Review of Medical Microbiology and Immunology, 13th Edition

46. Minor Viral Pathogens

CHAPTER CONTENTS

VIRUSES OF MINOR MEDICAL IMPORTANCE

Astroviruses

BK Virus

Borna Virus

Cache Valley Virus

Chikungunya Virus

Ebola Virus

Hantaviruses

Heartland Virus

Hendra Virus

Herpes B Virus

Human Bocavirus

Human Herpesvirus 6

Human Metapneumovirus

Jamestown Canyon Virus

Japanese Encephalitis Virus

Lassa Fever Virus

Lujo Virus

Lymphocytic Choriomeningitis Virus

Marburg Virus

Nipah Virus

Powassan Virus

Poxviruses of Animal Origin

Spumaviruses

Tacaribe Complex of Viruses

Whitewater Arroyo Virus

Zika Virus

Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations

VIRUSES OF MINOR MEDICAL IMPORTANCE

These viruses are presented in alphabetical order. They are listed in Table 46–1 in terms of their nucleic acid and presence of an envelope.

TABLE 46–1 Minor Viral Pathogens

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ASTROVIRUSES

Astroviruses are nonenveloped RNA viruses similar in size to polioviruses. They have a characteristic five- or six-pointed morphology. These viruses cause watery diarrhea, especially in children. Most adults have antibodies against astroviruses, suggesting that infection occurs commonly. No antiviral drugs or preventive measures are available.

BK VIRUS

BK virus is a member of the polyomavirus family. Polyomaviruses are nonenveloped viruses with a circular, double-stranded DNA genome. BK virus and JC virus (see Chapter 44) are the two polyomaviruses that infect humans.

BK virus infection is widespread as determined by the presence of antibody and is typically acquired in childhood, and infection is not associated with any disease at that time. It does, however, cause nephropathy and graft loss in immunosuppressed renal transplant patients. Asymptomatic shedding of BK virus in the urine of immunocompromised patients and pregnant women in the third trimester occurs. There is no antiviral therapy effective against BK virus.

BORNA VIRUS

Borna virus is an enveloped virus with a nonsegmented, single-strand, negative-polarity RNA genome. It has the smallest genome of any virus with this type of RNA and is the only virus of this type to replicate in the nucleus of the infected cell. DNA sequences homologous to the Borna virus genome are integrated into human cellular DNA. It is a neurotropic virus known to infect regions of the brain such as the hippocampus.

Borna is the name of a town in Germany where the virus caused a disease in horses in 1885. It is a zoonotic virus causing disease in domestic animals, such as cattle, sheep, dogs, and cats. Borna virus has not been established as a human pathogen, but there is some evidence that it is associated with human psychiatric diseases characterized by abnormal behavior, such as bipolar disorder.

CACHE VALLEY VIRUS

This virus was first isolated in Utah in 1956 but is found throughout the western hemisphere. It is a bunyavirus transmitted by Aedes, Anopheles, or Culiseta mosquitoes from domestic livestock to people. It is a rare cause of encephalitis in humans. There is no treatment or vaccine for Cache Valley virus infections.

CHIKUNGUNYA VIRUS

This virus causes chikungunya fever characterized by the sudden onset of high fever and joint pains, especially of the wrists and ankles. A macular or maculopapular rash over much of the body is common. Outbreaks involving millions of people in India, Africa, and the islands in the Indian Ocean have occurred in the years from 2004 to 2006.

Chikungunya virus is an RNA enveloped virus and is a member of the Togavirus family. It has a single-stranded, positive-polarity RNA genome. It is transmitted by species of Aedes mosquitoes, both Aedes aegypti and Aedes albopictus. The latter mosquito is found in the United States, so the potential for outbreaks exists. Individuals returning to the United States from areas where outbreaks have occurred have been diagnosed with chikungunya fever. Laboratory diagnosis involves detecting the virus in blood either by culturing or by enzyme-linked immunosorbent assay (ELISA). Antibody tests for either IgM or a rise in titer of IgG can also be used to make a diagnosis. There is no antiviral therapy, and no vaccine is available.

EBOLA VIRUS

Ebola virus is named for the river in Zaire that was the site of an outbreak of hemorrhagic fever in 1976. The disease begins with fever, headache, vomiting, and diarrhea. Later, bleeding into the gastrointestinal tract occurs, followed by shock and disseminated intravascular coagulation. The hemorrhages are caused by severe thrombocytopenia. The mortality rate associated with this virus approaches 100%. Most cases arise by secondary transmission from contact with the patient’s blood or secretions (e.g., in hospital staff). Reuse of needles and syringes is also implicated in the spread within hospitals. Although greatly feared, Ebola hemorrhagic fever is quite rare. As of this writing, approximately 1000 cases have occurred since its appearance in 1976.

