteal area should not be used. An equine antiserum is also available for passive immunization at a dose of 40 U/kg but is more likely than human antiserum to result in serum sickness. Postexposure prophylaxis for persons who have received preexposure prophylaxis consists of two doses of HDCV (1 mL IM) on days 0 and 3.

FIGURE 107-1. Postexposure rabies prophylaxis algorithm. *Instances of exposure to livestock or to normal-behaving, unvaccinated dogs or cats should be considered individually, and local and state public health officials should be consulted. (From L Corey: HPIM-15, p. 1150.)

PREVENTION   Preexposure prophylaxis should be given to individuals at high risk of exposure, such as veterinarians, cave explorers, laboratory workers, and animal handlers. Three doses of HDCV (1 mL IM or 0.1 mL intradermally) are given on days 0, 7, and 21 or 28, respectively. Serologic testing should be conducted after the series and then every 2–6 years, depending on risk. When antibody titers fall below 1:5, a booster dose of HDCV (1 mL IM or 0.1 mL intradermally) should be given.
Arthropod- and rodent-borne viruses are transmitted by a variety of vectors. Table 107-1 lists the syndromes and major viruses causing human disease in this category.

Table 107-1 Syndromes and Major Viruses Transmitted by Arthropods and Rodents

Viruses Causing Fever and Myalgia
Fever and myalgia constitute the syndrome most commonly associated with zoonotic virus infection. The syndrome, which is caused by many agents belonging to the seven major families of zoonotic viruses, typically begins with the abrupt onset of fever, chills, intense myalgia, and malaise. Arthralgias are frequent, but arthritis is not. Anorexia is characteristic and is frequently associated with nausea and vomiting. Headache may be severe. Some viruses cause a maculopapular rash and others aseptic meningitis. Most pts recover completely with only supportive therapy.
LYMPHOCYTIC CHORIOMENINGITIS (LCM)   Epidemiology   The common house mouse is the primary host for LCM, which is worldwide in distribution. Human infections are secondary to contact with an infected rodent, with transmission thought to be via airborne spread or contact with infected excrement.
Clinical Manifestations   The most common clinical pattern is an influenza- like illness. In one-fourth of pts, the illness may be biphasic, with initial fever and subsequent aseptic meningitis or encephalitis. Fever, malaise, weakness, myalgia (especially lumbar), retroorbital headache, photophobia, anorexia, nausea, and light-headedness are common. Physical findings may include skin rash, pharyngeal injection without exudate, mild cervical or axillary lymphadenopathy, alopecia, or meningeal signs. Testicular pain or frank orchitis may be present. LCM virus infection in pregnant women may lead to congenital hydrocephalus and fetal chorioretinitis.
Diagnosis   Leukopenia and thrombocytopenia are observed during the first week of illness. The CSF of pts with meningeal signs usually contains several hundred cells per microliter, with a lymphocytic predominance. Typical CSF findings are mononuclear cell counts of >1000/µL, elevated protein levels, and low glucose levels. Recovery of LCM virus from blood or spinal fluid is most likely in the initial phases of the illness. The most direct method for the diagnosis of LCM, therefore, is IgM-capture ELISA of serum or CSF; recently, reverse transcription (RT)-PCR assays have been developed for application to CSF.

There is no specific treatment for LCM.

DENGUE FEVER   Dengue viruses are flaviviruses. Four serotypes have been identified.
Epidemiology   Dengue is transmitted by Aedes mosquitoes and is endemic over large areas of the tropics and subtropics, Asia, Oceania, Africa, Australia, and the Americas, including the Caribbean. Classic dengue, also known as breakbone fever, usually occurs in nonimmune individuals, children, and adults who do not reside in an endemic area. Dengue hemorrhagic fever (DHF) occurs almost exclusively in indigenous populations and is thought to be immunologically mediated, with enhanced infection of the target cells (macrophages and monocytes) more likely in the presence of antibody from a previous infection.
Clinical Manifestations   Dengue viruses frequently produce inapparent infection. When symptoms develop, three clinical patterns are seen: classic dengue, a mild atypical form, and DHF.
1   Classic dengue: After an incubation period of 5–8 d, a short prodrome of mild conjunctivitis or coryza may precede by a few hours the abrupt onset of severe headache, retroorbital pain, backache (especially lumbar), and leg and joint pains. Ocular soreness, anorexia, and weakness are common; cough is rare. Skin rashes that vary in appearance are common, as is lymphadenopathy. The fever may follow a diphasic course. The febrile illness usually lasts for 5–6 d and terminates abruptly.
2   Atypical dengue: Symptoms of mild atypical illness include fever, anorexia, headache, and myalgia. An evanescent rash may develop; lymphadenopathy is absent. Symptoms usually last for <72 h.
3   DHF: Illness begins abruptly with a relatively mild stage (2–4 d) consisting of fever, cough, pharyngitis, headache, anorexia, nausea, vomiting, and abdominal pain, which may be severe. Myalgia, arthralgia, and bone pain, which are common in classic dengue, are unusual in DHF. Hemorrhagic manifestations include a positive tourniquet test, petechiae, purpura, ecchymoses, epistaxis, bleeding gums, hematemesis, melena, enlargement of the liver, thrombocytopenia, hemoconcentration, and hematocrit increased by ³20%. Dengue shock syndrome (DSS) is diagnosed when there is a rapid weak pulse with narrowing of the pulse pressure to £20 mmHg or hypotension with cold clammy skin and restlessness.
Diagnosis   Primary viral isolation may be accomplished by inoculation of blood obtained in the first 3–5 d of illness into mosquitoes or mosquito cell cultures. Serologic diagnosis can be made by IgM ELISA or testing of paired serum specimens during recovery or by antigen-detection ELISA or RT-PCR during the acute phase.

