Jawetz Chapter 31: Parvoviruses PDF

31 C H A P T E R Parvoviruses...

31 C H A P T E R Parvoviruses Parvoviruses are the smallest DNA animal viruses. Because of insects. The Parvovirinae comprise five genera. Human parvo- the limited coding capacity of their genome, viral replication virus B19 is the most common member of the Erythroparvovirus is dependent on functions supplied by replicating host cells or genus. The three human bocaviruses are in the Bocaparvovirus by coinfecting helper viruses. Parvovirus B19 is pathogenic for genus. Feline panleukopenia virus and canine parvovirus, both humans and has a tropism for erythroid progenitor cells. It is serious causes of veterinary diseases, are classified as mem- the cause of erythema infectiosum (“Fifth disease”), a common bers of the Protoparvovirus genus, as are isolates from many childhood exanthem; a polyarthralgia–arthritis syndrome in other animals. The genus Dependovirus contains members that normal adults; aplastic crisis in patients with hemolytic dis- are defective and depend on a helper virus (an adenovirus or orders; chronic anemia in immunocompromised individuals; herpesvirus) for replication. Human adeno-associated viruses and fetal death. The human bocaviruses have been detected (AAVs) have not been linked with any disease but are candidate in respiratory specimens from children with acute respiratory vectors for gene therapy treatments. disease and in stool samples, but a role in disease is unproven. Parvovirus Replication PROPERTIES OF PARVOVIRUSES It is difficult to culture human B19 parvovirus. Only pri- mary erythroid progenitors are known to be permissive for Important properties of parvoviruses are listed in Table 31-1. B19 infection. The cellular receptor for B19 is blood group P It is noteworthy that there are both autonomously replicat- antigen (globoside). P antigen is expressed on mature eryth- ing and defective parvoviruses that require a helper virus for rocytes, erythroid progenitors, megakaryocytes, endothelial replication. cells, placenta, and fetal liver and heart, which helps explain the narrow tissue tropism of B19 virus. The α5β1 integrin is believed to be a coreceptor for B19 entry. Structure and Composition The parvoviruses are highly dependent on cellular func- The icosahedral, nonenveloped particles are 18–26 nm tions for replication. Viral DNA replication occurs in the in diameter (Figure 31-1). The particles have a molecu- nucleus. The parvoviruses do not have the ability to stimulate lar weight of 5.5–6.2 × 106 and a heavy buoyant density of resting cells to initiate DNA synthesis, so they must infect 1.39–1.42 g/cm3. Virions are extremely resistant to inactiva- dividing cells. One or more cellular DNA polymerases are tion. They are stable between a pH of 3 and 9 and withstand involved. The nonstructural protein, NS1, is required for heating at 56°C for 60 minutes, but they can be inactivated by virus replication. There are two capsid proteins. Viral repli- formalin, β-propiolactone, and oxidizing agents. cation results in cell death. Virions contain two coat proteins that are encoded by an overlapping, in-frame DNA sequence, so that VP2 is identical in sequence to the carboxy portion of VP1. The major capsid pro- PARVOVIRUS INFECTIONS IN HUMANS tein, VP2, represents about 90% of virion protein. The genome is about 5 kb, linear, single-stranded DNA. Autonomous parvovi- Pathogenesis and Pathology ruses usually encapsidate primarily DNA strands complementary A typical course of human parvovirus B19 infection in adults to viral mRNA; defective viruses tend to encapsidate DNA strands is illustrated in Figure 31-2. B19 has been implicated as the of both polarities with equal frequency into separate virions. causative agent of several diseases (Table 31-2). Immature cells in the erythroid lineage are principal targets for human B19 parvovirus. Hence, the major sites of virus replication Classification in patients are assumed to be the adult marrow, some blood There are two subfamilies of Parvoviridae: the Parvovirinae, cells, and the fetal liver. Viral replication causes cell death, which infect vertebrates, and the Densovirinae, which infect interrupting red blood cell production. Bone marrow biopsies 457 Riedel_CH31_p457-p462.indd 457 04/04/19 5:01 PM  458   SECTION IV  Virology TABLE 31-1 Important Properties of Parvoviruses Virion: Icosahedral, 18–26 nm in diameter, 32 capsomeres Composition: DNA (20%), protein (80%) Genome: Single-stranded DNA, linear, 5.6 kb, MW 1.5–2.0 million Proteins: One major (VP2) and