Ebola virus is a member of the Filovirus family. The appearance of Filoviruses (filo-thread) is unique. They are the longest viruses, often measuring thousands of nanometers (Figure 46–1). The natural reservoir of Ebola virus is unknown. Monkeys can be infected but, because they become sick, are unlikely to be the reservoir. Bats are suspected of being the reservoir, but this has not been established. The high mortality rate of Ebola virus is attributed to several viral virulence factors: Its glycoprotein kills endothelial cells, resulting in hemorrhage, and two other proteins inhibit the induction and action of interferon. Lymphocytes are killed, and the antibody response is ineffective.

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FIGURE 46–1 Ebola virus—electron micrograph. Long arrow points to a typical virion of Ebola virus. Short arrow points to the “shepherd’s crook” appearance of some Ebola virions. (Figure courtesy of Dr. Erskine Palmer and Dr. Russell Regnery, Public Health Image Library, Centers for Disease Control and Prevention.)

Diagnosis is made by isolating the virus or by detecting a rise in antibody titer. (Extreme care must be taken when handling specimens in the laboratory.) No antiviral therapy is available. Treatment with immune serum globulins containing antibody to Ebola virus has had variable results.

Prevention centers on limiting secondary spread by proper handling of patient’s secretions and blood. There is no vaccine.

HANTAVIRUSES

Hantaviruses are members of the bunyavirus family. The prototype virus is Hantaan virus, the cause of Korean hemorrhagic fever (KHF). KHF is characterized by headache, petechial hemorrhages, shock, and renal failure. It occurs in Asia and Europe but not North America and has a mortality rate of about 10%. Hantaviruses are part of a heterogeneous group of viruses called roboviruses, which stands for “rodent-borne” viruses. Roboviruses are transmitted from rodents directly (without an arthropod vector), whereas arboviruses are “arthropod-borne.”

In 1993, an outbreak of a new disease, characterized by influenzalike symptoms followed rapidly by acute respiratory failure, occurred in the western United States, centered in New Mexico and Arizona. This disease, now called hantavirus pulmonary syndrome, is caused by a hantavirus (Sin Nombre virus) endemic in deer mice (Peromyscus) and is acquired by inhalation of aerosols of the rodent’s urine and feces. It is not transmitted from person to person. Very few people have antibody to the virus, indicating that asymptomatic infections are not common.

The diagnosis is made by detecting viral RNA in lung tissue with the polymerase chain reaction (PCR) assay, by performing immunohistochemistry on lung tissue, or by detecting IgM antibody in serum. The mortality rate of hantavirus pulmonary syndrome is very high, approximately 35%. Between 1993 and December 2009, a total of 534 cases of hantavirus pulmonary syndrome have been reported in the United States. Most cases occurred in the states west of the Mississippi, particularly in New Mexico, Arizona, California, and Colorado, in that order.

There is no effective drug; ribavirin has been used but appears to be ineffective. There is no vaccine for any hantavirus.

HEARTLAND VIRUS

This virus was first recognized as a human pathogen in 2012, when it caused fever, thrombocytopenia, and leukopenia in two men in the state of Missouri. It is a member of the bunyavirus family. It is transmitted by the bite of the Lone Star tick, Amblyomma. There is no antiviral treatment or vaccine for this virus.

HENDRA VIRUS

This virus was first recognized as a human pathogen in 1994, when it caused severe respiratory disease in Hendra, Australia. It is a paramyxovirus resembling measles virus and was previously called equine morbillivirus. The human infections were acquired by contact with infected horses, but fruit bats appear to be the natural reservoir. There is no treatment or vaccine for Hendra virus infections.

HERPES B VIRUS

This virus (monkey B virus or herpesvirus simiae) causes a rare, often fatal encephalitis in persons in close contact with monkeys or their tissues (e.g., zookeepers or cell culture technicians). The virus causes a latent infection in monkeys that is similar to herpes simplex virus (HSV)-1 infection in humans.

Herpes B virus and HSV-1 cross-react antigenically, but antibody to HSV-1 does not protect from herpes B encephalitis. The presence of HSV-1 antibody can, however, confuse serologic diagnosis by making the interpretation of a rise in antibody titer difficult. The diagnosis can therefore be made only by recovering the virus. Acyclovir may be beneficial. Prevention consists of using protective clothing and masks to prevent exposure to the virus. Immune globulin containing antibody to herpes B virus should be given after a monkey bite.

