May 18, 2007
Parvovirus B19 Infection in the Immunocompromised Host
By Florea, Anca V; Ionescu, Diana N; Melhem, Mona F
Human parvovirus B19 is a single-stranded DNA virus with a predilection for infecting rapidly dividing cell lines, such as bone marrow erythroid progenitor cells. People with defective cell- mediated immunity (eg, severe combined immunodeficiency syndrome; acquired immunodeficiency syndrome; and patients receiving immunosuppressive therapy, ie, post organ transplant) can develop pure red cell aplasia, in which suppression of erythroid precursors is permanent. Identification of parvovirus inclusions in marrow biopsies and subsequent confirmation of infection by in situ hybridization is important in the assessment of anemia in immunodeficient patients. Our objective is to provide a general overview of the parvovirus B19 infection and its characteristics in immunocompromised patients and to summarize updated information regarding the clinicopathologic features, pathobiology, and laboratory diagnosis of this subject. The pathologist should be aware of the wide spectrum of manifestations of parvovirus B19 infection depending on the patient's hematologic and immunologic status.
(Arch Pathol Lab Med. 2007;131:799-804)
Human parvovirus B19 (PV-B19) was discovered in the United Kingdom in 1975 by Cossart et al1 and has been associated with a variety of clinical manifestations, including rash, thrombocytopenia, leukopenia, fetal wastage, hypocomplementemia, autoimmune hemolytic anemia, arthritis, and vasculitis.2,3
Parvovirus B19 infection is found worldwide in persons of all ages. Most people become infected at some time during their life, up to 15% of individuals developing infection between 1 and 5 years of age, 15% to 60% between the ages of 5 and 19 years, and 30% to 60% in adulthood.4 Around 80% of the population is immune to the virus by the age of 50 years. PV-B19 acute infection occurs mainly in school-aged children and teenagers.5
Parvovirus B19 infection can be asymptomatic or can cause a broad range of diseases, including (1) diseases found among normal, nonimmunocompromised hosts (erythema infectiosum, arthropathy, hydrops fetalis); (2) hematologic diseases in immunocompromised hosts (aplastic crisis, chronic anemia, idiopathic thrombocytopenic purpura, transient erythroblastopenia of childhood, Blackfan- Diamond anemia); and (3) a heterogeneous group of diseases in which the etiologic role of PV-B19 is less clear and sometimes putative (neurologic disease, rheumatologic disease, and vasculitic and myocarditic syndromes). Less common clinical associations of PV-B19 virus infection include various skin eruptions, hematologic disorders such as neutropenia, hepatobiliary disease, neurologic disease, and rheumatic disease, including chronic fatigue syndrome.6
Symptomatic adult PV-B19 infection typically causes a brief arthritis, often with a rash. Persistent symptoms may occur, and PV- B19 has been linked with many rheumatic diseases.7 PV-B19 infection should be considered in the differential diagnosis of ill children with myocarditis and multiple organ system dysfunction.
Conditions shown to predispose to PV-B19-induced chronic anemia include Nezelof syndrome (an extremely rare immune deficiency disorder characterized by the impairment of cellular immunity against infections), acute lymphatic leukemia, acute myeloid leukemia, chronic myeloid leukemia, Burkitt lymphoma, lymphoblastic lymphoma, myelodysplastic syndrome, astrocytoma, Wilms tumor, human immunodeficiency virus (HIV) infected patients, severe combined immunodeficiency, bone marrow (BM) transplantation, organ transplantation, systemic lupus erythematosus, immunoglobulin isotype switching defects, patients receiving cancer chemotherapy, and patients with defect immunoglobulin specificity and neutralization.8
Human PV-B19 frequently causes transient red cell aplasia in children with sickle cell disease. Although the outcome of some transient red cell aplasia episodes in children with sickle cell disease is benign, many are treated with red cell transfusions to reduce the risk of circulatory collapse from severe anemia.9
Human PV-B19 is a small single-stranded DNA virus classified as a member of precursors. It is the only parvovirus that has been clearly linked with disease in humans. PV-B19 virus replicates only in human cells and belongs to the family Parvoviridae, genus Erythrovirus, whose tropism is primarily for erythroid autonomous, that is, not requiring the presence of a helper virus. Specific antiviral antibody production is thought to represent the major defense against PV-B19 virus, as human normal immunoglobulin frequently clears the virus from peripheral blood and results in clinical improvement in immunosuppressed persons.6