one minor (VP1) Envelope: None Replication: Nucleus, dependent on functions of dividing host cells Outstanding characteristics: Environmentally stable Human pathogen, B19, has tropism for red blood cell progenitors. MW, molecular weight. from infected patients show erythrocyte maturation arrest, with erythroblast intranuclear inclusions. In immunocom- FIGURE 31-1 Electron micrograph of parvovirus particles. promised patients, persistent B19 infections occur, resulting (Courtesy of FA Murphy and EL Palmer.) in chronic anemia. In cases of fetal death, chronic infections may have caused severe anemia in the fetus. infections occur in patients with immune deficiencies who fail Because nondefective parvoviruses require dividing host to make virus-neutralizing antibodies, resulting in anemia. cells to replicate, known parvovirus diseases reflect that tar- Persistence of low levels of B19 DNA has also been detected in get specificity (Figure 31-3). blood, skin, tonsil, liver, and synovial tissues of immunocom- Both virus-specific immunoglobulin M (IgM) and IgG petent persons. The rash associated with erythema infectio- antibodies are made after B19 infections. Persistent parvovirus sum is at least partly immune complex mediated. 15 100 12 Myalgias Arthralgias fever, malaise arthritis, rash 50 Units of antibody or DNA % of normal value 9 0 6 –50 3 0 –100 –2 0 2 4 6 8 10 12 14 16 18 20 22 Days after inoculation B19 DNA B19 IgM B19 IgG % Normal reticulocytes % Normal platelets Symptoms FIGURE 31-2 Clinical and laboratory findings during the course of human parvovirus B19 infection in adult volunteers. The first phase of illness with flu-like symptoms coincides with viremia (days 6–12); the second phase of illness with rash appears on about day 18. (Reproduced with permission from Anderson LJ, Erdman DD: Human parvovirus B19. In Richman DD, Whitley RJ, Hayden FG [editors]. Clinical Virology, 3rd ed. Washington DC: ASM Press, 2009; ©2009 American Society for Microbiology. No further reproduction or distribution is permitted without the prior written permission of American Society for Microbiology. Data taken from Anderson MJ, Higgins PG, Davis LR, et al: Experimental parvoviral infection in humans. J Infect Dis 1985;152:257–265.) Riedel_CH31_p457-p462.indd 458 04/04/19 5:01 PM  CHAPTER 31 Parvoviruses   459 TABLE 31-2 Human Diseases Associated with The virus can be transmitted parenterally by blood transfusions B19 Parvovirus or by infected blood products (coagulation factors and immu- noglobulin concentrates) and vertically from mother to fetus. Syndrome Host or Condition Clinical Features Because B19 can be present at extremely high titers and is resistant Erythema Children (Fifth disease) Cutaneous rash to harsh treatments that inactivate enveloped viruses, plasma- infectiosum Adults Arthralgia–arthritis derived clotting factor concentrates can end up contaminated Transient Underlying hemolysis Severe acute and are screened for the presence of B19 DNA. The prevalence of aplastic crisis anemia antibodies to B19 is higher among people with hemophilia than Pure red cell Immunodeficiencies Chronic anemia the general population; however, the minimal level of virus in aplasia blood products able to cause infections is not known. Hydrops fetalis Fetus Fatal anemia The pathogenesis of human bocavirus infection is not yet known, though some studies have associated its presence Modified with permission from Young NS: Parvoviruses. In Fields BN, Knipe DM, with respiratory disease. Because it has been found in respira- Howley PM (editors-in-chief). Fields Virology, 3rd ed. Lippincott-Raven, 1996. tory specimens, it is presumed to infect the respiratory tract and be transmitted by the respiratory route. It has also been B19 can be found in blood and respiratory secretions of detected in stool and serum samples. infected patients. Transmission is presumably by the respiratory Several pathogenic parvoviruses of animals replicate in route. There is no evidence of virus excretion in feces or urine. intestinal mucosal cells and cause enteritis. Consistent with Immune Fifth B19 complex disease deposition Antibody excess B19 TAC Hemolytic or stressed Virus excess erythron B19 PRCA No antibody, Commercial Ig A persistence of virus Heart B19 Hydrops Bone fetalis Liver marrow B FIGURE 31-3 Pathogenesis of diseases caused by B19 parvovirus. A: In children and adults. (PRCA, pure red cell aplasia; TAC, transient aplastic crisis.) B: In fetal infections. (Modified with permission from Brown KE, Young NS: Parvovirus B19 infection