Treatment is supportive, with close monitoring and administration of oxygen and IV fluids. Overall mortality at an experienced center in the tropics is probably as low as 1%.

Arboviruses Causing Encephalitis
EPIDEMIOLOGY   Since arboviruses causing encephalitis are transmitted by mosquitoes, infections occur during peak mosquito season (late spring to early fall). Table 107-2 lists prominent features of arboviral encephalitis.

Table 107-2 Prominent Features of Arboviral Encephalitis

CLINICAL MANIFESTATIONS   Features of arboviral encephalitis differ among age groups and depend on the specific infecting virus. In adults, initial symptoms include fever, abdominal pain, sore throat, vertigo, and respiratory symptoms followed by headache, meningeal signs, photophobia, and vomiting. Disturbances in mentation are the most prominent neurologic findings, ranging from subtle abnormalities detected by cerebral function tests to coma. Other findings include tremor, cranial nerve abnormalities, reflex abnormalities, paresis, and frontal lobe signs. Fever and neurologic symptoms and signs vary in duration from a few days to as long as 2–3 weeks; however, the time to full recovery may be weeks or months.
DIAGNOSIS   CSF findings include pleocytosis (usually several hundred cells per microliter, but occasionally >1000 cells/µL), with an initial neutrophil predominance shifting after several days to a lymphocyte predominance. The CSF protein level is usually slightly elevated and may increase with time; the CSF glucose concentration is normal. A specific diagnosis rests on demonstration of a rise in antibody level between acute- and convalescent-phase sera. A humoral immune response is usually detectable at the clinical onset of the disease; both serum and CSF should be examined for IgM. Virus generally cannot be isolated from blood or CSF. However, there is a heterogeneous distribution of virus and viral antigen in brain tissue.

Treatment is supportive.

Alphaviruses Causing Arthritis and Rash
True arthritis is a common accompaniment of several viral diseases, such as rubella, parvovirus B19 infection, and hepatitis B. In addition, the alphaviruses cause true arthritis and a maculopapular rash.
SINDBIS VIRUS INFECTION   Epidemiology   Sindbis virus is transmitted among birds by mosquitoes. Infections with the northern European and genetically related southern African strains are particularly likely to cause an arthritis-rash syndrome.
Clinical Manifestations   The incubation period is <1 week. Clinical symptoms begin with rash and arthralgia. The rash lasts about a week and spreads from the trunk to the extremities, evolving from macules to papules that frequently vesiculate. The arthritis is multiarticular, migratory, and incapacitating.

There is no specific therapy.

CHIKUNGUNYA VIRUS INFECTION   Epidemiology   Chikungunya virus is transmitted among humans by Aedes mosquitoes. The virus is endemic in rural Africa and is intermittently epidemic in towns and cities of Africa and Asia.
Clinical Manifestations   The incubation period is 2–3 d. Fever and severe arthralgia are accompanied by chills and constitutional symptoms such as headache, photophobia, conjunctival injection, anorexia, nausea, and abdominal pain. Migratory arthritis primarily affects small joints.

No specific therapy is available.

EPIDEMIC POLYARTHRITIS   Epidemiology   Ross River virus causes epidemics of distinctive disease in Australia, New Guinea, and the eastern Pacific islands. This virus is transmitted among humans by Aedes mosquitoes.
Clinical Manifestations   The incubation period is 7–11 d, and the onset of illness is sudden, with joint pain usually ushering in the disease. The rash develops around the same time. Most pts are incapacitated for considerable periods by joint involvement. Joint fluid contains 1000–60,000 mononuclear cells/µL. The detection of IgM antibodies is valuable, although these antibodies occasionally persist for years.

No specific therapy is available.

