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Parvoviruses
The parvoviruses are small, single-stranded DNA viruses. They are common infectious agents of a variety of animal species, including mammals, birds, and insects. Parvoviruses as a group include a number of important animal pathogens. There are 5 different types of parvoviruses known to infect humans: the dependoviruses, also called adeno-associated viruses (AAV), parvovirus B19 (B19V), human bocaviruses (HBoV), parvovirus 4 (PARV4), and human bufavirus (HBuV). B19V and HBoV are the only 2 parvoviruses known to be pathogenic in humans. B19V is the most well studied and clinically important of the human parvoviruses and the cause of erythema infectiosum or fifth disease . The more recently described human bocavirus is an emerging human pathogen.
Etiology
The 5 human parvoviruses are distinct enough from each other to represent 5 different genera within the Parvoviridae family. B19V is a member of the genus Erythroparvovirus . The virus is composed of an icosahedral protein capsid without an envelope and contains a single-stranded DNA genome of approximately 5.5 kb. It is relatively heat and solvent resistant. It is antigenically distinct from other mammalian parvoviruses and has only 1 known serotype, with 3 distinct genotypes described. The relatively short parvovirus genome does not encode a DNA polymerase, so all parvoviruses require either host cell factors present in late S phase or coinfection with another virus to replicate their DNA. B19V can be propagated effectively in vitro only in CD36+ erythroid progenitor cells derived from human bone marrow, umbilical cord blood, or peripheral blood.
HBoV is a member of the genus Bocaparvovirus . HBoV was first isolated from nasopharyngeal specimens from children with respiratory tract infection in 2005. It was identified using random polymerase chain reaction (PCR) amplification and sequencing methods specifically designed to detect previously unknown viral sequences. Analysis of the gene sequences showed similarities to both bovine and canine parvoviruses, and thus the virus was named human bocavirus. Later, 3 other HBoVs were identified in stool samples and named HBoV types 2, 3, and 4, with the initial respiratory isolate called HBoV1. The HBoV capsid structure and genome size are similar to those of B19V, but the genomic organization and replication are different (though not fully characterized to date). HBoVs cannot be propagated in conventional cell culture but have been grown in a pseudostratified human airway epithelial cell culture system.
The AAVs are members of the genus Dependoparvovirus and were the first parvoviruses to be found in humans. They were originally identified as contaminants in adenovirus preparations, resulting in the designation AAV. They were later isolated directly from human tissue samples, and now several AAV serotypes are known to commonly infect humans. AAVs have a unique life cycle that can take 1 of 2 paths: (1) a lytic infection with replication of viral DNA and production of new virus, or (2) viral integration into the host cell DNA. In the presence of a “helper” virus, usually an adenovirus or a herpesvirus, AAV can replicate its DNA, produce capsids, and release new virions by cell lysis. In the absence of a helper virus infection, the AAV genome becomes integrated into the host cell DNA. This feature has drawn interest in AAVs as potential vectors for gene therapy. Although human infection with AAVs is common, there is no known disease association and no evidence of pathogenicity, so this virus will not be discussed further in this chapter.
PARV4 was initially identified in 2005 from the blood of an adult patient with acute viral syndrome, who was also an intravenous drug user co-infected with hepatitis C. Subsequently, this virus has been found in blood donors and donated plasma pools in many different countries. It appears to be present in approximately 3% of blood donors in the United States and 4% of plasma pools. There is currently no known disease association or clinical symptomology associated with infection. Likewise, BuV is a parvovirus that has recently been found to infect humans but its role as a pathogen is undetermined. It was first identified in 2012 in the feces from children <5 yr of age with acute diarrhea. BuV is a member of the genus Protoparvovirus , and PARV4 has been assigned to a new parvovirus genus, Tetraparvovirus . The full epidemiology and clinical relevance of both of these viruses await further study.