and hematopoiesis. Blood Rev 1995;9:176. Copyright Elsevier.) Riedel_CH31_p457-p462.indd 459 04/04/19 5:01 PM  460   SECTION IV  Virology their highly stable nature, parvoviruses have also been found B. Transient Aplastic Crisis contaminating laboratory reagents. Parvovirus B19 is the cause of transient aplastic crisis that may complicate chronic hemolytic anemia, such as in patients with Clinical Findings sickle cell disease, thalassemias, and acquired hemolytic ane- mias in adults. Transient aplastic crisis may also occur after A. Erythema Infectiosum (Fifth Disease) bone marrow transplantation. The syndrome is an abrupt The most common manifestation of human parvovirus B19 cessation of red blood cell synthesis in the bone marrow and infection is erythema infectiosum, or Fifth disease. This is reflected by the reduction of erythroid precursors in the erythematous illness is most common in children of early marrow, accompanied by a rapid worsening of anemia. The school age and occasionally affects adults. Fever and mild infection lowers production of erythrocytes, causing a reduc- constitutional symptoms may accompany the rash, which tion in the hemoglobin level of peripheral blood. The tempo- has a typical “slapped cheek” appearance (Figure 31-4). rary arrest of production of red blood cells becomes apparent Both sporadic cases and epidemics have been described. only in patients with chronic hemolytic anemia because of the Joint involvement due to immune complex deposition is a shortened life span of their erythrocytes; a 7-day interruption prominent feature in adult cases; joints in the hands and the in erythropoiesis would not be expected to cause detectable knees are most frequently affected. The symptoms mimic anemia in a normal person. Few anemia patients have a rash. rheumatoid arthritis, and the arthropathy may persist for Symptoms of transient aplastic crisis occur during the viremic weeks, months, or years. phase of infection. The incubation period is usually 1–2 weeks but may extend to 3 weeks. Viremia occurs 1 week after infection and persists for about 5 days. During the period of vire- C. B19 Infection in Immunodeficient Patients mia, virus is present in nasal washes and gargle specimens, B19 may establish persistent infections and cause chronic identifying the upper respiratory tract—most probably the suppression of bone marrow and chronic anemia in immu- pharynx—as the site of viral shedding. The first phase of nocompromised patients. The disease is called pure red cell illness occurs at the end of the first week; symptoms are flu- aplasia. The anemia is severe, and patients are dependent on like, including fever, malaise, myalgia, chills, and itching. blood transfusions. It has been observed in patient popula- The first episode of illness coincides in time with viremia tions with congenital immunodeficiency, malignancies, and reticulocytopenia and with detection of circulating AIDS, and organ transplantation. IgM–parvovirus immune complexes. After an incubation period of about 2 weeks, a second phase of illness begins. D. B19 Infection During Pregnancy The appearance of an erythematous facial rash and a lace- Maternal infection with B19 virus may pose a serious risk to like rash on the limbs or trunk may be accompanied by the fetus, resulting in hydrops fetalis and fetal death due to joint symptoms, especially in adults. The illness is short- severe anemia. The overall risk of human parvovirus infection lived, with the rash fading after 2–4 days, although the during pregnancy is low; fetal loss occurs in fewer than 10% joint symptoms may persist longer. Specific IgG antibodies of primary maternal infections. Fetal death occurs most com- appear about 15 days postinfection. monly before the 20th week of pregnancy. Although there is frequent intrauterine transmission of human parvovirus (with estimates of vertical transmission rates of 30% or higher), there is no evidence that most B19 infections cause physical abnormalities. Maternal–fetal transmission may occur most commonly in pregnant women with high plasma viral loads. E. Human Bocavirus Respiratory and Gastrointestinal Infections Human bocavirus has been detected in 1.5–11.3% of respi- ratory tract samples from young children with respiratory infections. It is prevalent among children with acute wheez- ing. However, bocavirus is often found in mixed infections with other viruses and in asymptomatic individuals, so it remains unclear whether bocavirus is the cause of acute respiratory disease in children. The virus has been