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Background
The Parvovirus is at the center of many dermatologic and rheumatologic diseases, previously attributed to unknown factors. Of these viruses, only Human parvovirus 19 is known to infect humans. Its best known infection is erythema infectiosum or 5th disease.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION INCIDENCE Approximately 50% of adults carry antibodies to parvovirus
DISEASE ASSOCIATIONS CHARACTERIZATION AUTOIMMUNE DISEASES
Parvoviral infection of endothelial cells and stromal fibroblasts: a possible pathogenetic role in scleroderma.
Magro CM, Nuovo G, Ferri C, Crowson AN, Giuggioli D, Sebastiani M.
Department of Pathology, The Ohio State University, Columbus, OH, USA, Department of Internal Medicine, Rheumatology Unit, University of Pisa, Pisa, Italy, and Departments of Dermatology and Pathology, University of Oklahoma and Regional Medical Laboratory, St John Medical Center, Tulsa, OK, USA.
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J Cutan Pathol. 2004 Jan;31(1):43-50. Abstract quote
BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease (CTD) which differs from other CTDs by progressive irreversible fibrosis in lung, kidney, skin, and heart. It has a worse prognosis compared to several other CTDs. The pathogenesis may reflect a humorally mediated microangiopathy in concert with the overproduction of collagen triggered by immune-mediated cytokine production. Having previously demonstrated parvovirus B19 (B19) DNA in bone marrow and skin biopsies of SSc patients in the absence of B19 viremia, we sought to further elucidate a role for B19 in the pathogenesis of SSc.
DESIGN: Twelve patients who fulfilled American College of Rheumatology criteria for a diagnosis of SSc were encountered. Ten were serologically screened for B19 infection. Solution phase polymerase chain reaction (PCR) for B19 DNA was performed on skin tissue from six patients, and in all biopsies, reverse transcriptase in situ PCR (RT in situ PCR) for B19 and tumor necrosis factor (TNF)-alpha mRNA was performed. B19 viral protein (VP2) expression was sought by immunohistochemistry and correlated to PCR findings and to light microscopy of hematoxylin and eosin-stained sections. Frozen tissue was also available on five of the patients. Two control groups were assessed for B19 and TNF expression comprising one with irrelevant primers and the other representing 18 cases of inflammatory skin lesions where the etiology was known and unrelated to B19 infection. In addition, frozen and paraffin-embedded tissues procured from skin lesions unrelated to B19 infection were assessed for B19 genome. In all cases, pretreatment with RNase was also performed to verify that any positive signal was indeed RNA based.
RESULTS: Diffuse SSc was seen in seven patients, and limited disease in five. All patients had an antinuclear antibody - specifically, an antinucleolar, anticentromere, and/or anti-Scl 70 antibody. Eleven of the 12 had lung involvement, whereas eight patients had myocardial disease. Of 12 patients tested serologically, nine had B19-specific antibodies, which included immunoglobulin M (IgM)-specific antibodies in two cases. Solution phase PCR showed B19 DNA in the skin in three cases and in the bone marrow in three cases, including two in whom skin-based B19 DNA was observed. In all cases, RT in situ PCR demonstrated B19 and TNF-alpha mRNA in endothelia, fibroblasts, mast cells, and perivascular inflammatory cells. Immunohistochemistry to assess VP2 was either negative or equivocal. Immunofluorescent studies revealed prominent deposition of C5b-9 within the cutaneous vasculature from biopsies of all patients tested. The control samples were negative for B19 and TNF RNA and DNA.
CONCLUSIONS: Parasitism of endothelia and fibroblasts by B19 with resultant enhanced TNF-alpha expression may be of pathogenetic importance in SSc even in the absence of demonstrable viremia. The vascular deposition of C5b-9 suggests a role for humoral immunity possibly induced by a state of endothelial neoantigenicity evoked by virally mediated cell injury. Treatment strategies include anti-viral therapy, including in the context of intravenous gamma-globulin and anti-TNF therapy.
