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InternalMed_Harrison. Most persons with measles recover and develop long-term protective immunity to reinfection. Measles case-fatality proportions vary with the average age of infection, the nutritional and immunologic status of the population, measles vaccine coverage, and access to health care. Among previously vaccinated persons who do become infected, disease is less severe and mortality rates are significantly lower. In developed countries, <1 in 1000 children with measles die. In endemic areas of sub-Saharan Africa, the measles case-fatality proportion may be 5–10% or even higher. Measles is a major cause of childhood deaths in refugee camps and in internally displaced populations, where case-fatality proportions have been as high as 20–30%.


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InternalMed_Harrison. PREVENTION Passive Immunization Human immunoglobulin given shortly after exposure can attenuate the clinical course of measles. In immunocompetent persons, administration of immunoglobulin within 72 h of exposure usually prevents measles virus infection and almost always prevents clinical measles. Administered up to 6 days after exposure, immunoglobulin will still prevent or modify the disease. Prophylaxis with immunoglobulin is recommended for susceptible household and nosocomial contacts who are at risk of developing severe measles, particularly children <1 year of age, immunocompromised persons (including HIV-infected persons previously immunized with live attenuated measles vaccine), and pregnant women. Except for premature infants, children <6 months of age usually will be partially or completely protected by passively acquired maternal antibody. If measles is diagnosed in a household member, all unimmunized children in the household should receive immunoglobulin. The recommended


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InternalMed_Harrison. completely protected by passively acquired maternal antibody. If measles is diagnosed in a household member, all unimmunized children in the household should receive immunoglobulin. The recommended dose is 0.25 mL/kg given intramuscularly. Immunocompromised persons should receive 0.5 mL/ kg. The maximum total dose is 15 mL. IV immunoglobulin contains antibodies to measles virus; the usual dose of 100–400 mg/kg generally provides adequate prophylaxis for measles exposures occurring as long as 3 weeks or more after IV immunoglobulin administration.


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InternalMed_Harrison. Active Immunization The first live attenuated measles vaccine was developed by passage of the Edmonston strain in chick embryo fibroblasts to produce the Edmonston B virus, which was licensed in 1963 in the United States. Further passage of Edmonston B virus produced the more attenuated Schwarz vaccine that currently serves as the standard in much of the world. The Moraten (“more attenuated Enders”) strain, which was licensed in 1968 and is used in the United States, is genetically closely related to the Schwarz strain.


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InternalMed_Harrison. Lyophilized measles vaccines are relatively stable, but reconstituted vaccine rapidly loses potency. Live attenuated measles vaccines are inactivated by light and heat and lose about half their potency at 20°C and almost all their potency at 37 within 1 h after reconstitution. 12 Therefore, a cold chain must be maintained before and after reconstitution. Antibodies first appear 12–15 days after vaccination, and titers peak at 1–3 months. Measles vaccines are often combined with other live attenuated virus vaccines, such as those for mumps and rubella (MMR) and for mumps, rubella, and varicella (MMR-V).


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InternalMed_Harrison. The recommended age of first vaccination varies from 6 to 15 months and represents a balance between the optimal age for seroconversion and the probability of acquiring measles before that age. The proportions of children who develop protective levels of antibody after measles vaccination approximate 85% at 9 months of age and 95% at 12 months. Common childhood illnesses concomitant with vaccination may reduce the level of immune response, but such illness is not a valid reason to withhold vaccination. Measles vaccines have been well tolerated and immunogenic in HIV-1-infected children and adults, although antibody levels may wane. Because of the potential severity of wild-type measles virus infection in HIV-1-infected children, routine measles vaccination is recommended except for those who are severely immunocompromised. Measles vaccination is contraindicated in individuals with other severe deficiencies of cellular immunity because of the possibility of disease due to progressive


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InternalMed_Harrison. who are severely immunocompromised. Measles vaccination is contraindicated in individuals with other severe deficiencies of cellular immunity because of the possibility of disease due to progressive pulmonary or CNS infection with the vaccine virus.


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InternalMed_Harrison. The duration of vaccine-induced immunity is at least several decades if not longer. Rates of secondary vaccine failure 10–15 years after immunization have been estimated at ~5% but are probably lower when vaccination takes place after 12 months of age. Decreasing antibody concentrations do not necessarily imply a complete loss of protective immunity: a secondary immune response usually develops after reexposure to measles virus, with a rapid rise in antibody titers in the absence of overt clinical disease. Standard doses of currently licensed measles vaccines are safe for immunocompetent children and adults. Fever to 39.4 (103) occurs in ~5% of seronegative vaccine recipients, and 2% of vaccine recipients develop a transient rash. Mild transient thrombocytopenia has been reported, with an incidence of ~1 case per 40,000 doses of MMR vaccine.


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InternalMed_Harrison. Since the publication of a report in 1998 hypothesizing that MMR vaccine may cause a syndrome of autism and intestinal inflammation, much public attention has focused on this purported association. The events that followed publication of this report led to diminished vaccine coverage in the United Kingdom and provide important lessons in the misinterpretation of epidemiologic evidence and the communication of scientific results to the public. The publication that incited the concern was a case series describing 12 children with a regressive developmental disorder and chronic enterocolitis; 9 of these children had autism. In 8 of the 12 cases, the parents associated onset of the developmental delay with MMR vaccination. This simple temporal association was misinterpreted and misrepresented as a possible causal relationship, first by the lead author of the study and then by elements of the media and the public. Subsequently, several comprehensive reviews and additional epidemiologic


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InternalMed_Harrison. as a possible causal relationship, first by the lead author of the study and then by elements of the media and the public. Subsequently, several comprehensive reviews and additional epidemiologic studies refuted evidence of a causal relationship between MMR vaccination and autism.


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InternalMed_Harrison. Progress in global measles control has renewed discussion of measles eradication. In contrast to poliovirus eradication, the eradication of measles virus will not entail challenges posed by prolonged shedding of potentially virulent vaccine viruses and environmental viral reservoirs. However, in comparison with smallpox eradication, higher levels of population immunity will be necessary to interrupt measles virus transmission, more highly skilled health care workers will be required to administer measles vaccines, and containment through case detection and ring vaccination will be more difficult for measles virus because of infectivity before rash onset. New tools, such as aerosol administration of measles vaccines, will facilitate mass vaccination campaigns. Despite enormous progress, measles remains a leading vaccine-preventable cause of childhood mortality worldwide and continues to cause outbreaks in communities with low vaccination coverage rates in industrialized nations.


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InternalMed_Harrison. Laura A. Zimmerman, Susan E. Reef Rubella was historically viewed as a variant of measles or scarlet fever. Not until 1962 was a separate viral agent for rubella isolated. After an epidemic of rubella in Australia in the early 1940s, the ophthalmologist Norman Gregg noticed the occurrence of congenital cataracts among infants whose mothers had reported rubella infection during early pregnancy, and congenital rubella syndrome (CRS; see “Clinical Manifestations,” below) was first described. Rubella virus is a member of the Togaviridae family and the only member of the genus Rubivirus. This single-stranded RNA enveloped virus measures 50–70 nm in diameter. Its core protein is surrounded by a single-layer lipoprotein envelope with spike-like projections containing two glycoproteins, E1 and E2. There is only one antigenic type of rubella virus, and humans are its only known reservoir.


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InternalMed_Harrison. Although the pathogenesis of postnatal (acquired) rubella has been well documented, data on pathology are limited because of the mildness of the disease. Rubella virus is spread from person to person via respiratory droplets. Primary implantation and replication in the nasopharynx are followed by spread to the lymph nodes. Subsequent viremia occurs, which in pregnant women often results in infection of the placenta. Placental virus replication may lead to infection of fetal organs. The pathology of CRS in the infected fetus is well defined, with almost all organs found to be infected; however, the pathogenesis of CRS is only poorly delineated. In tissue, infections with rubella virus have diverse effects, ranging from no obvious impact to cell destruction. The hallmark of fetal infection is chronicity, with persistence throughout fetal development in utero and for up to 1 year after birth.


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InternalMed_Harrison. Individuals with acquired rubella may shed virus from 7 days before rash onset to ~5–7 days thereafter. Both clinical and subclinical infections are considered contagious. Infants with CRS may shed large quantities of virus from bodily secretions, particularly from the throat and in the urine, up to 1 year of age. Outbreaks of rubella, including some in nosocomial settings, have originated with index cases of CRS. Thus only individuals immune to rubella should have contact with infants who have CRS or who are congenitally infected with rubella virus but are not showing signs of CRS.


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InternalMed_Harrison. The largest recent rubella epidemic in the United States took place in 1964–1965, when an estimated 12.5 million cases occurred, resulting in ~20,000 cases of CRS. Since the introduction of the routine rubella vaccination program in the United States in 1969, the number of rubella cases reported each year has dropped by >99%; the rate of vaccination coverage with rubella-containing vaccine has been >90% among children 19–35 months old since 1995 and >95% for kindergarten and first-grade entrants since 1980. In 1989 a goal for the elimination of rubella and CRS in the United States was set, and in 2004 a panel of experts agreed unanimously that rubella was no longer an endemic disease in this country. The criteria used to document lack of endemic transmission included low disease incidence, high nationwide rubella antibody seroprevalence, outbreaks that were few and contained (i.e., small numbers of cases), and lack of endemic virus transmission (as assessed by genetic sequencing). In


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InternalMed_Harrison. high nationwide rubella antibody seroprevalence, outbreaks that were few and contained (i.e., small numbers of cases), and lack of endemic virus transmission (as assessed by genetic sequencing). In the United States, interruption of endemic transmission of rubella virus has been sustained since 2001; in 2012, however, three cases of CRS were reported in infants whose mothers had acquired rubella infection abroad. Thus health care providers should remain vigilant, considering the possibility of rubella infection in patients emigrating or returning from countries without rubella control programs and the accompanying potential for CRS among their infants.


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InternalMed_Harrison. FIGURE 230e-1 Mild maculopapular rash of rubella in a child. Although rubella and CRS are no longer endemic in the United States, they remain important public health problems globally. The number of rubella cases reported worldwide in 1999 was ~900,000; this figure declined steadily to 94,030 in 2012. However, numbers of rubella cases are substantially underestimated because cases in many countries are identified through measles surveillance systems that are not specific for rubella. In 2010, it was estimated that 103,000 cases of CRS occur globally.