detected in about 3% of stool samples from children with acute gastro- FIGURE 31-4 Erythema infectiosum (fifth disease). Typical enteritis. Coinfection rates with other enteric pathogens are “slapped cheek” appearance of the rash on the face. (Courtesy of also high, so any causative role of bocavirus in gastroenteritis Dr. Philip S. Brachman, CDC Public Health Image Library.) remains uncertain. Riedel_CH31_p457-p462.indd 460 04/04/19 5:01 PM  CHAPTER 31 Parvoviruses   461 Laboratory Diagnosis Treatment The most sensitive tests detect viral DNA. Available tests Fifth disease and transient aplastic crisis are treated symp- are polymerase chain reaction (PCR), probe hybridization tomatically. Severe anemia due to the latter may require of serum or tissue extracts, and in situ hybridization of fixed transfusion therapy. tissue. PCR is the most sensitive assay. B19 DNA has been Commercial immunoglobulin preparations contain detected in serum, blood cells, tissue samples, and respira- neutralizing antibodies to human parvovirus. These can tory secretions. During acute infections, viral loads in the sometimes ameliorate persistent B19 infections in immuno- blood can reach approximately 1011 genome copies/mL. compromised patients and in those with anemia. PCR assays based on B19 may miss non-B19 strains There is no treatment for human bocavirus infections. because of sequence differences. The only assay currently available for human bocavirus is PCR. Bocavirus DNA has been found in serum, saliva, stool samples, and respiratory Prevention and Control specimens. There is no vaccine against human parvovirus, although Serologic assays are performed to determine recent prospects are good that a vaccine can be developed. There are and past exposure to parvovirus B19. Detection of B19 IgM effective vaccines against animal parvoviruses for use in cats, antibody is indicative of recent infection; it is present for dogs, and pigs. There is no antiviral drug therapy. 2–3 months after infection. B19 IgG antibody against con- Good hygienic practices, such as hand washing and formational epitopes on VP1 and VP2 persists for years, not sharing drinks, should help prevent the spread of B19 although antibody responses against linear epitopes decline through respiratory secretions, aerosols, and fomites. Con- within months postinfection. Antibody may not be found tact precautions and extensive patient room cleaning may in immunodeficient patients with chronic B19 infections. In help prevent transmission of B19 from patients with aplastic those patients, chronic infection is diagnosed by detecting crisis and from immunodeficient patients with chronic B19 viral DNA. infection. Antigen detection assays can identify high-titered B19 virus in clinical samples. Immunohistochemistry has been used to detect B19 antigens in fetal tissues and bone CHAPTER SUMMARY marrow. Human B19 and human bocaviruses are difficult to Parvoviruses are small viruses with single-stranded DNA grow. Virus isolation is not used to detect infection. genomes. Human B19 virus targets erythroid progenitor cells. B19 is associated with erythema infectiosum (fifth disease), transient aplastic crisis, pure red cell aplasia, and hydrops Epidemiology fetalis (most commonly in early pregnancy). The B19 virus is widespread. Infections can occur throughout Human bocaviruses have been associated with acute respi- the year in all age groups and as outbreaks or as sporadic cases. ratory disease and gastroenteritis in children, but causation Infections are commonly seen as outbreaks in schools. Parvo- has not been proven. virus infection is common in childhood; antibody most often Human B19 and bocaviruses are difficult to grow; lab- develops between the ages of 5 and 19 years. Up to 60% of all oratory diagnosis depends on serology and molecular adults and 90% of elderly people are seropositive. assays. B19 infection seems to be transmitted via the respiratory tract. The viruses are stable in the environment, and contami- nated surfaces may also be involved in transmission. Transfer REVIEW QUESTIONS among siblings and children in schools and daycare centers is 1. Which one of the following best describes a physicochemical the main path of transmission. The source of maternal infec- property of parvoviruses? tion during pregnancy is often the mother’s older child. Many (A) Enveloped virus particle. infections are subclinical. Estimates of attack rates in suscep- (B) Single-stranded DNA genome. tible contacts range from 20 to 50%. (C) Infectivity is inactivated by ether