HUMAN BOCAVIRUS

Human bocavirus (HBoV) is a parvovirus isolated from young children with respiratory tract infections. Antibody to HBoV is found in most adults worldwide. A description of this virus was first reported in 2005, and its precise role in respiratory tract disease has yet to be defined.

HUMAN HERPESVIRUS 6

This herpesvirus is the cause of exanthem subitum (roseola infantum), a common disease in infants that is characterized by a high fever and a transient macular or maculopapular rash. The virus is found worldwide, and up to 80% of people are seropositive. The virus is lymphotropic and infects both T and B cells. It remains latent within these cells but can be reactivated in immunocompromised patients and cause pneumonia. Many virologic and clinical features of human herpesvirus 6 are similar to those of cytomegalovirus, another member of the herpesvirus family.

HUMAN METAPNEUMOVIRUS

This paramyxovirus was first reported in 2001 as a cause of severe bronchiolitis and pneumonia in young children in the Netherlands. It is similar to respiratory syncytial virus (also a paramyxovirus) in the range of respiratory tract disease it causes. Serologic studies showed that most children have been infected by 5 years of age and that this virus has been present in the human population for at least 50 years.

JAMESTOWN CANYON VIRUS

Jamestown Canyon virus (JCV) is a member of the bunyavirus family that causes encephalitis. It is transmitted by mosquito bite, most commonly by Aedes species. JCV circulates widely among deer in North America but human disease is rare. In the United States, cases are primarily in the northeastern and midwestern states. There is no antiviral treatment or vaccine for JCV infections.

JAPANESE ENCEPHALITIS VIRUS

This virus is the most common cause of epidemic encephalitis. The disease is characterized by fever, headache, nuchal rigidity, altered states of consciousness, tremors, incoordination, and convulsions. The mortality rate is high, and neurologic sequelae are severe and can be detected in most survivors. The disease occurs throughout Asia but is most prevalent in Southeast Asia. The rare cases seen in the United States have occurred in travelers returning from that continent. American military personnel in Asia have been affected.

Japanese encephalitis virus is a member of the flavivirus family. It is transmitted to humans by certain species of Culex mosquitoes endemic to Asian rice fields. There are two main reservoir hosts—birds and pigs. The diagnosis can be made by isolating the virus, by detecting IgM antibody in serum or spinal fluid, or by staining brain tissue with fluorescent antibody. There is no antiviral therapy. Prevention consists of an inactivated vaccine and pesticides to control the mosquito vector. Immunization is recommended for individuals living in areas of endemic infection for several months or longer.

LASSA FEVER VIRUS

Lassa fever virus was first seen in 1969 in the Nigerian town of that name. It causes a severe, often fatal hemorrhagic fever characterized by multiorgan involvement. The disease begins slowly with fever, headache, vomiting, and diarrhea and progresses to involve the lungs, heart, kidneys, and brain. A petechial rash and gastrointestinal tract hemorrhage ensue, followed by death from vascular collapse.

Lassa fever virus is a member of the arenavirus family, which includes other infrequent human pathogens such as lymphocytic choriomeningitis virus and certain members of the Tacaribe group. Arenaviruses (“arena” means sand) are united by their unusual appearance in the electron microscope. Their most striking feature is the “sandlike” particles on their surface, which are ribosomes. The function, if any, of these ribosomes is unknown. Arenaviruses are enveloped viruses with surface spikes, a helical nucleocapsid, and single-stranded RNA with negative polarity.

The natural host for Lassa fever virus is the small rodent Mastomys, which undergoes a chronic, lifelong infection. The virus is transmitted to humans by contamination of food or water with animal urine. Secondary transmission among hospital personnel occurs also. Asymptomatic infection is widespread in areas of endemic infection.

The diagnosis is made either by isolating the virus or by detecting a rise in antibody titer. Ribavirin reduces the mortality rate if given early, and hyperimmune serum, obtained from persons who have recovered from the disease, has been beneficial in some cases. No vaccine is available, and prevention centers on proper infection control practices and rodent control.

LUJO VIRUS

Lujo virus is an arenavirus that causes a hemorrhagic fever similar to Lassa fever. This virus emerged in Zambia in 2008 and caused an outbreak in which four of the five infected patients died. The one survivor was treated with ribavirin. The identification of this virus was made by sequencing the viral RNA from the liver and serum of patients. The animal reservoir and mode of transmission are unknown, but other arenaviruses are transmitted by rodent excreta.