The virus replicates in human erythroid progenitor cells of the BM and blood, inhibiting erythropoiesis. Tropism of productive PV- B19 infection is mainly due to the restrictive cellular distribution of the P blood group antigen globoside (Gb4), which is found most commonly on cells of the erythroid lineage but also on platelets; on tissues from the heart, liver, lung, kidney, and endothelium; and on synovium. Individuals who lack erythrocyte P antigens are very rare (1 in 200 000) and apparently cannot be infected by PV-B19.10
Human PV-B19 capsids are composed of 2 structural polypeptides, the minor (4%) VP1 protein (83 kDa) and the major (96%) VP2 protein (58 kDa). VP1 immunoglobulin (Ig) M and/or IgG antibodies are always associated with the clearance of PV-B19 virus from serum.11,12
The detection of anti-VP1 and anti-VP2 antibodies is the basis for the diagnosis of acute or past PV-B19 infections. The dominant humoral immune response is to VP2 during early convalescence and to VP1 during late convalescence. Anti-VP1 and anti-VP2 antibodies play a major role in limiting PV-B19 infection in humans.4
Viremia occurs during the first week of infection, accompanied by constitutional symptoms of fever and malaise and by erythroid progenitor cell depletion in the BM. At the height of the viremia, a precipitous drop in the reticulocyte count occurs and is followed by anemia, which is rarely clinically apparent in healthy patients but can cause serious anemia if the red blood cell count is already low. The reduction in the reticulocyte count is occasionally accompanied by leukopenia and thrombocytopenia.13
Specific IgM and IgG antibodies appear 10 to 12 days and 2 weeks, respectively, after experimental and natural human PV-B19 infection.14 Immunoglobulin M antibodies may be found in serum for 3 to 6 months, and IgG antibodies presumably persist for life, with an increase in their level after reexposure. Immunoglobulin G and IgM antibody assays remain the most sensitive way to detect PVB19 infection.15
A chemiluminescence in situ hybridization method was developed for the search of PV-B19 DNA in BM cells, employing digoxigenin- labeled PV-B19 DNA probes, immunoenzymatically detected with a highly sensitive 1,2-dioxetane phosphate as chemiluminescent substrate. The chemiluminescent assay provided an objective estimation of the data, proved specific, and showed an increased sensitivity in detecting PV-B19 DNA compared with in situ hybridization with colorimetric detection.16
The polymerase chain reaction (PCR) with ethidium bromide for detection is at least 104 times more sensitive than dot blot hybridization for the detection of PV-B19 DNA in serum. Using dot blot hybridization to detect virus, Anderson et al15 showed that PV- B19 viremia precedes the appearance of PV-B19-specific IgM and that IgM persists for weeks after viremia has cleared. Thus, patient sera obtained early in infection may lack IgM to PV-B19 but be PCR positive. Later during infection, sera may be PCR negative but contain immunoglobulin. In immunocompromised patients with chronic PV-B19 infections, antigen or DNA detection is required for diagnosis. For these immunocompromised patients, PCR, because of its excellent sensitivity and specificity, is likely to be the most useful of the currently available diagnostic tests.17
The finding of very large, abnormal pronormoblasts on BM examination of patients with anemia is suggestive of PV-B19 infection. Identification of PV-B19 inclusions in marrow biopsies and subsequent confirmation of infection by in situ hybridization or immunohistochemical staining is important in the assessment of anemia in immunodeficient patients because serologic studies for PV- B19 are frequently negative.
The diagnosis of PV-B19 infection may also be hinted at by the histopathologic aspect of BM: overall hypercellularity and the presence of giant pronormoblasts with finely granulated cytoplasm and glassy, variably eosinophilic, intranuclear inclusions with a clear central halo (lantern cells) (Figure 1).
Bone marrow examination shows giant, multinucleated erythroblasts and pronormoblasts. Late normoblasts are almost completely absent. The numbers of granulocytic cells and megakaryocytes are normal, although the myeloid-erythroid ratio is elevated because of the paucity of normoblasts. Pronormoblasts show prominent intranuclear viral inclusions, which are eosinophilic and compress the chromatin against the nuclear membrane (Figures 2 and 3). Many of these pronormoblasts show cytoplasmic immunoreactivity with a monoclonal antibody to PV-B19. Characteristic giant early erythroid cells are seen on Wright-G\iemsa stain (Figure 4).