Epidemiology
Parvovirus B19
Infections with B19V are common and occur worldwide. Clinically apparent infections, such as the rash illness of erythema infectiosum and transient aplastic crisis, are most prevalent in school-age children (70% of cases occur in patients between 5 and 15 yr of age). Seasonal peaks occur in the late winter and spring, with sporadic infections throughout the year. Seroprevalence increases with age, with 40–60% of adults having evidence of prior infection.
Transmission of B19V is by the respiratory route, presumably via large-droplet spread from nasopharyngeal viral shedding. The transmission rate is 15–30% among susceptible household contacts, and mothers are more commonly infected than fathers. In outbreaks of erythema infectiosum in elementary schools, the secondary attack rates range from 10% to 60%. Nosocomial outbreaks also occur, with secondary attack rates of 30% among susceptible healthcare workers.
Although respiratory spread is the primary mode of transmission, B19V is also transmissible in blood and blood products, as documented among children with hemophilia receiving pooled-donor clotting factor. Given the resistance of the virus to solvents, fomite transmission could be important in childcare centers and other group settings, but this mode of transmission has not been established.
Human Bocaviruses
The majority of published studies have used molecular methods to detect HBoV DNA in respiratory secretions, fecal samples, blood, and other tissues. HBoV DNA (HBoV1) can be found commonly in respiratory secretions from children hospitalized with acute lower respiratory tract infections (LRTIs). It is more prevalent in children younger than 2 yr of age and seems to be associated with wheezing respiratory illness. However, it can be isolated from respiratory secretions from asymptomatic children and can often be found as a coinfection with other common respiratory pathogens of children this age, including respiratory syncytial virus, human metapneumovirus, and rhinoviruses. This has caused some confusion as to the pathogenic role of HBoV in acute LRTI, including whether it can persist in secretions long after a subclinical infection or requires a helper virus. A limited number of seroepidemiologic studies have been performed, and these suggest that infection is common in children younger than 5 yr of age. The most recent studies provide evidence that the virus is in fact pathogenic, especially in children younger than 2 yr with wheezing and LRTI, as HBoV1 is more likely to be the only virus isolated in these patients and more likely to have an acute antibody response when coupled with antibody testing. When quantitative PCR is used, the virus is found to be much higher in titer in these symptomatic cases.
HBoV DNA (HBoV2, HBoV3, and HBoV4) has also been found in fecal samples in studies from various countries, but its role as a cause of viral gastroenteritis is still undetermined.
Pathogenesis
Parvovirus B19
The primary target of B19V infection is the erythroid cell line, specifically erythroid precursors near the pronormoblast stage. Viral infection produces cell lysis, leading to a progressive depletion of erythroid precursors and a transient arrest of erythropoiesis. The virus has no apparent effect on the myeloid cell line. The tropism for erythroid cells is related to the erythrocyte P blood group antigen, which is the primary cell receptor for the virus and is also found on endothelial cells, placental cells, and fetal myocardial cells. Thrombocytopenia and neutropenia are often observed clinically, but the pathogenesis of these abnormalities is unexplained.
Experimental infection of normal volunteers with B19V revealed a biphasic illness. From 7 to 11 days after inoculation, subjects had viremia and nasopharyngeal viral shedding with fever, malaise, and rhinorrhea. Reticulocyte counts dropped to undetectable levels but resulted in only a mild, clinically insignificant fall in serum hemoglobin. With the appearance of specific antibodies, symptoms resolved and serum hemoglobin returned to normal. Several subjects experienced a rash associated with arthralgia 17-18 days after inoculation. Some manifestations of B19 infection, such as transient aplastic crisis, appear to be a direct result of viral infection, whereas others, including the exanthem and arthritis, appear to be postinfectious phenomena related to the immune response. Skin biopsy of patients with erythema infectiosum reveals edema in the epidermis and a perivascular mononuclear infiltrate compatible with an immune-mediated process.