LYMPHOCYTIC CHORIOMENINGITIS VIRUS

Lymphocytic choriomeningitis virus is a member of the arenavirus family. It is a rare cause of aseptic meningitis and cannot be distinguished clinically from the more frequent viral causes (e.g., echovirus, Coxsackie virus, or mumps virus). The usual picture consists of fever, headache, vomiting, stiff neck, and changes in mental status. Spinal fluid shows an increased number of cells, mostly lymphocytes, with an elevated protein level and a normal or low sugar level.

The virus is endemic in the mouse population, in which chronic infection occurs. Animals infected transplacentally become healthy lifelong carriers. The virus is transmitted to humans via food or water contaminated by mouse urine or feces. There is no human-to-human spread (i.e., humans are accidental dead-end hosts), although transmission of the virus via solid organ transplants has occurred. In 2005, seven of eight transplant recipients who became infected died. Diagnosis is made by isolating the virus from the spinal fluid or by detecting an increase in antibody titer. No antiviral therapy or vaccine is available.

This disease is the prototype used to illustrate immunopathogenesis. If immunocompetent adult mice are inoculated, meningitis and death ensue. If, however, newborn mice or X-irradiated immunodeficient adults are inoculated, no meningitis occurs despite extensive viral replication. If sensitized T cells are transplanted to the immunodeficient adults, meningitis and death occur. The immunodeficient adult mice, who are apparently well, slowly develop glomerulonephritis. It appears that the mice are partially tolerant to the virus in that their cell-mediated immunity is inactive, but sufficient antibody is produced to cause immune complex disease.

MARBURG VIRUS

Marburg virus and Ebola virus are similar in that they both cause hemorrhagic fever and are members of the Filovirus family; however, they are antigenically distinct. Marburg virus was first recognized as a cause of human disease in 1967 in Marburg, Germany. The common feature of the infected individuals was their exposure to African green monkeys that had recently arrived from Uganda. As with Ebola virus, the natural reservoir of Marburg virus is unknown, although bats are suspected.

The clinical picture of this hemorrhagic fever is as described for Ebola virus (see page 378). In 2005, an outbreak of hemorrhagic fever caused by Marburg virus killed hundreds of people in Angola. No cases of disease caused by either Ebola or Marburg virus have occurred in the United States prior to 2008. However, in that year, a U.S. traveler became ill after visiting a cave in Uganda inhabited by fruit bats. He returned to the United States, where he was diagnosed with Marburg hemorrhagic fever. He recovered without sequelae.

The diagnosis is made by isolating the virus or detecting a rise in antibody titer. No antiviral therapy or vaccine is available. As with Ebola virus, secondary cases among medical personnel have occurred; therefore, stringent infection control practices must be instituted to prevent nosocomial spread.

NIPAH VIRUS

Nipah virus is a paramyxovirus that causes encephalitis, primarily in the South Asian countries of Bangladesh, Malaysia, and Singapore. The natural reservoir appears to be fruit bats. People who have contact with pigs are particularly at risk for encephalitis, and some human-to-human transmission occurs. In general, paramyxoviruses are transmitted by saliva or sputum and that is the likely mode of transmission. There is no treatment, or vaccine for Nipah virus infections.

POWASSAN VIRUS

Powassan virus is a flavivirus that causes a severe encephalitis with significant sequelae. It is transmitted by Ixodes ticks, and rodents are the reservoir. It is the only flavivirus transmitted by ticks.

It is named for the town of Powassan, Ontario, Canada, where one of the first cases occurred. Most cases in the United States occur in Minnesota and Wisconsin. There are typically 0 to 10 cases in the United States each year. The diagnosis can be made by PCR or serologic tests. There is no antiviral drug or vaccine.

POXVIRUSES OF ANIMAL ORIGIN

Four poxviruses cause disease in animals and also cause poxlike lesions in humans on rare occasions. They are transmitted by contact with the infected animals, usually in an occupational setting.

Cowpox virus causes vesicular lesions on the udders of cows and can cause similar lesions on the skin of persons who milk cows. Pseudocowpox virus causes a similar picture but is antigenically distinct. Orf virus is the cause of contagious pustular dermatitis in sheep and of vesicular lesions on the hands of sheepshearers.