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InternalMed_Harrison. CLINICAL FEATURES Acquired Rubella Acquired rubella commonly presents with a generalized maculopapular rash that usually lasts for up to 3 days (Fig. 230e-1), although as many as 50% of cases may be subclinical or without rash. When it occurs, the rash is usually mild and may be difficult to detect in persons with darker skin. In children, rash is usually the first sign of illness. However, in older children and adults, a 1to 5-day prodrome often precedes the rash and may include low-grade fever, malaise, and upper respiratory symptoms. The incubation period is 14 days (range, 12–23 days). Lymphadenopathy, particularly occipital and postauricular, may be noted during the second week after exposure. Although acquired rubella is usually thought of as a benign disease, arthralgia and arthritis are common in infected adults, particularly women. Thrombocytopenia and encephalitis are less common complications.


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InternalMed_Harrison. Congenital Rubella Syndrome The most serious consequence of rubella virus infection can develop when a woman becomes infected during pregnancy, particularly during the first trimester. The resulting complications may include miscarriage, fetal death, premature delivery, or live birth with congenital defects. Infants infected with rubella virus in utero may have myriad physical defects (Table 230e-1), which most commonly relate to the eyes, ears, and heart. This constellation of severe birth defects is known as congenital rubella syndrome. In addition to permanent manifestations, there are a host of transient physical manifestations, including thrombocytopenia with purpura/petechiae (e.g., dermal erythropoiesis, “blueberry muffin syndrome”). Some infants may be born with congenital rubella virus infection but have no apparent signs or symptoms of CRS and are referred to as “infants with congenital rubella infection only.”


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InternalMed_Harrison. DIAGNOSIS Acquired Rubella Clinical diagnosis of acquired rubella is difficult because of the mimicry of many illnesses with rashes, the varied Interstitial pneumonitis Congenital heart defects (patent ductus arteriosus, pulmonary arterial


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InternalMed_Harrison. Interstitial pneumonitis Congenital heart defects (patent ductus arteriosus, pulmonary arterial Thrombocytopenia with purpura/ stenosis) petechiae (e.g., dermal erythropoiesis, or “blueberry muffin syndrome”) Eye defects (cataracts, cloudy cornea, microphthalmos, pigmentary reti-Hemolytic anemia nopathy, congenital glaucoma) Bony radiolucencies Microcephaly Intrauterine growth retardation Central nervous system sequelae Adenopathy (mental and motor delay, autism) Meningoencephalitis clinical presentations, and the high rates of subclinical and mild disease. Illnesses that may be similar to rubella in presentation include scarlet fever, roseola, toxoplasmosis, fifth disease, measles, and illnesses with suboccipital and postauricular lymphadenopathy. Thus laboratory documentation of rubella virus infection is considered the only reliable way to confirm acute disease.


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InternalMed_Harrison. Laboratory assessment of rubella infection is conducted by serologic and virologic methods. For acquired rubella, serologic diagnosis is most common and depends on the demonstration of IgM antibodies in an acute-phase serum specimen or a fourfold rise in IgG antibody titer between acuteand convalescent-phase specimens. The enzyme-linked immunosorbent assay IgM capture technique is considered most accurate for serologic diagnosis, but the indirect IgM assay also is acceptable. After rubella virus infection, IgM antibody may be detectable for up to 6 weeks. In case of a negative result for IgM in specimens taken earlier than day 5 after rash onset, serologic testing should be repeated. Although uncommon, reinfection with rubella virus is possible, and IgM antibodies may be present. To detect a rise in IgG antibody titer indicative of acute disease, the acute-phase serum specimen should be collected within 7–10 days after onset of illness and the convalescent-phase specimen ~14–21 days


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InternalMed_Harrison. a rise in IgG antibody titer indicative of acute disease, the acute-phase serum specimen should be collected within 7–10 days after onset of illness and the convalescent-phase specimen ~14–21 days after the first specimen.


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InternalMed_Harrison. IgG avidity testing is used in conjunction with IgG testing. Low-avidity antibodies indicate recent infection. Mature (high-avidity) IgG antibodies most likely indicate an infection occurring at least 2 months previously. This test helps distinguish primary infection from reinfection. Avidity testing may be particularly useful in diagnosing rubella in pregnant women and assessing the risk of CRS. Rubella virus can be isolated from the blood and nasopharynx during the prodromal period and for as long as 2 weeks after rash onset. However, as the secretion of virus in individuals with acquired rubella is maximal just before or up to 4 days after rash onset, this is the optimal time frame for collecting specimens for viral cultures. Rubella can also be diagnosed by viral RNA detection in a reverse-transcriptase polymerase chain reaction (RT-PCR) assay.


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InternalMed_Harrison. Congenital Rubella Syndrome A clinical diagnosis of CRS is reasonable when an infant presents with a combination of cataracts, hearing impairment, and heart defects; this pattern is seen in ~10% of infants with CRS. Infants may present with different combinations of defects depending on when infection occurs during gestation. Hearing impairment is the most common single defect of CRS. However, as with acquired rubella, laboratory diagnosis of congenital infection is highly recommended, particularly because most features of the clinical presentation are nonspecific and may be associated with other intrauterine infections. Early diagnosis of CRS facilitates appropriate medical intervention for specific disabilities and prompts implementation of infection control measures.


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InternalMed_Harrison. Diagnostic tests used to confirm CRS include serologic assays and virus detection. In an infant with congenital infection, serum IgM antibodies are normally present for up to 6 months but may be detectable for up to 1 year after birth. In some instances, IgM may not be detectable until 1 month of age; thus infants who have symptoms consistent with CRS but who test negative shortly after birth should be retested at 1 month. A rubella serum IgG titer persisting beyond the time expected after passive transfer of maternal IgG antibody (i.e., a rubella titer that does not decline at the expected rate of a twofold dilution per month) is another serologic criterion used to confirm CRS.


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InternalMed_Harrison. In congenital infection, rubella virus is isolated most commonly from throat swabs and less commonly from urine and cerebrospinal fluid. Infants with congenital rubella may excrete virus for up to 1 year, but specimens for virus isolation are most likely to be positive if obtained within the first 6 months after birth. Rubella virus in infants with CRS can also be detected by RT-PCR. Rubella Diagnosis in Pregnant Women In the United States, screening for rubella IgG antibodies is recommended as part of routine prenatal care. Pregnant women with a positive IgG antibody serologic test are considered immune. Susceptible pregnant women should be vaccinated postpartum.


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InternalMed_Harrison. A susceptible pregnant woman exposed to rubella virus should be tested for IgM antibodies and/or a fourfold rise in IgG antibody titer between acuteand convalescent-phase serum specimens to determine whether she was infected during pregnancy. Pregnant women with evidence of acute infection must be clinically monitored, and gestational age at the time of maternal infection must be determined to assess the possibility of risk to the fetus. Of women infected with rubella virus during the first 11 weeks of gestation, up to 90% deliver an infant with CRS; for maternal infection during the first 20 weeks of pregnancy, the CRS rate is 20%.


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InternalMed_Harrison. No specific therapy is available for rubella virus infection. Symptom-based treatment for various manifestations, such as fever and arthralgia, is appropriate. Immunoglobulin does not prevent rubella virus infection after exposure and therefore is not recommended as routine postexposure prophylaxis. Although immunoglobulin may modify or suppress symptoms, it can create an unwarranted sense of security: infants with congenital rubella have been born to women who received immunoglobulin shortly after exposure. Administration of immunoglobulin should be considered only if a pregnant woman who has been exposed to rubella will not consider termination of the pregnancy under any circumstances. In such cases, IM administration of 20 mL of immunoglobulin within 72 h of rubella exposure may reduce—but does not eliminate—the risk of rubella.


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InternalMed_Harrison. After the isolation of rubella virus in the early 1960s and the occurrence of a devastating pandemic, a vaccine for rubella was developed and licensed in 1969. Currently, the majority of rubella-containing vaccines (RCVs) used worldwide are combined measles and rubella (MR) or measles, mumps, and rubella (MMR) formulations. A tetravalent measles, mumps, rubella, and varicella (MMRV) vaccine is available but is not widely used. The public health burden of rubella infection is measured primarily through the resulting CRS cases. The 1964–1965 rubella epidemic in the United States encompassed >30,000 infections during pregnancy. CRS occurred in ~20,000 infants born alive, including >11,000 infants who were deaf, >3500 infants who were blind, and almost 2000 infants who were mentally retarded. The cost of this epidemic exceeded $1.5 billion. In 1983, the cost per child with CRS was estimated at $200,000.


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InternalMed_Harrison. In most countries, there is little documented evidence to illuminate the epidemiology of CRS. Clusters of CRS cases have been reported in developing countries. Before the introduction of an immunization program, the incidence of CRS is 0.1–0.2 per 1000 live births during endemic periods and 1–4 per 1000 live births during epidemic periods. Where rubella virus is circulating and women of childbearing age are susceptible, CRS cases will continue to occur. The most effective method of preventing acquired rubella and CRS is through vaccination with an RCV. One dose induces seroconversion in ≥95% of persons ≥1 year of age. Immunity is considered long-term and 230e-3 3,500 Kilometers No (60 countries or 31%) Yes (134 countries or 69%) 0 875 1,750


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InternalMed_Harrison. FIGURE 230e-2 Countries using rubella vaccine in their national immunization schedule, 2012. (From the World Health Organization.) is probably lifelong. The most commonly used vaccine globally is the RA27/3 virus strain. The current recommendation for routine rubella vaccination in the United States is a first dose of MMR vaccine at 12–15 months of age and a second dose at 4–6 years. Target groups for rubella vaccine include children ≥1 year of age, adolescents and adults without documented evidence of immunity, individuals in congregate settings (e.g., college students, military personnel, child care and health care workers), and susceptible women before and after pregnancy.


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InternalMed_Harrison. Because of the theoretical risk of transmission of live attenuated rubella vaccine virus to the developing fetus, women known to be pregnant should not receive an RCV. In addition, pregnancy should be avoided for 28 days after receipt of an RCV. In follow-up studies of 680 unknowingly pregnant women who received rubella vaccine, no infant was born with CRS. Receipt of an RCV during pregnancy is not ordinarily a reason to consider termination of the pregnancy. As of 2012, 134 (69%) of the 194 member countries of the World Health Organization recommended inclusion of an RCV in the routine childhood vaccination schedule (Fig. 230e-2). Goals for control or elimination of rubella and CRS have been established in the American Region, the European Region, the South-East Asia Region, and the Western Pacific Region. The other two regions (Eastern Mediterranean and African) have not yet set such goals.