Viruses Causing Hemorrhagic Fevers
LASSA FEVER   Epidemiology   Lassa fever is a highly contagious arenavirus first described in Lassa, a town in northeastern Nigeria, in 1969 and subsequently found in Sierra Leone, Guinea, and Liberia. The virus is carried in a species of rat that is widespread in Africa. Spread takes place through small- particle aerosols, but person-to-person transmission also occurs.
Clinical Manifestations   The incubation period is 7–18 d. The onset of illness is insidious, with fevers, rigors, headache, malaise, and myalgia. The average case has a gradual onset that gives way to more constitutional symptoms and prostration. Bleeding occurs in 15–30% of cases, a maculopapular rash is noted in light-skinned pts, and effusions (especially pericarditis in males) are seen. Deafness occurs in 20% of cases and is occasionally permanent. The WBC count may be slightly high, and platelet counts may be somewhat low. High aspartate aminotransferase (AST) levels predict a fatal outcome, and AST levels of >150 IU/mL warrant treatment with IV ribavirin.
Diagnosis   The diagnosis can be made by the demonstration of a fourfold rise in antibody titer between acute- and convalescent-phase sera. The diagnosis is unlikely if IgM antibodies are absent by day 14 of illness.

Ribavirin appears to be effective in reducing mortality rates and should be administered to pts with AST levels of >150 IU/mL. The drug should be given by slow IV infusion in a dose of 32 mg/kg; this dose should be followed by 16 mg/kg q6h for 4 d and then by 8 mg/kg q8h for 6 d.

HANTAVIRUS PULMONARY SYNDROME   Epidemiology   The causative agents of hantavirus pulmonary syndrome are hantaviruses associated with the rodent subfamily Sigmodontinae. Sin Nombre virus chronically infects the deer mouse and is the most important virus causing hantavirus pulmonary syndrome in the U.S.
Clinical Manifestations   The disease begins with a prodrome of 3–4 d comprising fever, myalgia, malaise, and (in many cases) GI disturbances. Pts usually present as the pulmonary phase begins. Typical findings include slightly lowered blood pressure, tachycardia, tachypnea, mild hypoxemia, and early pulmonary edema. Over several hours, decompensation progresses rapidly to respiratory failure.
Diagnosis   A specific diagnosis is made by IgM testing of acute-phase serum. RT-PCR is usually positive when used to test blood clots or tissues in the first 7–9 d of illness.

Appropriate management during the first few hours after presentation is critical. The goal is to prevent severe hypoxemia with oxygen therapy and, if needed, intubation and intensive respiratory management. Mortality remains at ~30–40% with good management. Ribavirin inhibits the virus in vitro but did not have a marked clinical effect on pts in an open-label study.

EPIDEMIOLOGY   Marburg and Ebola viruses are antigenically and genetically distinct viruses in the family Filoviridae. Of the 25 cases of primary Marburg infection, 7 ended in death. Isolated cases have been reported in Africa. In a 1976 epidemic of severe hemorrhagic fever due to Ebola virus in Zaire and Sudan, there were >470 deaths among 550 cases. The virus was spread by close person-to-person contact and reuse of needles for injections. Another Ebola epidemic occurred in the Democratic Republic of Congo in 1995, and smaller epidemics took place in Gabon in 1994–1996; these epidemics included 317 cases, with a mortality rate of 88%. Strict quarantine measures arrested the Congo epidemic. The reservoirs for the filoviruses are unknown, although evidence points to a nonprimate reservoir.
CLINICAL MANIFESTATIONS   After an incubation period ranging from 3 to 16 d, pts develop fever, severe headache, malaise, myalgias, nausea, and vomiting. Between 1 and 3 d after onset, watery diarrhea, lethargy, and a change in mentation are noted. A nonpruritic maculopapular rash begins on the fifth to seventh day and is followed by desquamation. Hemorrhagic manifestations develop at about this time; bleeding can be apparent from any mucosal site, although it does not always occur and has been absent even in fatal cases. The temperature response is frequently biphasic, with lysis after the first 10– 12 d and a recurrence that may be associated with secondary bacterial infections or possibly with localized viral persistence.
DIAGNOSIS   Leukopenia and thrombocytopenia are typical, and pts with fatal cases develop DIC. AST and alanine aminotransferase levels progressively rise, and jaundice is evident in some cases. Amylase levels may be elevated. Renal insufficiency is proportional to shock; proteinuria is common. Antigen- detection ELISA–based IgM and IgG tests are positive in recovering pts. Antigen detection in skin biopsies is a useful postmortem diagnostic tool.

Supportive care is all that can currently be offered. Barrier nursing precautions can decrease the spread of the virus.


For a more detailed discussion, see Corey L: Rabies Virus and Other Rhabdoviruses, Chap. 197, p. 1149; Peters CJ: Infections Caused by Arthropod- and Rodent-Borne Viruses, Chap. 198, p. 1152; and Peters CJ: Filoviridae (Marburg and Ebola Viruses), Chap. 199, p. 1166, in HPIM-15.


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