treatment. Transmission of B19 from patients with aplastic cri- (D) Virion exhibits helical symmetry. sis to members of the hospital staff has been documented. (E) Virion is about the same size as herpesviruses. Whereas patients with aplastic crisis are likely to be infec- 2. An 8-year-old child recently had erythema infectiosum. Her tious during the course of their illness, patients with fifth 33-year-old mother subsequently developed arthralgia followed disease are probably no longer infectious by the time of by painful arthritis with swelling in the small joints of both onset of rash. hands. In addition to the apparent tropism for joints, human The epidemiology of human bocavirus is not known. It parvovirus B19 is highly tropic for which cell type? has been found mostly in young children and appears to be (A) CD4 T lymphocytes global in distribution. (B) Renal tubule cells Riedel_CH31_p457-p462.indd 461 04/04/19 5:01 PM  462   SECTION IV  Virology (C) Erythroid cells 9. Which of the following is available as a treatment or preventive (D) Glial cells for parvovirus B19 infections? (E) Peyer patches (A) Commercial immunoglobulin 3. The 8-year-old child in Question 2 had an illness with more (B) Vaccine containing recombinant VP2 viral antigen than one phase. Which symptoms coincide with the second (C) Bone marrow transplantation phase of the illness? (D) Antiviral drug that blocks virus–receptor interaction (A) Sore throat 10. Human erythroviruses and bocaviruses share the following (B) Skin rash properties except for which one? (C) Headache (A) Small, nonenveloped virus particles (D) Diarrhea (B) Difficult to culture (E) Cough (C) Cause anemia 4. A 42-year-old man with HIV/AIDS presented with aplastic ane- (D) Global distribution mia. Using PCR, parvovirus B19 was detected in his serum. The (E) No vaccine exists patient presumably acquired his parvovirus B19 infection from another person. The most likely route of transmission is Answers (A) By contact with respiratory secretions or droplets 1. B 5. D 9. A (B) By contact with a skin rash 2. C 6. B 10. C (C) Through sexual activity (D) Through a recent blood transfusion 3. B 7. D 4. A 8. C 5. Which one of the following is a disease in which the role of par- vovirus B19 has not been established? (A) Erythema infectiosum (fifth disease) (B) Transient aplastic crisis REFERENCES (C) Hydrops fetalis Allander T, Jartti T, Gupta S, et al: Human bocavirus and acute (D) Fulminant hepatitis wheezing in children. Clin Infect Dis 2007;44:904. 6. Which one of the following best describes the replication of Corcoran A, Doyle S: Advances in the biology, diagnosis, and human parvovirus B19? host-pathogen interactions of parvovirus B19. J Med Microbiol (A) Stimulates resting cells to proliferate 2004;53:459. (B) Uses blood group antigen P as cellular receptor Faisst S, Rommelaere J (editors): Parvoviruses: From Molecular (C) Readily establishes persistent infections Biology to Pathology and Therapeutic Uses. Karger, 2000. (D) Entire replication cycle occurs in cytoplasm Magro CM, Dawood MR, Crowson AN: The cutaneous mani- (E) Production of infectious progeny requires the presence of a festations of human parvovirus B19 infection. Hum Pathol helper virus 2000;31:488. Norja P, Hokynar K, Aaltonen LM, et al: Bioportfolio: Lifelong 7. Which one of the following statements is most accurate con- persistence of variant and prototypic erythrovirus DNA cerning human infections by parvovirus B19? genomes in human tissue. Proc Natl Acad Sci USA 2006;103:7450. (A) Parvovirus B19 is transmitted readily by sexual intercourse. Saldanha J, Lelie N, Yu MW, et al: Establishment of the first World (B) Patients with disseminated disease caused by parvovirus Health Organization International Standard for human parvo- B19 should be treated with acyclovir. virus B19 DNA nucleic acid amplification techniques. Vox Sang (C) Parvovirus B19 does not cause any human disease. 2002;82:24. (D) There is no vaccine for human parvovirus. Servant-Delmas A, Lefrère JJ, Morinet F, et al: Advances in human 8. Human bocavirus is a newly discovered parvovirus. It has been B19 erythrovirus biology. J Virol 2010;84:9658. detected most frequently in which type of sample? Wang K, Wang W, Yan H, et al: Correlation between bocavirus (A) Urine infection and humoral response, and co-infection with other (B) Cord blood respiratory viruses in children with acute respiratory infection. (C) Respiratory secretions J Clin Virol 2010;47:148. (D) Fetal liver (E) Bone marrow Riedel_CH31_p457-p462.indd 462 04/04/19 5:01 PM