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InternalMed_Harrison. Mumps Steven A. Rubin, Kathryn M. Carbone DEFINITION Mumps is an illness characterized by acute-onset unilateral or bilateral tender, self-limited swelling of the parotid or other salivary gland(s) that lasts at least 2 days and has no other apparent cause. 231e


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InternalMed_Harrison. Mumps is caused by a paramyxovirus with a negative-strand, nonsegmented RNA genome of 15,384 bases encoding at least 8 proteins: the nucleo(N), phospho(P), V, matrix (M), fusion (F), small hydrophobic (SH), hemagglutinin-neuraminidase (HN), and large (L) proteins. The N, P, and L proteins together provide the polymerase activity responsible for genome transcription and replication. The viral genome is surrounded by a host cell–derived lipid bilayer envelope containing the M, F, SH, and HN proteins. The M protein is involved in viral assembly, whereas the HN and F proteins are responsible for cell attachment and entry and are the major targets of virus-neutralizing antibody. The V and SH proteins are accessory proteins, acting as antagonists of the host antiviral response; the former interferes with the interferon response and the latter with the tumor necrosis factor α (TNF-α)–mediated apoptotic signaling pathway. Because of the hypervariability of the SH gene, its nucleotide sequence


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InternalMed_Harrison. with the interferon response and the latter with the tumor necrosis factor α (TNF-α)–mediated apoptotic signaling pathway. Because of the hypervariability of the SH gene, its nucleotide sequence is used to “genotype” the virus for molecular epidemiologic purposes. Thus far, 12 mumps virus genotypes have been assigned by SH gene sequence and are designated A–N (with the exclusion of E and M, which have been merged with genotypes C and K, respectively).


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InternalMed_Harrison. Nucleotide sequencing of clinical isolates shows that virus genotypes D and G circulate predominantly in the Western Hemisphere; genotypes F, C, and I in the Asia–Pacific region; and genotypes B, H, J, and K in the Southern Hemisphere (Fig. 231e-1). Although numerous mumps virus genotypes have been identified and some vary antigenically from others, only one serotype exists, and there is no evidence to suggest that certain circulating virus strains are more virulent or contagious than others.


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InternalMed_Harrison. Mumps is endemic worldwide, with epidemics every 3–5 years in unvaccinated populations. These epidemics typically occur in locations where children and young adults congregate, such as schools, military barracks, and other institutions. In countries without national mumps vaccination programs, the estimated annual global incidence is 100–1000 cases per 100,000 population. After the introduction of mumps vaccine in the United States in 1967, the number of reported cases declined dramatically. By 2001, fewer than 300 cases were reported, representing a 99.8% reduction from prevaccineera levels. Mumps incidence remained at historic lows in the United States until 2006, when 6584 cases were reported—the largest outbreak since 1987. At the time of the 2006 outbreak, the disease was resurging globally, even in populations with high-level vaccination coverage. The number of reported U.S. cases declined precipitously in the 2 years that followed but then spiked in 2009–2010, with focal


InternalMed_Harrison

InternalMed_Harrison. globally, even in populations with high-level vaccination coverage. The number of reported U.S. cases declined precipitously in the 2 years that followed but then spiked in 2009–2010, with focal outbreaks in New York and New Jersey, and again in 2011, with a focal outbreak in California. A recent study by the Centers for Disease Control and Prevention (CDC) showed that two-dose coverage with measles– mumps–rubella (MMR) vaccine in major U.S. cities (94.8%) remains at or very near the level needed to contain these childhood infections; however, focal areas with inadequate vaccination coverage still leave some children at risk. Sporadic, large-scale mumps outbreaks continue to be reported worldwide, sometimes in countries where the disease was once under control.


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InternalMed_Harrison. Although historically a disease of unvaccinated children, with the largest proportion of cases occurring in children 5–9 years of age during the prevaccine era, mumps now frequently occurs in older age groups—primarily college students, most of whom were vaccinated in early childhood. This shift in age distribution and the occurrence of mumps in vaccinated populations are probably the result of several coincident circumstances, including (1) situations promoting the spread of respiratory viruses among young adults (e.g., residence in college dormitories), (2) waning of vaccine immunity with time, (3) lack of endemically circulating wild-type virus to periodically boost vaccine-induced immune responses, and (4) continuing global epidemics (due to either lack of mumps vaccination programs or, where such programs do exist, low rates of mumps vaccination). The notable


InternalMed_Harrison

InternalMed_Harrison. FIGurE 231e-1 Distribution of reported mumps genotypes, 2005–2011 (data as of April 20, 2012). Pie-slice size is proportional to the number of years each genotype was reported. (Figure courtesy of WHO, with permission; http://www.who.int/immunization_monitoring/diseases/ mumps/en/index.html; accessed September 11, 2012.) decline in mumps vaccination–induced immunity with time may be due to both declining titers and decreasing avidity of antibodies. The waning of mumps immunity over time is supported by studies suggesting that a third dose of MMR vaccine significantly reduces the mumps attack rate; however, these studies were not adequately controlled to rule out the possibility that the observed declines in mumps incidence were unrelated to the intervention. Therefore, the effectiveness of a third dose of MMR vaccine remains to be demonstrated.


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InternalMed_Harrison. Humans are the only natural hosts for mumps virus infection. The incubation period of mumps is ~19 days (range, 7–23 days). The virus is transmitted by the respiratory route via droplets, saliva, and fomites. Mumps virus is typically shed from 1 week before to 1 week after symptom onset, although this window appears to be narrower in vaccinated individuals. Persons are most contagious 1–2 days before onset of clinical symptoms. Inference from related respiratory diseases and animal studies indicates that primary replication likely occurs in the nasal mucosa or upper respiratory mucosal epithelium. Mononuclear cells and cells within regional lymph nodes can become infected; such infection facilitates the development of viremia and poses a risk for a wide array of acute inflammatory reactions. Classic sites of mumps virus replication include the salivary glands, testes, pancreas, ovaries, mammary glands, and central nervous system (CNS).


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InternalMed_Harrison. Little is known about the pathology of mumps since the disease is rarely fatal. The virus replicates well in glandular epithelium, but classic parotitis is not a necessary component of mumps infection. Affected glands contain perivascular and interstitial mononuclear cell infiltrates and exhibit hemorrhage with prominent edema. Necrosis of acinar and epithelial duct cells is evident in the salivary glands and in the germinal epithelium of the seminiferous tubules of the testes. The virus probably enters cerebrospinal fluid (CSF) through the choroid plexus or via transiting mononuclear cells during plasma viremia. Although relevant data are limited, typical mumps encephalitis appears to be secondary to respiratory spread and is probably a parainfectious process, as suggested by perivenous demyelination, perivascular mononuclear cell inflammation, and relative sparing of neurons. Although rare, presumed primary encephalitis has been associated with mumps virus isolation from brain


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InternalMed_Harrison. demyelination, perivascular mononuclear cell inflammation, and relative sparing of neurons. Although rare, presumed primary encephalitis has been associated with mumps virus isolation from brain tissue. Evidence of placental and intrauterine spread in pregnancy has been found in both early and late gestation.


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InternalMed_Harrison. Up to half of mumps virus infections are asymptomatic or lead to nonspecific respiratory symptoms. Inapparent infections are more common in adults than in children. The prodrome of mumps consists of low-grade fever, malaise, myalgia, headache, and anorexia. Mumps parotitis—acute-onset unilateral or bilateral swelling of the parotid or other salivary glands that lasts >2 days and has no other apparent cause—develops in 70–90% of symptomatic infections, usually within 24 h of prodromal symptoms but sometimes as long as 1 week thereafter. Parotitis is generally bilateral, although the two sides may not be involved synchronously. Unilateral involvement is documented in about one-third of cases. Swelling of the parotid is accompanied by tenderness and obliteration of the space between the earlobe and the angle of the mandible (Figs. 231e-2 and 231e-3). The patient frequently reports an earache and finds it difficult to eat, swallow, or talk. The orifice of the parotid duct is commonly red


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InternalMed_Harrison. and the angle of the mandible (Figs. 231e-2 and 231e-3). The patient frequently reports an earache and finds it difficult to eat, swallow, or talk. The orifice of the parotid duct is commonly red and swollen. The submaxillary and sublingual glands are involved less often than the parotid gland and are almost never involved alone. Glandular swelling increases for a few days and then gradually subsides, disappearing within 1 week. Recurrent sialadenitis is a rare sequela of mumps parotitis. In ~6% of mumps cases, obstruction of lymphatic drainage secondary to bilateral salivary gland swelling may lead to presternal pitting edema, associated often with submandibular adenitis and rarely with the more life-threatening supraglottic edema.


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InternalMed_Harrison. FIGurE 231e-2 A comparison of a person before acquiring mumps (A) and on day 3 (B) of acute bilateral parotitis. (Courtesy of patient C.M. From Shanley JD. The resurgence of mumps in young adults and adolescents. Cleve Clin J Med 2007; 74:42-48. Reprinted with permission. Copyright © 2007 Cleveland Clinic Foundation. All rights reserved.)


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InternalMed_Harrison. Epididymo-orchitis is the next most common manifestation of mumps, developing in 15–30% of cases in postpubertal males, with bilateral involvement in 10–30% of those cases. Orchitis, accompanied by fever, typically occurs during the first week of parotitis but can develop up to 6 weeks after parotitis or in its absence. The testis is painful and tender and can be enlarged to several times its normal size; this condition usually resolves within 1 week. Testicular atrophy develops in one-half of affected men. Sterility after mumps is rare, although subfertility is estimated to occur in 13% of cases of unilateral orchitis and in 30–87% of cases of bilateral orchitis. Oophoritis occurs in ~5% of women with mumps and may be associated with lower abdominal pain and vomiting but has only rarely been associated with sterility or premature menopause. Mumps infection in postpubertal women may also present with mastitis.