Immunohistochemistry studies using the antimonoclonal antibody R92F6 have been found to be a useful, rapid, and sensitive test in confirming the PV-B19 infection.8
Infection with PV-B19 is very common, and cases of infection have been reported all over the world in all seasons. Seroprevalence increases with age, and by adulthood more than 70% of the adult population is seropositive. Children are the main source of transmission and outbreaks can persist for months in schools and day- care centers, because of the relatively large number of seronegative children and close contact of children within this environment. The annual seroconversion rate among women of childbearing age has been estimated to be 1.5% during endemic periods and 13% during epidemics.
In the immunocompromised host, persistent PV-B19 infection is manifested as pure red cell aplasia and chronic anemia.18
A host with a compromised immune system is particularly at risk of PV-B19 infection, including people with acquired immunodeficiency syndrome (AIDS), cancer patients who are receiving chemotherapy, and transplant patients on immunosuppressive drugs. Many are unable to produce neutralizing antibodies to clear the virus and this can lead to persistent infection, resulting in anemia.
Parvovirus B19 infects erythroid progenitor cells in the BM and causes temporary cessation of red blood cell production. The erythroid lineage is most affected; however, neutropenia and thrombocytopenia are also frequently reported.14
Persistent PV-B19 infection results in chronic suppression of erythropoiesis with chronic anemia. Chronic anemia is frequently characterized by a selective decrease of red cell precursors in the BM, reticulocytopenia, and normocytic anemia. The onset of anemia after transplantation varies from 2 to 34 months. However, the onset of red blood cell aplasia has been reported to occur a few days after renal transplantation, suggesting different paths of infection, for example, airway transmission (blood transfusion, viral reactivation) and the transplanted kidney.
The diagnosis may be missed, especially in immunosuppressed subjects, when only antibody levels are measured. Direct demonstration of the virus genome by PCR or other assays has consequently been preferred. In solidorgan transplant recipients, a PV-B19 infection should be suspected in the presence of aplastic anemia following nonspecific symptoms of viral infection (fever, fatigue, cutaneous rash), or even if no such symptoms are detected. The infection is confirmed by the seroconversion and/or by isolation of the viral genome from the blood, because PV-B19 IgM antibodies, PV-B19 DNA, or both are rarely found in patients with an outbreak and without an illness suggesting parvovirus infection.19
There has been an association between acute lymphoblastic leukemia and persistent PV-B19 infection, which until recently, has been assumed to represent an opportunistic infection, the chronicity of which results from immunosuppression. However, several reports describe PVB19 infection preceding and mimicking acute lymphoblastic leukemia. One published study examined serum from 65 patients with acute lymphoblastic leukemia for PV-B19 DNA and specific IgG. The results showed that, although there was 1 positive case that was also published separately, serum anti-PV-B19 IgG was positive in 30% of patients, which is consistent with the population prevalence adjusted for age.
It has been hypothesized that if PV-B19 does play a role in the pathogenesis of acute leukemia, the virus may no longer be present in the serum at the time of diagnosis but may be present at other more cryptic sites because clearance from these areas may be delayed. One such site is the cerebrospinal fluid, samples of which are commonly taken as part of routine investigations in new cases of leukemia. In support of this approach, PV-B19 is known to cause meningoencephalitis.20
Parvovirus B19 infection should be suspected in leukemic patients if unexplained cytopenia (mainly anemia) follows an acute febrile illness. Very sensitive methods are often needed to confirm the diagnosis, because routine serologic tests may be unreliable in immunocompromised patients. Acute cytopenias in leukemic patients in remission often herald hematologic relapse; they may also come from drug toxicity or intercurrent viral infections. PV-B19 virus lytically infects erythroid precursors, leading to transient BM erythroblastopenia, which may be inapparent in healthy subjects but is a cause of acute hyporegenerative anemia in hemolytic patients.
The persistence of PV-B19 infection in immunocompromised patients has been reported as a cause of chronic hyporegenerative anemia.14 Up to 25% of severe chronic anemia in AIDS has been ascribed to PV- B19 infection. Knowing that an AIDS patient has chronic PV-B19 anemia lessens concern about drug anemia, protects the patient from invasive diagnostic maneuvers, and prevents the patient from disseminating the infection. In AIDS patients with pure red cell aplasia, a search for PV-B19 DNA in the serum or in the BM is warranted.