Individuals with chronic hemolytic anemia and increased red blood cell (RBC) turnover are very sensitive to minor perturbations in erythropoiesis. Infection with B19V leads to a transient arrest in RBC production and a precipitous fall in serum hemoglobin, often requiring transfusion. The reticulocyte count drops to undetectable levels, reflecting the lysis of infected erythroid precursors. Humoral immunity is crucial in controlling infection. Specific immunoglobulin (Ig) M appears within 1-2 days of infection and is followed by anti-B19 IgG, which leads to control of the infection, restoration of reticulocytosis, and a rise in serum hemoglobin.
Individuals with impaired humoral immunity are at increased risk for more serious or persistent infection with B19V, which usually manifests as chronic RBC aplasia, although neutropenia, thrombocytopenia, and marrow failure are also described. Children undergoing chemotherapy for leukemia or other forms of cancer, transplant recipients, and patients with congenital or acquired immunodeficiency states (including AIDS) are at risk for chronic B19V infections.
Infections in the fetus and neonate are somewhat analogous to infections in immunocompromised persons. B19V is associated with nonimmune fetal hydrops and stillbirth in women experiencing a primary infection but does not appear to be teratogenic. Like most mammalian parvoviruses, B19V can cross the placenta and cause fetal infection during primary maternal infection. Parvovirus cytopathic effects are seen primarily in erythroblasts of the bone marrow and sites of extramedullary hematopoiesis in the liver and spleen. Fetal infection can presumably occur as early as 6 wk of gestation, when erythroblasts are first found in the fetal liver; after the 4th mo of gestation, hematopoiesis switches to the bone marrow. In some cases, fetal infection leads to profound fetal anemia and subsequent high-output cardiac failure (see Chapter 124 ). Fetal hydrops ensues and is often associated with fetal death. There may also be a direct effect of the virus on myocardial tissue that contributes to the cardiac failure. However, most infections during pregnancy result in normal deliveries at term. Some of the asymptomatic infants from these deliveries have been reported to have chronic postnatal infection with B19V that is of unknown significance.
Human Bocaviruses
Mechanisms of HBoV replication and pathogenesis are poorly characterized to date. Growth of HBoV1 in tissue culture is difficult, though the virus has been cultured in primary respiratory epithelial cells as noted above. The primary site of viral replication appears to be the respiratory tract, as the virus has been detected most frequently and in highest copy numbers here. HBoV1 has also been found occasionally in the serum, suggesting the potential for systemic spread. HBoV1 has also been detected in stool, but copy numbers are very low. In contrast, HBoV types 2-4 are found predominantly in the stool, but host cell types are not known.
Clinical Manifestations
Parvovirus B19
Many infections are clinically inapparent. Infected children characteristically demonstrate the rash illness of erythema infectiosum. Adults, especially women, frequently experience acute polyarthropathy with or without a rash.
Erythema Infectiosum (Fifth Disease)
The most common manifestation of B19V is erythema infectiosum, also known as fifth disease , which is a benign, self-limited exanthematous illness of childhood.
The incubation period for erythema infectiosum is 4-28 days (average: 16-17 days). The prodromal phase is mild and consists of low-grade fever in 15–30% of cases, headache, and symptoms of mild upper respiratory tract infection. The hallmark of erythema infectiosum is the characteristic rash, which occurs in 3 stages that are not always distinguishable. The initial stage is an erythematous facial flushing, often described as a slapped-cheek appearance ( Fig. 278.1 ). The rash spreads rapidly or concurrently to the trunk and proximal extremities as a diffuse macular erythema in the second stage. Central clearing of macular lesions occurs promptly, giving the rash a lacy, reticulated appearance ( Fig. 278.2 ). The rash tends to be more prominent on extensor surfaces, sparing the palms and soles. Affected children are afebrile and do not appear ill. Some have petechiae. Older children and adults often complain of mild pruritus. The rash resolves spontaneously without desquamation, but tends to wax and wane over 1-3 wk. It can recur with exposure to sunlight, heat, exercise, and stress. Lymphadenopathy and atypical papular, purpuric, vesicular rashes are also described.
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