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InternalMed_Harrison. Documented CSF pleocytosis indicates that mumps virus invades the CNS in ~50% of cases; however, symptomatic CNS disease, typically in the form of aseptic meningitis, occurs in <10% of cases, with a male predominance. CNS symptoms of aseptic meningitis (e.g., stiff neck, headache, and drowsiness) appear ~5 days after parotitis and also occur often in the absence of parotid involvement. Within the first 24 h polymorphonuclear leukocytes may predominate in CSF (1000–2000 cells/μL), but by the second day nearly all the cells are lymphocytes. The glucose level in CSF may be low and the protein concentration high, a pattern reminiscent of bacterial meningitis. Mumps meningitis is a self-limited manifestation without significant risk of death or long-term sequelae. Cranial nerve palsies have occasionally led to permanent sequelae, particularly deafness. The reported incidence of mumps-associated hearing loss varies between 1 in 1000 and 1 in 100,000. In ~0.1% of infections, mumps virus may


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InternalMed_Harrison. led to permanent sequelae, particularly deafness. The reported incidence of mumps-associated hearing loss varies between 1 in 1000 and 1 in 100,000. In ~0.1% of infections, mumps virus may cause encephalitis, which presents as high fever with marked changes in the level of consciousness, seizures, and focal neurologic symptoms. Electroencephalographic abnormalities may be seen. Permanent sequelae are sometimes identified in survivors, and adult infections more commonly have poor outcomes than do pediatric infections. The mortality rate associated with mumps encephalitis is ~1.5%. Other CNS problems occasionally associated with mumps include cerebellar ataxia, facial palsy, transverse myelitis, hydrocephalus, Guillain-Barré syndrome, flaccid paralysis, and behavioral changes.


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InternalMed_Harrison. FIGurE 231e-3 Schematic drawing of a parotid gland infected with mumps virus (right) compared with a normal gland (left). An enlarged cervical lymph node is usually posterior to the imaginary line. (Reprinted with permission from Gershon A et al: Mumps, in Krugman’s Infectious Diseases of Children, 11th ed. Philadelphia, Elsevier, 2004, p 392.)


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InternalMed_Harrison. Mumps pancreatitis, which may present as abdominal pain, occurs in ~4% of infections but is difficult to diagnose because an elevated serum amylase level can be associated with either parotitis or pancreatitis. An etiologic association of mumps virus and juvenile diabetes mellitus remains controversial. Myocarditis and endocardial fibroelastosis are rare and self-limited but may represent severe complications of mumps infection; however, mumps-associated electrocardiographic abnormalities have been reported in up to 15% of cases. Other unusual complications include thyroiditis, nephritis, arthritis, hepatic disease, keratouveitis, and thrombocytopenic purpura. Abnormal renal function is common, but severe, life-threatening nephritis is rare. It remains at issue whether an excessive number of spontaneous abortions are associated with gestational mumps. Mumps in pregnancy does not appear to lead to premature birth, low birth weight, or fetal malformations.


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InternalMed_Harrison. During a mumps outbreak, the diagnosis is made easily in patients with parotitis and a history of recent exposure; however, when disease incidence is low, other causes of parotitis should be considered and laboratory testing is required for case confirmation. Infectious causes of parotitis include other viruses (e.g., HIV, coxsackievirus, parainfluenza virus type 3, influenza A virus, Epstein-Barr virus, adenovirus, parvovirus B19, lymphocytic choriomeningitis virus, human herpes-virus 6), gram-positive bacteria, atypical mycobacteria, and Bartonella species. Rarely, other gram-negative or anaerobic bacteria are associated with parotitis. Parotitis can also develop in the setting of sarcoidosis, Sjögren’s syndrome, Mikulicz’s syndrome, Parinaud’s syndrome, uremia, diabetes mellitus, laundry starch ingestion, malnutrition, cirrhosis, and some drug treatments. Unilateral parotitis can be caused by ductal obstruction, cysts, and tumors. In the absence of parotitis or other salivary gland


InternalMed_Harrison

InternalMed_Harrison. starch ingestion, malnutrition, cirrhosis, and some drug treatments. Unilateral parotitis can be caused by ductal obstruction, cysts, and tumors. In the absence of parotitis or other salivary gland enlargement, symptoms of other visceral organ and/or CNS involvement may predominate, and a laboratory diagnosis is required. Other entities should be considered when manifestations consistent with mumps appear in organs other than the parotid. Testicular torsion may produce a painful scrotal mass resembling that seen in mumps orchitis. Other viruses (e.g., enteroviruses) may cause aseptic meningitis that is clinically indistinguishable from that due to mumps virus.


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InternalMed_Harrison. Laboratory diagnosis is primarily based on detection of viral RNA by reverse-transcriptase polymerase chain reaction (RT-PCR) or on serology. Detection of viral antigens (e.g., via mumps virus–specific immunofluorescent staining of cultured clinical specimens) is comparatively inefficient and is no longer commonly performed.


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InternalMed_Harrison. For RT-PCR-based testing, viral RNA can be extracted either directly from clinical samples or from cell cultures incubated with clinical samples. Buccal swabs appear to be the best specimens for virus detection, particularly when obtained within 2 days of clinical onset; however, mumps virus can also be detected readily in throat swabs and saliva and, in cases of meningitis, in CSF. Despite the apparent high frequency of viremia during mumps, mumps virus has rarely been detected in blood. The ability to detect viral RNA in clinical samples rapidly diminishes beyond the first week after symptom onset, and 231e-3 in several studies rates of virus detection were substantially lower in recipients of two vaccine doses than in unvaccinated persons or recipients of one dose. The rate of false-negative RT-PCR findings can be quite high, approaching 70% in some studies.


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InternalMed_Harrison. A serologic diagnosis of mumps is typically made by enzyme-linked immunosorbent assay (ELISA). The data must be interpreted with caution. In vaccinated persons with mumps, IgM is typically absent; thus, a negative IgM result in a vaccinated person does not rule out mumps. In addition, regardless of vaccination status, IgM may not be detectable if serum is assayed too early (prior to day 3 of symptom onset) or too late (beyond 6 weeks after symptom onset) in the course of disease. Reliance on a rise in IgG titer in paired acuteand convalescent-phase sera also is problematic: IgG titers in convalescent-phase sera may be only nominally greater than those in acute-phase sera. Thus, at present, the capacity of RNA or viral antigen detection to confirm cases is much greater than that of serologic testing. Traditional and labor-intensive serologic tests such as complement fixation, hemagglutination inhibition, and virus neutralization are now performed only rarely. The main downside to


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InternalMed_Harrison. testing. Traditional and labor-intensive serologic tests such as complement fixation, hemagglutination inhibition, and virus neutralization are now performed only rarely. The main downside to replacement of these functional serologic assays with the more rapid ELISA method is the latter’s detection of all virus-specific antibodies, including those that are nonneutralizing (i.e., nonprotective). Thus, an individual who is seropositive by ELISA may lack protective levels of antibody. While there is a strong association between the presence of mumps virus neutralizing antibody and protection from disease, an absolute antibody titer predictive of serologic protection is lacking; in this respect, mumps differs from other respiratory infections, such as measles.


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InternalMed_Harrison. Mumps is generally a benign, self-resolving illness. Therapy for parotitis and other clinical manifestations is symptom based and supportive. The administration of analgesics and the application of warm or cold compresses to the parotid area may be helpful. Testicular pain may be minimized by the local application of cold compresses and gentle support for the scrotum. Anesthetic blocks also may be used. Neither the administration of glucocorticoids nor incision of the tunica albuginea is of proven value in severe orchitis. Anecdotal information on a small number of patients with orchitis suggests that SC administration of interferon α2b may help preserve the organ and fertility. Lumbar puncture is occasionally performed to relieve headache associated with meningitis. Mumps immune globulin has not been consistently shown to be effective in preventing mumps and is not recommended for treatment or postexposure prophylaxis.


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InternalMed_Harrison. Vaccination is the only practical control measure. Nearly all developed countries use mumps-containing vaccines, but in many countries mumps is not a notifiable disease and vaccination is often voluntary. However, where used, mumps vaccination has had a tremendous impact, with reductions in incidence and morbidity typically exceeding 90%. Despite the tremendous success of mumps vaccination programs, large mumps outbreaks continue to occur globally, even in settings of high-level two-dose vaccine coverage. Whereas outbreaks historically involved young (often unvaccinated) children in primary and secondary schools, more recent outbreaks have predominantly involved young adults, particularly on college and university campuses. While primary and secondary (waning-immunity) vaccine failures have been hypothesized to be factors in mumps outbreaks in several countries, in some countries other factors may have played a role, such as lack of compliance with the recommended vaccine schedule,


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InternalMed_Harrison. have been hypothesized to be factors in mumps outbreaks in several countries, in some countries other factors may have played a role, such as lack of compliance with the recommended vaccine schedule, changes to vaccination schedules resulting in missed cohorts, or changes in population demographics, such as large-scale immigration. In the United States, the benefit-cost ratios for mumps vaccination alone are >13 for direct costs (e.g., medical expenses) and >24 for societal costs (including productivity losses for patients and caregivers).


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InternalMed_Harrison. Several mumps virus vaccines are used throughout the world; in the United States, only the live attenuated Jeryl Lynn strain is used. Current recommendations are that mumps vaccine be administered as part of the combined trivalent measles-mumps-rubella vaccine (M-M-R® II) or the quadrivalent measles-mumps-rubella-varicella vaccine (ProQuad®). Monovalent vaccine is no longer produced for the U.S. market but is available in other countries. Before administering mumps-containing vaccine, physicians should always consult the latest recommendations from the Advisory Committee on Immunization Practices (ACIP). Current recommendations for children specify two doses of mumps-containing vaccine: the first dose given on or after the first birthday and the second dose administered no earlier than 28 days after the first. In the United States, children often receive the second dose between the ages of 4 and 6 years.


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InternalMed_Harrison. In 2009, the ACIP revised its recommendations for evidence of mumps immunity in health care personnel to include (1) documented administration of two doses of a preparation containing live mumps vaccine, (2) laboratory evidence of immunity or laboratory confirmation of disease, or (3) birth date before 1957. For unvaccinated health care personnel born before 1957 who lack laboratory evidence of mumps immunity or laboratory confirmation of mumps, health care facilities should consider two doses of MMR vaccine separated by the appropriate interval; during a mumps outbreak, vaccination of these individuals is recommended.


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InternalMed_Harrison. Mumps vaccine contains live attenuated virus. It is not recommended for pregnant women, for individuals who have had a life-threatening allergic reaction to components of the vaccine, or for people in settings of clinically significant primary or secondary immunosuppression. (For details, see the ACIP guidelines on the CDC’s website [www.cdc.gov/vaccines/pubs/acip-list.htm].) Occasionally, febrile reactions and parotitis have been reported soon after mumps vaccination. Allergic reactions after vaccination (e.g., rash and pruritus) are uncommon and are usually mild and self-limited. More serious complications, such as aseptic meningitis, have been causally associated with certain vaccine strains but not with the Jeryl Lynn strain.