In AIDS patients, persisting PV-B19 infection resulting from impaired immunity may, as it approaches or exceeds the normal red cell life span, result in anemia. This anemia is not as severe as that resulting from transient aplastic crisis in sickle cell disease but may last months or even years and be confused with other anemias that may complicate the course of AIDS. The clinical picture is one of BM failure or hypoplasia and is usually restricted to the erythrocytic lineage (acquired pure red cell aplasia).
Exposure to community outbreaks of PV-B19, often seen in spring and autumn, should raise the possibility of PVB19 infection in the differential diagnosis of diffuse rashes and arthralgia in adults with HIV infection.21 In HIV-positive patients without AIDS the infection evolves as a mild exanthematous disease.
The diagnosis of PV-B19 infection may be difficult in immunodeficient patients. Although Ig and IgM anti-PVB19 antibodies may be more prevalent in AIDS patients than in the general population, in AIDS patients with pure red cell aplasia anti-PV-B19 antibodies may be undetectable or show only weak IgM titers. The inconstant humoral response may preclude the serologic diagnosis in this setting, compelling to the use of more sophisticated diagnostic methods, such as PCR, in situ hybridization, dot blot, and not withstanding its lower sensitivity, immunohistochemistry with monoclonal antibodies. This does not necessarily apply to HIV- positive patients with normal or near normal immune responses, in whom a serologic diagnosis is frequently possible.
Erythema infectiosum and/or the articular syndrome normally accompanying PV-B19 infection are thought to be due to immune complex depositions in vessels and synovia and once the patient has produced antibodies, these symptoms ensue. The appearance of the same symptoms after human immunoglobulin administration to immunodeficient patients with asymptomatic PV-B19 infection is consistent with this.
Musiani and colleagues22 described 2 HIV-positive patients with persistently positive PCR (ascribed to low-level viremia) and one of them was PCR positive 2 years before the onset of an aplastic crisis and the other 7 months before the onset of an illness similar to fifth disease. Antibody assays for PV-B19 were not done, however. The HIV infections in these patients were described as grade II (asymptomatic), according to the Centers for Disease Control and Prevention 1987 classification system, but they both progressed to grade IV during the observation period. It is not clear at what stage in this progression they developed PV-B19-related clinical manifestations. It is also possible to have PV-B19 IgG antibodies prior to the detection of PV-B19 viremia, as was the case in 1 HIV- positive patient prospectively followed by Goedert and colleagues. 23 He had IgG PV-B19 antibodies some 3 years before developing a positive nested PCR for PV-B19 DNA in the serum. It is impossible to exclude the passive acquisition of antibodies by blood transfusion. The PCR reaction turned to negative, but the patient remained IgG positive.
In short, HIV patients with unimpaired immunity are likely to manifest their PV-B19 infection as an exanthematic or joint disease, without hematologic involvement. In HIV patients with more advanced immunodeficiency, there may be persistent anemia and no rash.24
Patients who have underlying hematologic abnormalities (and thus depend on a high rate of erythropoiesis) are prone to cessation of red blood cell production if they become infected. This can result in a transient aplastic crisis, which may occur in persons with chronic hemolytic anemia and conditions of BM stress. However, any person suffering from decreased red cell production or increased destruction or loss will be in danger of developing aplastic crisis following PV-B19 infection. Cessation of the production of erythrocytes for 10 to 15 days, as seen during infection in healthy individuals, will lead in hemolytic patients to a marked drop in hemoglobin resulting from the underlying decrease in red cell survival in these patients. Thus, patients with sickle cell anemia, thalassemia, acute hemorrhage, and iron deficiency anemia are at risk. Typically, these patients have a viral prodrome followed by anemia, often with hemoglobin concentrations falling below 5.0 g/dL and reticulocytosis. Although recovery is usually spontaneous and recurrence does not occur, severe disease with heart failure and death is possible.
Therefore, such patients are best monitored carefully, usually in the hospital, for signs of congestive heart failure. Life-saving red blood cell transfusions may be required. These patients are contagious during the acute illness and thus need to be kept in respiratory i\solation to prevent nosocomial transmission.25
Although the anemia may be lethal, the aplastic crisis itself is usually terminated by the appearance of specific antibodies and thus rarely lasts for longer than 2 weeks. In predisposed individuals, 70% to 80% of aplastic episodes are caused by PV-B19 infection. Aplastic crisis usually presents with pallor, weakness, and lethargy, and patients are highly viremic, thereby posing a risk of transmission to others.18 Reticulocytopenia is the main manifestation of transient aplastic crisis.