Monkeypox virus is different from the other three; it causes a human disease that resembles smallpox. It occurs almost exclusively in Central Africa. In 2003, an outbreak of monkeypox occurred in Wisconsin, Illinois, and Indiana. In this outbreak, the source of the virus was animals imported from Africa. It appears that the virus from the imported animals infected local prairie dogs, which then were the source of the human infection. None of those affected died. In Africa, monkeypox has a death rate of between 1% and 10%, in contrast to 50% for smallpox. There is no effective antiviral treatment. The vaccine against smallpox appears to have some protective effect against monkeypox.

Any new case of smallpox-like disease must be precisely diagnosed to ensure that it is not due to smallpox virus. There has not been a case of smallpox in the world since 1977,1 and smallpox immunization has been allowed to lapse.

For these reasons, it is important to ensure that new cases of smallpox-like disease are due to monkeypox virus. Monkeypox virus can be distinguished from smallpox virus in the laboratory both antigenically and by the distinctive lesions it causes on the chorioallantoic membrane of chicken eggs.

SPUMAVIRUSES

Spumaviruses are a subfamily of retroviruses that cause a foamy appearance in cultured cells. They can present a problem in the production of viral vaccines if they contaminate the cell cultures used to make the vaccine. There are no known human pathogens.

TACARIBE COMPLEX OF VIRUSES

The Tacaribe complex contains several human pathogens, all of which cause hemorrhagic fever.

The best known are Sabia virus in Brazil, Junin virus in Argentina, and Machupo virus in Bolivia. Hemorrhagic fevers, as the name implies, are characterized by fever and bleeding into the gastrointestinal tract, skin, and other organs. The bleeding is due to thrombocytopenia. Death occurs in up to 20% of cases, and outbreaks can involve thousands of people. Agricultural workers are particularly at risk.

Similar to other arenaviruses such as Lassa fever virus and lymphocytic choriomeningitis virus, these viruses are endemic in the rodent population and are transmitted to humans by accidental contamination of food and water by rodent excreta. The diagnosis can be made either by isolating the virus or by detecting a rise in antibody titer. In a laboratory-acquired Sabia virus infection, ribavirin was an effective treatment. No vaccine is available.

WHITEWATER ARROYO VIRUS

This virus is the cause of a hemorrhagic fever/acute respiratory distress syndrome in the western part of the United States. It is a member of the arenavirus family, as is Lassa fever virus, a cause of hemorrhagic fever in Africa (see page 380). Wood rats are the reservoir of this virus, and it is transmitted by inhalation of dried rat excrement. This mode of transmission is the same as that of the hantavirus, Sin Nombre virus (see page 379). There is no established antiviral therapy, and there is no vaccine.

ZIKA VIRUS

Zika virus is a flavivirus that causes an illness similar to dengue characterized by fever, arthralgia, rash, and conjunctivitis. The vector is various species of the mosquito, Aedes. In 2007, an outbreak in Yap, an island in Micronesia, affected at least 49 people. No deaths occurred. There is no effective antiviral drug and no vaccine.

SELF-ASSESSMENT QUESTIONS

1. Regarding Ebola virus, which one of the following is most accurate?

(A) Skunks and raccoons are the main natural reservoirs for Ebola virus.

(B) In endemic areas, most people are latently infected with Ebola virus.

(C) People known to be exposed to Ebola virus should be given ganciclovir to prevent disease.

(D) Ebola hemorrhagic fever occurs primarily in people with deficient cell-mediated immunity.

(E) The appearance of Ebola virus in the electron microscope is that of a long thread, which often has a curved end.

2. Regarding Sin Nombre virus (a hantavirus), which one of the following is most accurate?

(A) Its main clinical manifestation is encephalitis.

(B) The main reservoir is domestic animals such as pigs.

(C) Infection is acquired by inhalation of dried mouse feces and urine.

(D) Oseltamivir is an effective prophylactic drug if given within 48 hours of exposure.

(E) Immunization of children at the age of 15 months with the killed vaccine has greatly reduced the incidence of disease.

3. Regarding Japanese encephalitis virus (JEV), which one of the following is most accurate?

(A) The principal reservoir of JEV is bats.

(B) It is transmitted by the bite of the dog tick, Dermacentor.

(C) Acyclovir is the drug of choice for encephalitis caused by JEV.

(D) The killed vaccine should be given to those living in an endemic area.

(E) JEV is a nonenveloped virus with a circular double-stranded RNA genome.

ANSWERS

1. (E)

2. (C)

3. (D)

SUMMARIES OF ORGANISMS

Brief summaries of the organisms described in this chapter begin on page 648. Please consult these summaries for a rapid review of the essential material.

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Clinical Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

1With the exception of two laboratory-acquired cases in 1978.