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InternalMed_Harrison. Immunity to mumps is associated with the development of neutralizing antibody, although a specific correlate of protection has not been established. Seroconversion occurs in ~95% of recipients of the Jeryl Lynn strain; however, vaccine efficacy is ~80% for one dose and 90% for two doses. Recent data indicate declining seropositivity rates with time since vaccination. Studies are under way to assess the value of including a third dose in the immunization schedule. Although it is generally accepted that mumps virus is serologically monotypic, antigenic differences between virus isolates have been detected. It is unclear whether such differences can lead to immune escape. The role of the cellular arm of the immune response is unclear, but there is evidence that it may help limit virus spread and complications. The authors thank and acknowledge Dr. Anne Gershon, the author of this chapter in earlier editions.


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InternalMed_Harrison. The authors thank and acknowledge Dr. Anne Gershon, the author of this chapter in earlier editions. Rabies and Other Rhabdovirus InfectionsCHAPTER 232Rabies and Other Rhabdovirus Infections Alan C. Jackson RABIES Rabies is a rapidly progressive, acute infectious disease of the central 232 nervous system (CNS) in humans and animals that is caused by infection with rabies virus. The infection is normally transmitted from animal vectors. Rabies has encephalitic and paralytic forms that progress to death.


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InternalMed_Harrison. Rabies virus is a member of the family Rhabdoviridae. Two genera in this family, Lyssavirus and Vesiculovirus, contain species that cause human disease. Rabies virus is a lyssavirus that infects a broad range of animals and causes serious neurologic disease when transmitted to humans. This single-strand RNA virus has a nonsegmented, negative-sense (antisense) genome that consists of 11,932 nucleotides and encodes 5 proteins: nucleocapsid protein, phosphoprotein, matrix protein, glycoprotein, and a large polymerase protein. Rabies virus variants, which can be characterized by distinctive nucleotide sequences, are associated with specific animal reservoirs. Six other non–rabies virus species in the Lyssavirus genus have been reported to cause a clinical picture similar to rabies. Vesicular stomatitis virus, a vesiculovirus, causes vesiculation and ulceration in cattle, horses, and other animals and causes a self-limited, mild, systemic illness in humans (see “Other Rhabdoviruses,”


InternalMed_Harrison

InternalMed_Harrison. stomatitis virus, a vesiculovirus, causes vesiculation and ulceration in cattle, horses, and other animals and causes a self-limited, mild, systemic illness in humans (see “Other Rhabdoviruses,” below).


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InternalMed_Harrison. 1300 EPIDEMIOLOGY Rabies is a zoonotic infection that occurs in a variety of mammals throughout the world except in Antarctica and on some islands. Rabies virus is usually transmitted to humans by the bite of an infected animal. Worldwide, endemic canine rabies is estimated to cause 55,000 human deaths annually. Most of these deaths occur in Asia and Africa, with rural populations and children most frequently affected. Thus, in many resource-poor and resource-limited countries, canine rabies continues to be a threat to humans. However, in Latin America, rabies control efforts in dogs have been quite successful in recent years. Endemic canine rabies has been eliminated from the United States and most other resource-rich countries. Rabies is endemic in wildlife species, and a variety of animal reservoirs have been identified in different countries. Surveillance data from 2012 identified 6162 confirmed animal cases of rabies in the United States (including Puerto Rico). Only 8% of these


InternalMed_Harrison

InternalMed_Harrison. reservoirs have been identified in different countries. Surveillance data from 2012 identified 6162 confirmed animal cases of rabies in the United States (including Puerto Rico). Only 8% of these cases were in domestic animals, including 257 cases in cats, 84 in dogs, and 115 in cattle. In North American wildlife reservoirs, including bats, raccoons, skunks, and foxes, the infection is endemic, with involvement of one or more rabies virus variants in each reservoir species (Fig. 232-1). “Spillover” of rabies to other wildlife species and to domestic animals occurs. Bat rabies virus variants are present in every state except Hawaii and are responsible for most indigenously acquired human rabies cases in the United States. Raccoon rabies is endemic along the entire eastern coast of the United States. Skunk rabies is present in the midwestern states, with another focus in California. Rabies in foxes occurs in Texas, New Mexico, Arizona, and Alaska. In Canada and Europe, epizootics of


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InternalMed_Harrison. States. Skunk rabies is present in the midwestern states, with another focus in California. Rabies in foxes occurs in Texas, New Mexico, Arizona, and Alaska. In Canada and Europe, epizootics of rabies in red foxes have been well controlled with the use of baits containing rabies vaccine. A similar approach is used in Canada to control raccoon rabies. Rabies virus variants isolated from humans or other mammalian species can be identified by reverse-transcription polymerase chain reaction (RT-PCR) amplification and sequencing or by characterization with monoclonal antibodies. These techniques are helpful in human cases with no known history of exposure. Worldwide, most human rabies is transmitted from dogs in countries with endemic canine rabies and dog-to-dog transmission, and human cases can be imported by travelers returning from these regions. In North America, human disease is usually associated with transmission from bats; there may be no known history of bat bite or other bat


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InternalMed_Harrison. can be imported by travelers returning from these regions. In North America, human disease is usually associated with transmission from bats; there may be no known history of bat bite or other bat exposure in these cases. Most human cases are due to a bat rabies virus variant associated with silver-haired and tricolored bats. These are small bats whose bite may not be recognized, and the virus has adapted for replication at skin temperature and in cell types that are present in the skin.


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InternalMed_Harrison. Transmission from nonbite exposures is relatively uncommon. Aerosols generated in the laboratory or in caves containing millions of Brazilian free-tail bats have rarely caused human rabies. Transmission has resulted from corneal transplantation and also from solid organ transplantation and a vascular conduit (for a liver transplant) from undiagnosed donors with rabies in Texas, Florida, and Germany. Human-to-human transmission is extremely rare, although hypothetical concern about transmission to health care workers has prompted the implementation of barrier techniques to prevent exposures.


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InternalMed_Harrison. The incubation period of rabies (defined as the interval between exposure and the onset of clinical disease) is usually 20–90 days but in rare cases is as short as a few days or >1 year. During most of the incubation period, rabies virus is thought to be present at or close to the site of inoculation (Fig. 232-2). In muscles, the virus is known to bind to nicotinic acetylcholine receptors on postsynaptic membranes at neuromuscular junctions, but the exact details of viral entry into the skin and SC tissues have not yet been clarified. Rabies virus spreads centripetally along peripheral nerves toward the CNS at a rate of up to ~250 mm/d via retrograde fast axonal transport to the spinal cord or brainstem. Once the virus enters the CNS, it rapidly disseminates to other regions of the CNS via fast axonal transport along neuroanatomic connections. Neurons are prominently infected in rabies; infection of astrocytes is unusual. After CNS infection becomes established, there is centrifugal


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InternalMed_Harrison. fast axonal transport along neuroanatomic connections. Neurons are prominently infected in rabies; infection of astrocytes is unusual. After CNS infection becomes established, there is centrifugal spread along sensory and autonomic nerves to other tissues, including the salivary glands, heart, adrenal glands, and skin. Rabies virus replicates in acinar cells of the salivary glands and is secreted in the saliva of rabid animals that serve as vectors of


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InternalMed_Harrison. FIGuRE 232-1 Distribution of the major rabies virus variants among wild terrestrial reservoirs in the United States and Puerto Rico, 2008–2012. *Potential host-shift event. (From JL Dyer et al: J Am Vet Med Assoc 243:805, 2013.)


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InternalMed_Harrison. Eye Salivary glands Dorsal root ganglion Spinal cord Brain Infection of brain neurons with neuronal dysfunction 6 Centrifugal spread along nerves to salivary glands, skin, cornea, and other organs 7 Virus binds to nicotinic acetylcholine receptors at neuromuscular junction 3 Replication in motor neurons of the spinal cord and local dorsal root ganglia and rapid ascent to brain 5 Virus inoculated 1 Viral replication in muscle 2 Virus travels within axons in peripheral nerves via retrograde fast axonal transport 4 Sensory nerves to skin Skeletal muscle FIGuRE 232-2 Schematic representation of the pathogenetic events following periph-eral inoculation of rabies virus by an animal bite. (Adapted from Jackson AC: Human disease, in Rabies: scientific basis of the disease and its management, 3rd ed., AC Jackson [ed], Oxford, UK, Elsevier Academic Press, 2013, pp 269–298; with permission.)


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InternalMed_Harrison. In rabies, the emphasis must be on postexposure prophylaxis (PEP) initiated before any symptoms or signs develop. Rabies should usually be suspected on the basis of the clinical presentation. The disease usually presents as atypical encephalitis with relative preservation of consciousness. Rabies may be difficult to recognize late in the clinical course when progression to coma has occurred. A minority of patients present with acute flaccid paralysis. There are prodromal, acute neurologic, and comatose phases that usually progress to death despite aggressive therapy (Table 232-1).


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InternalMed_Harrison. Prodromal Features The clinical features of rabies begin with nonspecific prodromal manifestations, including fever, malaise, headache, nausea, and vomiting. Anxiety or agitation may also occur. The earliest specific neurologic symptoms of rabies include paresthesias, pain, or pruritus near the site of the exposure, one or more of which occur in 50–80% of patients and strongly suggest rabies. The wound has usually healed by this point, and these symptoms probably reflect infection with associated inflammatory changes in local dorsal root or cranial sensory ganglia.


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InternalMed_Harrison. Encephalitic Rabies Two acute neurologic forms of rabies are seen in humans: encephalitic (furious) in 80% and paralytic in 20%. Some of the manifestations of encephalitic rabies, including fever, confusion, hallucinations, combativeness, and seizures, may be seen in other viral encephalitides as well. Autonomic dysfunction is common and may result in hypersalivation, gooseflesh, cardiac arrhythmia, and priapism. In encephalitic rabies, episodes of hyperexcitability are typically followed by periods of complete lucidity that become shorter as the disease progresses. Rabies encephalitis is distinguished by early brainstem involvement, which results in the classic features of hydrophobia (involuntary, painful contraction of the diaphragm and accessory respiratory, laryngeal, and pharyngeal muscles in response to swallowing liquids) the disease. There is no well-documented evidence for hematogenous spread of rabies virus.