Parvovirus B19 was incriminated as a cause of pure red blood cell aplasia in several congenital chronic hemolytic syndromes and occasionally in immunocompromised patients, including HIV patients and children treated for hematologic malignancies. Patients with chronic T-cell lymphocytosis often present with autoimmune phenomenon, especially rheumatoid arthritis and occasionally Sjgren syndrome. This viral infection may play an etiologic role in some cases of pure red blood cell aplasia developing in patients with large granular lymphocyte leukemia.26
Meningoencephalitis associated with acute infection by human PV- B19 is not uncommon, particularly during years of peak incidence of infection. PV-B19 virus could not be detected in the brain in cases of PV-B19 associated meningoencephalitis, suggesting that it is an inappropriate host immune response rather than a direct viral cytotoxicity that leads to neurologic symptoms and neuronal cell loss in this condition. It is important to mention that, of those cases of PV-B19 associated meningoencephalitis tested, PV-B19 DNA was almost invariably detected in the cerebrospinal fluid.
There was also a significant increase in proinflammatory cytokines in acute PV-B19 infection, which suggested that a persistent elevation of tumor necrosis factor alpha and interferon gamma may be associated with clinical sequelae of acute PV-B19 infection. It is possible that disturbance of the cytokine network may play a role in PV-B19 meningoencephalitis.22
Recently, it has been suggested that PV-B19 exacerbates or even induces systemic lupus erythematosus. There are striking similarities between PV-B19 infection and systemic lupus erythematosus. PV-B19 infection in patients with systemic lupus erythematosus may be due to lack of anti-PV-B19 antibodies because of either the immunocompromised nature of the host or the use of immunosuppressive drugs.
Parvovirus B19 might also play some role, direct or indirect, in the etiology or development of testicular germ cell tumor.27
The management of PV-B19 infections must take into account the severity of the infection and the patient's health status. Because infection in healthy children and adults is self-limited, no specific therapy is warranted.
Patients with transient aplastic crisis may require blood transfusions to prevent congestive heart failure. Intravenous immunoglobulin has been used to treat immunocompromised patients who develop chronic anemia from PV-B19 infection. Intrauterine fetal blood transfusions have been attempted in cases of PV-B19 related severe hydrops fetalis.
Patients hospitalized with transient aplastic crisis from PV-B19 superimposed on chronic anemia should be kept in droplet isolation to prevent nosocomial spread and to minimize health care worker exposure.
Because parenteral transmission of PV-B19 has been demonstrated via the transfusion of blood products from blood donated during the viremic stage of PV-B19 infection, screened blood should be considered, particularly for patients with sickle cell disease and other congenital anemias, immunocompromised hosts, and women during pregnancy.28,29
Human PV-B19 is a small single-stranded DNA virus that can infect immunocompromised and nonimmunocompromised hosts, causing viremia and constitutional symptoms. It replicates in human erythroid progenitor cells, resulting in severe red cell aplasia and anemia. The infection is usually self-limited in the immunocompetent host and has been implicated as a cause of erythema infectiosum in children and hydrops fetalis in pregnant women.
Parvovirus B19 infection should be included in the differential diagnosis of unexplained severe chronic anemia and thrombocytopenia in the immunocompromised, including HIV-positive and organ transplant patients.
Accepted for publication October 11, 2006.
From the Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pa (Dr Florea); the Department of Pathology, British Columbia Cancer Agency, Vancouver (Dr Ionescu); and the Department of Pathology, University of Pittsburgh School of Medicine And Veterans Affairs, Pittsburgh Healthcare System, Pittsburgh, Pa (Dr Melhem).
The authors have no relevant financial interest in the products or companies described in this article.
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Anca V. \Florea, MD; Diana N. Ionescu, MD; Mona F. Melhem, MD
Reprints: Anca V. Florea, MD, University of Pittsburgh Medical Center, Department of Pathology, A711.2 Scaife Hall, 3550 Terrace St, Room C901, Pittsburgh, PA 15261 (e-mail: [email protected]).
Copyright College of American Pathologists May 2007
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