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InternalMed_Harrison. Pathologic studies show mild inflammatory changes in the CNS in rabies, with mononuclear inflammatory infiltration in the leptomeninges, perivascular regions, and parenchyma, including microglial nodules called Babes nodules. Degenerative neuronal changes usually are not prominent, and there is little evidence of neuronal death; neuronophagia is observed occasionally. The pathologic changes are surprisingly mild in light of the clinical severity and fatal outcome of the disease. The most characteristic pathologic finding in rabies is the Negri body (Fig. 232-3). Negri bodies are eosinophilic cytoplasmic inclusions in brain neurons that are composed of rabies virus proteins and viral RNA. These inclusions occur in a minority of infected neurons, are commonly observed in Purkinje cells of the cerebellum and in pyramidal neurons of the hippocampus, and are less frequently seen in cortical and brainstem neurons. Negri bodies are not observed in all cases of rabies. The lack of prominent


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InternalMed_Harrison. the cerebellum and in pyramidal neurons of the hippocampus, and are less frequently seen in cortical and brainstem neurons. Negri bodies are not observed in all cases of rabies. The lack of prominent degenerative neuronal changes has led to the concept that neuronal dysfunction—rather than neuronal death—is responsible for clinical disease in rabies. The basis for behavioral changes, including the aggressive behavior of rabid animals, is not well understood.


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InternalMed_Harrison. and aerophobia (the same features caused by stimulation from a draft of air). These symptoms are probably due to dysfunction of infected brainstem neurons that normally inhibit inspiratory neurons near the nucleus ambiguus, resulting in exaggerated defense reflexes that protect the respiratory tract. The combination of hypersalivation and pharyngeal dysfunction is also responsible for the classic appearance of “foaming at the mouth” (Fig. 232-4). Brainstem dysfunction progresses rapidly, and coma—followed within days by death—is the rule unless the course is prolonged by supportive measures. With such measures, late complications can include cardiac and/or respiratory failure, disturbances of water balance (syndrome of inappropriate antidiuretic hormone secretion or diabetes insipidus), noncardiogenic pulmonary edema, and gastrointestinal hemorrhage. Cardiac arrhythmias may be due to dysfunction affecting vital centers in the brainstem or to myocarditis. Multiple-organ failure is


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InternalMed_Harrison. noncardiogenic pulmonary edema, and gastrointestinal hemorrhage. Cardiac arrhythmias may be due to dysfunction affecting vital centers in the brainstem or to myocarditis. Multiple-organ failure is common in patients treated aggressively in critical care units.


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InternalMed_Harrison. Paralytic Rabies About 20% of patients have paralytic rabies in which muscle weakness predominates and cardinal features of encephalitic rabies (hyperexcitability, hydrophobia, and aerophobia) are lacking. There is early and prominent flaccid muscle weakness, often beginning in the bitten extremity and spreading to produce quadriparesis and facial FIGuRE 232-3 Three large Negri bodies in the cytoplasm of a cerebellar Purkinje cell from an 8-year-old boy who died of rabies after being bitten by a rabid dog in Mexico. (From AC Jackson, E Lopez-Corella: N Engl J Med 335:568, 1996. © Massachusetts Medical Society.) weakness. Sphincter involvement is common, sensory involvement is usually mild, and these cases are commonly misdiagnosed as Guillain-Barré syndrome. Patients with paralytic rabies generally survive a few days longer than those with encephalitic rabies, but multiple-organ failure nevertheless ensues.


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InternalMed_Harrison. Most routine laboratory tests in rabies yield normal results or show nonspecific abnormalities. Complete blood counts are usually normal. Examination of cerebrospinal fluid (CSF) often reveals mild mononuclear cell pleocytosis with a mildly elevated protein level. Severe pleocytosis (>1000 white cells/μL) is unusual and should prompt a search for an alternative diagnosis. CT head scans are usually normal in rabies. MRI brain scans may show signal abnormalities in the brainstem or other gray-matter areas, but these findings are variable and nonspecific. Electroencephalograms show only nonspecific abnormalities. Of course, important tests in suspected cases of rabies include those that may identify an alternative, potentially treatable diagnosis (see “Differential Diagnosis,” below). Source: MAW Hattwick: Rabies virus, in Principles and Practice of Infectious Diseases, GL Mandell et al (eds). New York, Wiley, 1979, pp 1217–1228. Adapted with permission from Elsevier.


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InternalMed_Harrison. Source: MAW Hattwick: Rabies virus, in Principles and Practice of Infectious Diseases, GL Mandell et al (eds). New York, Wiley, 1979, pp 1217–1228. Adapted with permission from Elsevier. FIGuRE 232-4 Hydrophobic spasm of inspiratory muscles associ-ated with terror in a patient with encephalitic (furious) rabies who is attempting to swallow water. (Copyright DA Warrell, Oxford, UK; with permission.)


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InternalMed_Harrison. In North America, a diagnosis of rabies often is not considered until relatively late in the clinical course, even with a typical clinical presentation. This diagnosis should be considered in patients presenting with acute atypical encephalitis or acute flaccid paralysis, including those in whom Guillain-Barré syndrome is suspected. The absence of an animal-bite history is common in North America. The lack of hydrophobia is not unusual in rabies. Once rabies is suspected, rabies-specific laboratory tests should be performed to confirm the diagnosis. Diagnostically useful specimens include serum, CSF, fresh saliva, skin biopsy samples from the neck, and brain tissue (rarely obtained before death). Because skin biopsy relies on the demonstration of rabies virus antigen in cutaneous nerves at the base of hair follicles, samples are usually taken from hairy skin at the nape of the neck. Corneal impression smears are of low diagnostic yield and are generally not performed. Negative


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InternalMed_Harrison. at the base of hair follicles, samples are usually taken from hairy skin at the nape of the neck. Corneal impression smears are of low diagnostic yield and are generally not performed. Negative antemortem rabies-specific laboratory tests never exclude a diagnosis of rabies, and tests may need to be repeated after an interval for diagnostic confirmation.


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InternalMed_Harrison. Rabies Virus–Specific Antibodies In a previously unimmunized patient, serum neutralizing antibodies to rabies virus are diagnostic. However, because rabies virus infects immunologically privileged neuronal tissues, serum antibodies may not develop until late in the disease. Antibodies may be detected within a few days after the onset of symptoms, but some patients die without detectable antibodies. The presence of rabies virus–specific antibodies in the CSF suggests rabies encephalitis, regardless of immunization status. A diagnosis of rabies is questionable in patients who recover from rabies without developing serum neutralizing antibodies to rabies virus.


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InternalMed_Harrison. RT-PCR Amplification Detection of rabies virus RNA by RT-PCR is highly sensitive and specific. This technique can detect virus in fresh saliva samples, skin, CSF, and brain tissues. In addition, RT-PCR with genetic sequencing can distinguish among rabies virus variants, permitting identification of the probable source of an infection. Direct Fluorescent Antibody Testing Direct fluorescent antibody (DFA) testing with rabies virus antibodies conjugated to fluorescent dyes is highly sensitive and specific and can be performed quickly and applied to skin biopsies and brain tissue. In skin biopsies, rabies virus antigen may be detected in cutaneous nerves at the base of hair follicles.


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InternalMed_Harrison. The diagnosis of rabies may be difficult without a history of animal exposure, and no exposure to an animal (e.g., a bat) may be recalled. The presentation of rabies is usually quite different from that of acute viral encephalitis due to most other causes, including herpes simplex encephalitis and arboviral (e.g., West Nile) encephalitis. Early neurologic symptoms may occur at the site of the bite, and there may be early features of brainstem involvement with preservation of consciousness. Anti-N-methyl-d-aspartate receptor (anti-NMDA) encephalitis occurs in young patients (especially females) and is characterized by behavioral changes, autonomic instability, hypoventilation, and seizures. Postinfectious (immune-mediated) encephalomyelitis may follow influenza, measles, mumps, and other infections; it may also occur as a sequela of immunization with rabies vaccine derived from neural tissues, which are used only in resource-limited and resource-poor countries. Rabies may present with


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InternalMed_Harrison. it may also occur as a sequela of immunization with rabies vaccine derived from neural tissues, which are used only in resource-limited and resource-poor countries. Rabies may present with unusual neuropsychiatric symptoms and may be misdiagnosed as a psychiatric disorder. Rabies hysteria may occur as a psychological response to the fear of rabies and is often characterized by a shorter incubation period than rabies, aggressive behavior, inability to communicate, and a long course with recovery.


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InternalMed_Harrison. As previously mentioned, paralytic rabies may mimic Guillain-Barré syndrome. In these cases, fever, bladder dysfunction, a normal sensory examination, and CSF pleocytosis favor a diagnosis of rabies. Conversely, Guillain-Barré syndrome may occur as a complication of rabies vaccination with a neural tissue–derived product (e.g., suckling mouse brain vaccine) and may be mistaken for paralytic rabies (i.e., vaccine failure). There is no established treatment for rabies. There have been many recent treatment failures with the combination of antiviral drugs, ketamine, and therapeutic (induced) coma—measures that were used in a healthy survivor in whom antibodies to rabies virus were detected at presentation. Expert opinion should be sought before a course of experimental therapy is embarked upon. A palliative approach may be appropriate for some patients.


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InternalMed_Harrison. Rabies is an almost uniformly fatal disease but is nearly always preventable with appropriate postexposure therapy during the early incubation period (see below). There are seven well-documented cases of survival from rabies. All but one of these patients had received rabies vaccine before disease onset. The single survivor who had not received vaccine had neutralizing antibodies to rabies virus in serum and CSF at clinical presentation. Most patients with rabies die within several days of the onset of illness, despite aggressive care in a critical care unit.


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InternalMed_Harrison. PREVENTION Postexposure Prophylaxis Since there is no effective therapy for rabies, it is extremely important to prevent the disease after an animal exposure. Figure 232-5 shows the steps involved in making decisions about PEP. On the basis of the history of the exposure and local epidemiologic information, the physician must decide whether initiation of PEP is warranted. Healthy dogs, cats, or ferrets may be confined and observed for 10 days. PEP is not necessary if the animal remains healthy. If the animal develops signs of rabies during the observation period, it should be euthanized immediately; the head should be transported to the laboratory under refrigeration, rabies virus should be sought by DFA testing, and viral isolation should be attempted by cell culture and/or mouse inoculation. Any animal other than a dog, cat, or ferret should be euthanized immediately and the head submitted for laboratory examination. In high-risk exposures and in areas where canine rabies is


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InternalMed_Harrison. inoculation. Any animal other than a dog, cat, or ferret should be euthanized immediately and the head submitted for laboratory examination. In high-risk exposures and in areas where canine rabies is endemic, rabies prophylaxis should be initiated without waiting for laboratory results. If the laboratory results prove to be negative, it may safely be concluded that the animal’s saliva did not


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InternalMed_Harrison. Did the animal bite the patient or did saliva contaminate a scratch, abrasion, open wound, or mucous membrane? Is rabies known or suspected to be present in the species and the geographic area? Was the animal captured? Does laboratory examination of the brain by fluorescent antibody staining confirm rabies? Was the animal a normally behaving dog, cat, or ferret? Does the animal become ill under observation over the next 10 days?


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InternalMed_Harrison. Was the animal a normally behaving dog, cat, or ferret? Does the animal become ill under observation over the next 10 days? FIGuRE 232-5 Algorithm for rabies postexposure prophylaxis. RIG, rabies immune globulin. (From L Corey, in Harrison’s Principles of Internal Medicine, 15th ed. E Braunwald et al [eds]: New York, McGraw-Hill, 2001; adapted with permission.) contain rabies virus, and immunization should be discontinued. If an animal escapes after an exposure, it must be considered rabid, and PEP must be initiated unless information from public health officials indicates otherwise (i.e., there is no endemic rabies in the area). Although controversial, the use of PEP may be warranted when a person (e.g., a small child or a sleeping adult) has been present in the same space as a bat and an unrecognized bite cannot be reliably excluded.


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InternalMed_Harrison. PEP includes local wound care and both active and passive immunization. Local wound care is essential and may greatly decrease the risk of rabies virus infection. Wound care should not be delayed, even if the initiation of immunization is postponed pending the results of the 10-day observation period. All bite wounds and scratches should be washed thoroughly with soap and water. Devitalized tissues should be debrided, tetanus prophylaxis given, and antibiotic treatment initiated whenever indicated.


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InternalMed_Harrison. All previously unvaccinated persons (but not those who have previously been immunized) should be passively immunized with rabies immune globulin (RIG). If RIG is not immediately available, it should be administered no later than 7 days after the first vaccine dose. After day 7, endogenous antibodies are being produced, and passive immunization may actually be counterproductive. If anatomically feasible, the entire dose of RIG (20 IU/kg) should be infiltrated at the site of the bite; otherwise, any RIG remaining after infiltration of the bite site should be administered IM at a distant site. With multiple or large wounds, the RIG preparation may need to be diluted in order to obtain a sufficient volume for adequate infiltration of all wound sites. If the exposure involves a mucous membrane, the entire dose should be administered IM. Rabies vaccine and RIG should never be administered at the same site or with the same syringe. Commercially available RIG in the United States is purified


InternalMed_Harrison

InternalMed_Harrison. the entire dose should be administered IM. Rabies vaccine and RIG should never be administered at the same site or with the same syringe. Commercially available RIG in the United States is purified from the serum of hyper-immunized human donors. These human RIG preparations are much better tolerated than are the equine-derived preparations still in use in 1304 some countries (see below). Serious adverse effects of human RIG are uncommon. Local pain and low-grade fever may occur. Two purified inactivated rabies vaccines are available for rabies PEP in the United States. They are highly immunogenic and remarkably safe compared with earlier vaccines. Four 1-mL doses of rabies vaccine should be given IM in the deltoid area. (The anterolateral aspect of the thigh also is acceptable in children.) Gluteal injections, which may not always reach muscle, should not be given and have been associated with rare vaccine failures. Ideally, the first dose should be given as soon as possible after


InternalMed_Harrison

InternalMed_Harrison. Gluteal injections, which may not always reach muscle, should not be given and have been associated with rare vaccine failures. Ideally, the first dose should be given as soon as possible after exposure; failing that, it should be given without further delay. The three additional doses should be given on days 3, 7, and 14; a fifth dose on day 28 is no longer recommended. Pregnancy is not a contraindication for immunization. Glucocorticoids and other immunosuppressive medications may interfere with the development of active immunity and should not be administered during PEP unless they are essential. Routine measurement of serum neutralizing antibody titers is not required, but titers should be measured 2–4 weeks after immunization in immunocompromised persons. Local reactions (pain, erythema, edema, and pruritus) and mild systemic reactions (fever, myalgias, headache, and nausea) are common; anti-inflammatory and antipyretic medications may be used, but immunization should not be


InternalMed_Harrison

InternalMed_Harrison. edema, and pruritus) and mild systemic reactions (fever, myalgias, headache, and nausea) are common; anti-inflammatory and antipyretic medications may be used, but immunization should not be discontinued. Systemic allergic reactions are uncommon, but anaphylaxis does occur rarely and can be treated with epinephrine and antihistamines. The risk of rabies development should be carefully considered before the decision is made to discontinue vaccination because of an adverse reaction. Most of the burden of rabies PEP is borne by persons with the fewest resources. In addition to the rabies vaccines discussed above, vaccines grown in either primary cell lines (hamster or dog kidney) or continuous cell lines (Vero cells) are satisfactory and are available in many countries outside the United States. Less expensive vaccines derived from neural tissues are still used in a diminishing number of developing countries; however, these vaccines are associated with serious neuroparalytic


InternalMed_Harrison

InternalMed_Harrison. United States. Less expensive vaccines derived from neural tissues are still used in a diminishing number of developing countries; however, these vaccines are associated with serious neuroparalytic complications, including postinfectious encephalomyelitis and Guillain-Barré syndrome. The use of these vaccines should be discontinued as soon as possible, and progress has been made in this regard. Worldwide, >10 million individuals receive postexposure rabies vaccine each year. If human RIG is unavailable, purified equine RIG can be used in the same manner at a dose of 40 IU/kg. Before the administration of equine RIG, hypersensitivity should be assessed by intradermal testing with a 1:10 dilution. The incidence of anaphylactic reactions and serum sickness has been low with recent equine RIG products.


InternalMed_Harrison

InternalMed_Harrison. Preexposure Rabies Vaccination Preexposure rabies prophylaxis should be considered for people with an occupational or recreational risk of rabies exposures, including certain travelers to rabies-endemic areas. The primary schedule consists of three doses of rabies vaccine given on days 0, 7, and 21 or 28. Serum neutralizing antibody tests help determine the need for subsequent booster doses. When a previously immunized individual is exposed to rabies, two booster doses of vaccine should be administered on days 0 and 3. Wound care remains essential. As stated above, RIG should not be administered to previously vaccinated persons. A growing number of lyssaviruses other than rabies virus have been discovered to infect bat populations in Europe, Africa,


InternalMed_Harrison

InternalMed_Harrison. A growing number of lyssaviruses other than rabies virus have been discovered to infect bat populations in Europe, Africa, Asia, and Australia. Six of these viruses have produced a very small number of cases of a human disease indistinguishable from rabies: European bat lyssaviruses 1 and 2, Australian bat lyssavirus, Irkut virus, and Duvenhage virus. Mokola virus, a lyssavirus that has been isolated from shrews with an unknown reservoir species in Africa, may also produce human disease indistinguishable from rabies.


InternalMed_Harrison

InternalMed_Harrison. Vesicular stomatitis is a viral disease of cattle, horses, pigs, and some wild mammals. Vesicular stomatitis virus is a member of the genus Vesiculovirus in the family Rhabdoviridae. Outbreaks of vesicular stomatitis in horses and cattle occur sporadically in the southwestern United States. The animal infection is associated with severe vesiculation and ulceration of oral tissues, teats, and feet and may be clinically indistinguishable from the more dangerous foot-and-mouth disease. Epidemics are usually seasonal, typically beginning in the late spring, and are probably due to arthropod vectors. Direct animal-to-animal spread can also occur, although the virus cannot penetrate intact skin. Transmission to humans usually results from direct contact with infected animals (particularly cattle) and occasionally follows laboratory exposure. In human disease, early conjunctivitis is followed by an acute influenza-like illness with fever, chills, nausea, vomiting, headache, retrobulbar pain,


InternalMed_Harrison

InternalMed_Harrison. and occasionally follows laboratory exposure. In human disease, early conjunctivitis is followed by an acute influenza-like illness with fever, chills, nausea, vomiting, headache, retrobulbar pain, myalgias, substernal pain, malaise, pharyngitis, and lymphadenitis. Small vesicular lesions may be present on the buccal mucosa or on the fingers. Encephalitis is very rare. The illness usually lasts 3–6 days, with complete recovery. Subclinical infections are common. A serologic diagnosis can be made on the basis of a rise in titer of complement-fixing or neutralizing antibodies. Therapy is symptom-based.


InternalMed_Harrison

Jens H. Kuhn, Clarence J. Peters

InternalMed_Harrison. Jens H. Kuhn, Clarence J. Peters


InternalMed_Harrison

InternalMed_Harrison. This chapter summarizes the major features of selected arthropod-borne and rodent-borne viruses. Numerous viruses of this category are transmitted in nature among animals without ever infecting humans. Other viruses incidentally infect humans, but only a proportion of these viruses induce human disease. In addition, certain viral agents are regularly introduced into human populations or spread among humans by certain arthropods (specifically, insects and ticks) or by chronically infected rodents. These zoonotic viruses are taxonomically diverse and therefore differ fundamentally from one another in terms of virion morphology, replication strategies, genomic organization, and genome sequence. While a virus’s classification in a taxon is enlightening with regard to natural maintenance strategies, sensitivity to antiviral agents, and particular aspects of pathogenesis, the classification does not necessarily predict which clinical signs and symptoms (if any) the virus will cause in


InternalMed_Harrison

InternalMed_Harrison. strategies, sensitivity to antiviral agents, and particular aspects of pathogenesis, the classification does not necessarily predict which clinical signs and symptoms (if any) the virus will cause in humans. Zoonotic viruses are evolving, and “new” zoonotic viruses are regularly discovered. The epizootiology and epidemiology of zoonotic viruses continue to change as a result of environmental alterations affecting vectors, reservoirs, wildlife, livestock, and humans. Zoonotic viruses are most numerous in the tropics but are also found in temperate and even frigid climates. The distribution and seasonal activity of a zoonotic virus may vary, and the rate at which it changes is likely to depend largely on ecologic conditions (e.g., rainfall and temperature), which can affect the density of virus vectors and reservoirs and the development of infection.


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InternalMed_Harrison. Arthropod-borne viruses (arboviruses) infect their vectors after ingestion of a blood meal from a viremic, usually nonhuman vertebrate; some arthropods may also become infected by saliva-activated transmission. The arthropod vectors then develop chronic, systemic infection as the viruses penetrate the gut and spread throughout the body to the salivary glands; such virus dissemination, referred to as extrinsic incubation, typically lasts 1–3 weeks in mosquitoes. At this point, if the salivary glands become involved, the arthropod vector is competent to continue the chain of transmission by infecting a vertebrate during a subsequent blood meal. An alternative mechanism for virus maintenance in its arthropod vector is transovarial transmission. The arthropod generally is unharmed by the infection, and the natural vertebrate partner usually has only transient viremia with no overt disease.


InternalMed_Harrison

InternalMed_Harrison. Rodent-borne viruses are maintained in nature by transmission between rodents, which become chronically infected. Usually a high degree of rodent–virus specificity is observed, and overt disease in the reservoir host is rare. Arthropod-borne and rodent-borne zoonotic viruses belong to at least seven families: Arenaviridae, Bunyaviridae, Flaviviridae, Orthomyxoviridae, Reoviridae, Rhabdoviridae, and Togaviridae (Table 233-1).


InternalMed_Harrison

InternalMed_Harrison. The members of the family Arenaviridae that infect humans are all assigned to the genus Arenavirus. The members of this genus are divided into two main phylogenetic branches: Old World viruses (the Lassa–lymphocytic choriomeningitis serocomplex) and New World viruses (the Tacaribe serocomplex). Human arenaviruses form spherical, oval, or pleomorphic enveloped and spiked virions (~50–300 nm in diameter) that bud from the infected cell’s plasma membrane. The particles contain two genomic single-stranded RNAs (S, ~3.5 kb; and L, ~7.5 kb) encoding structural proteins in an ambisense orientation. Most arenaviruses persist in nature by chronically infecting rodents. The Old World viruses are maintained by murid rodents that often are persistently viremic and commonly transmit viruses vertically and horizontally. New World viruses are found in cricetid rodents; horizontal transmission is typical, vertical infection may occur, and persistent viremia may be observed. Strikingly, each


InternalMed_Harrison

InternalMed_Harrison. and horizontally. New World viruses are found in cricetid rodents; horizontal transmission is typical, vertical infection may occur, and persistent viremia may be observed. Strikingly, each arenavirus is predominantly adapted to one particular type of rodent. Humans usually become infected through inhalation of or direct contact with infected rodent excreta or secreta (e.g., aerosols of rodents in harvesting machines; aerosolized dried rodent urine or feces in barns or houses; direct contact with rodents in traps). Person-to-person transmission of arenaviruses is uncommon.


InternalMed_Harrison

InternalMed_Harrison. The family Bunyaviridae includes four medically significant genera: Hantavirus, Nairovirus, Orthobunyavirus, and Phlebovirus. The members of all these genera form spherical to pleomorphic enveloped virions containing three genomic single-stranded RNAs (S, ~1–2 kb; M, 3.6–5.3 kb; and L, 6.4–12.3 kb) of negative (hantaviruses, nairoviruses, orthobunyaviruses) or ambisense (nairoviruses) polarity. Bunyaviruses mature into particles ~80–120 nm in diameter in the Golgi complex of infected cells and exit these cells by exocytosis.


InternalMed_Harrison

InternalMed_Harrison. Hantaviruses are unique among the bunyaviruses in that they are not transmitted by arthropods but instead are maintained in nature by rodents that chronically shed virions. Old World hantaviruses are harbored by murid and cricetid rodents, and New World hantaviruses are maintained by cricetid rodents. As with arenaviruses, individual hantaviruses usually are specifically adapted to a particular type of rodent. However, hantaviruses do not cause chronic viremia in their rodent hosts and are transmitted only horizontally from rodent to rodent. Similar to arenaviruses, hantaviruses infect humans primarily through inhalation of or direct contact with rodent excreta or secreta, and person-to-person transmission is not a common event (with the notable exception of Andes virus). Although there is overlap, the human Old World hantaviruses usually are the etiologic agents of hemorrhagic fever with renal syndrome, whereas the New World viruses usually cause hantavirus pulmonary syndrome.


InternalMed_Harrison

InternalMed_Harrison. Nairoviruses are maintained by ixodid ticks, which vertically (transovarially and transstadially) transmit these viruses to progeny tick generations and horizontally spread them through viremic vertebrate hosts. Humans are usually infected via a tick bite or during handling of infected vertebrates. Orthobunyaviruses are largely mosquito-borne and rarely midge-borne and have viremic vertebrate intermediate hosts. Many orthobunyaviruses are also transovarially transmitted in their mosquito host. Numerous orthobunyaviruses have been associated with human infection and disease. They have been considered to be members of ~19 serogroups based on antigenic cross-reactions, but this grouping is currently undergoing revision with the accumulation of new genomic 1305 data and phylogenetic analyses. Human viruses are found in at least nine serogroups.


InternalMed_Harrison

InternalMed_Harrison. Phleboviruses are transmitted vertically (transovarially) in their arthropod hosts and horizontally through viremic vertebrate hosts. Phleboviruses are divided into two groups: the phlebotomus group viruses are transmitted by sandflies and the Uukuniemi group viruses by ticks. Phleboviruses are assigned to at least 10 serocomplexes; human pathogens are found in at least four of these serocomplexes.


InternalMed_Harrison

InternalMed_Harrison. The family Flaviviridae currently includes four genera, one of which (Flavivirus) comprises arthropod-borne human viruses. Flaviviruses sensu stricto have single-stranded positive-sense RNA genomes (~11 kb) and form spherical enveloped particles 40–60 nm in diameter. The flaviviruses discussed here belong to two phylogenetically and antigenically distinct groups and are transmitted among vertebrates by mosquitoes and ixodid ticks, respectively. Vectors are usually infected when they feed on viremic hosts; as in the case of most other viruses discussed here, humans are accidental hosts who usually are infected by arthropod bites. Arthropods maintain flavivirus infections horizontally, although transovarial transmission has been documented. Under certain circumstances, flaviviruses can also be transmitted by aerosols or via contaminated food products; in particular, raw milk can transmit tick-borne encephalitis virus.


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InternalMed_Harrison. The family Orthomyxoviridae includes two genera of medically relevant arthropod-borne viruses: Quaranjavirus and Thogotovirus. Quaranjaviruses are transmitted among birds by ixodid ticks, whereas thogotoviruses have a predilection for mammalian host reservoirs and can be transmitted by both ixodid ticks and mosquitoes.


InternalMed_Harrison

InternalMed_Harrison. The family Reoviridae contains viruses with linear, multisegmented, double-stranded RNA genomes (~16–29 kb in total). These viruses produce particles that have icosahedral symmetry and are 60–80 nm in diameter. In contrast to all other virions discussed here, reovirions are not enveloped and thus are insensitive to detergent inactivation. Fifteen genera of reoviruses are currently recognized. Human arthropod-borne viruses are found among the genera Coltivirus (subfamily Spinareovirinae), Orbivirus, and Seadornavirus (subfamily Sedoreovirinae). Arthropod-borne coltiviruses possess 12 genome segments. Coltiviruses are transmitted by numerous tick types transstadially but not transovarially. Overall maintenance of the transmission cycle, therefore, involves viremic mammalian hosts infected by tick bites. Arthropod-borne orbiviruses have 10 genome segments and are transmitted by mosquitoes or ixodid ticks, whereas relevant seadornaviruses have 12 genome segments and are transmitted


InternalMed_Harrison

InternalMed_Harrison. by tick bites. Arthropod-borne orbiviruses have 10 genome segments and are transmitted by mosquitoes or ixodid ticks, whereas relevant seadornaviruses have 12 genome segments and are transmitted exclusively by mosquitoes.


InternalMed_Harrison

InternalMed_Harrison. The family Rhabdoviridae is included in the order Mononegavirales. Viruses of the nine rhabdovirus genera have linear, nonsegmented, single-stranded RNA genomes of negative polarity (~11–15 kb) and form bullet-shaped to pleomorphic enveloped particles (100–430 nm long and 45–100 nm wide). Only the genus Vesiculovirus includes human arthropod-borne viruses, all of which are transmitted by insects (biting midges, mosquitoes, and sandflies). The general properties of rhabdoviruses are discussed in more detail in Chap. 232. The members of the family Togaviridae have linear, singleand positive-stranded RNA genomes (~9.7–11.8 kb) and form enveloped icosahedral virions (~60–70 nm in diameter) that bud from the plasma membrane of the infected cell. The togaviruses discussed here are all members of the genus Alphavirus and are transmitted among vertebrates by mosquitoes. Unknown Unknown Eulipotyphla, least weasles (Mustela nivalis), rodents Unknown Unknown Birds, cattle, rodents


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InternalMed_Harrison. Unknown Unknown Eulipotyphla, least weasles (Mustela nivalis), rodents Unknown Unknown Birds, cattle, rodents Birds Cattle, pigs Bats, camels, horses Camels, cattle Gray four-eyed opossums (Philander opossum) Cattle, horses, pigs Cattle, horses, pigs Unknown Sandflies (Phlebotomus papatasi, P. perfiliewi, P. perniciosus) Sandflies (Phlebotomus spp.) Sandflies (Phlebotomus papatasi, P. perfiliewi) Ixodid ticks (Ixodes spp.) Mosquitoes (Aedes, Anopheles, Culiseta spp.) Mosquitoes (Aedes, Anopheles, Culex spp.), ixodid ticks (Dermacentor, Hyalomma, Ornithodoros spp.) Ixodid ticks (Amblyomma, Hyalomma, Rhipicephalus spp.) Mosquitoes (Aedes aegypti), sandflies (Phlebotomus, Sergentomyia spp.) Mosquitoes (Aedes, Culex, Toxorhynchites spp.) Sandflies (Lutzomyia spp.) Biting midges (Culicoides spp.), chloropid flies, mosquitoes (Culex, Mansonia spp.), muscoid flies (Musca spp.), simuliid flies F/M F/M F/M F/M E, F/M F/M E, F/M


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InternalMed_Harrison. E, F/M E, F/M F/M aAbbreviations refer to the syndrome most commonly associated with the virus: A/R, arthritis/rash; E, encephalitis; F/M, fever/myalgia; P, pulmonary; VHF, viral hemorrhagic fever. Abbreviations are placed in parentheses when cases are either extremely rare or controversial. bIn the older literature, chikungunya virus often is also listed as a causative agent of VHF. However, later studies revealed that, in most cases, people with “chikungunya hemorrhagic fever” were co-infected with one or more dengue viruses, an observation suggesting that the VHF was actually severe dengue. cWhitewater Arroyo virus is often listed as a causative agent of VHF in the literature, but convincing data associating this virus with VHF have not been published. dAlso includes Kunjin virus. 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