Detection of parvovirus B19 capsid proteins in lymphocytic cells in synovial tissue of autoimmune chronic arthritis.Mehraein Y, Lennerz C, Ehlhardt S, Venzke T, Ojak A, Remberger K, Zang KD.
Department of Human Genetics, Saarland University, University Hospital, Homburg/Saar, Germany.
Mod Pathol. 2003 Aug;16(8):811-7. Abstract quote The pathogenic influence of viral agents in chronic inflammatory joint diseases like rheumatoid arthritis has been discussed for many years. More recently, DNA of several viruses, among them parvovirus B19 (B19), was traceable by PCR analysis in synovial fluid and synovial tissue.
To investigate the potential role of parvovirus B19 in rheumatoid arthritis, we analyzed the expression of B19 VP1/VP2 proteins by immunohistochemistry in paraffin sections of 63 synovial specimens in rheumatoid arthritis (RA; n = 29), psoriatic arthritis (PSA; n = 6), nonspecific arthritis or synovitis (n = 26), and normal synovia (n = 2). Thereby we could demonstrate replicative virus infection in a variable number of cells in about 90% of rheumatoid specimens and in four of six (66%) cases of psoriatic arthritis, but only in 38% of cases with chronic reactive inflammation and one case of normal synovia. In virus-positive rheumatoid specimens, moreover, the average number of affected cells was significantly higher than in virus-expressing synovia of nonspecific reactive inflammation.
These findings support the importance of B19-viral infection in the pathogenesis of chronic arthritis. B19-positive cells in the synovia could be ascribed to CD20- or CD3-positive B- or T-lymphocytes by double immunostaining. Based on these results, B19 infection of lymphocytic cells also seems possible.Parvovirus B19-induced systemic connective diseases including LE Lab Invest 2000;80:61A
Hum Pathol 2000;31:488
A causal role for parvovirus B19 infection in adult dermatomyositis and other autoimmune syndromes.Crowson AN, Magro CM, Dawood MR.
Central Medical Laboratories, Winnipeg, Canada.
J Cutan Pathol 2000 Nov;27(10):505-15 Abstract quote BACKGROUND: Infection with parvovirus B19 (B19) has been associated with connective tissue disease (CTD) stigmata, namely, a systemic lupus erythematosus (SLE)-like illness, seronegative polyarthritis resembling rheumatoid arthritis, and vasculitis. The dermatopathology and pathogenetic basis of such B19-associated CTD-like syndromes have not been elucidated.
OBJECTIVE: We attempted to document persistence of the B19 genome in skin lesions of 7 patients with CTD-like symptomatology following B19 infection and to correlate systemic manifestations to dermatopathological findings.
METHOD: In 7 prospectively encountered patients in whom history, clinical signs and/or serology supported a diagnosis of CTD in the setting of B19 infection, dermatopathological and clinical features were correlated. Parvovirus B19 viral genome was sought in skin tissue using the polymerase chain reaction (PCR).
RESULTS: Two patients had clinical features diagnostic of myopathic dermatomyositis (DM), 1 of whom is still symptomatic 1.5 years after the onset of her illness, and the other has had typical clinical features of DM for a duration of 3.5 years. A 3rd patient with SLE remains symptomatic 4 years after the onset of her illness. A 4th patient has persistent seronegative symmetrical polyarthritis of 6 years' duration and cutaneous lesions of granuloma annulare (GA). The 5th patient has a 1.5-year history of debilitating polyarthritis and cutaneous lesions with overlap features of DM and subacute cutaneous LE (SCLE). The 6th patient has had a persistent folliculocentric necrotizing vasculitis for 3 years. The 7th patient has a 1-year history of microscopic polyarteritis nodosa (PAN) with cutaneous vasculitis and persistent active renal disease. In 4 patients, exposure to children with fifth disease immediately preceded the onset of their CTD. Parvovirus B19 infection was documented serologically in 6 patients with antibodies of IgG subclass in 6 and of IgM subclass in 1. Four of 6 patients questioned had a history of atopy. Skin biopsies from patients with clinical features of SLE or DM demonstrated an interface dermatitis with dermal mucinosis. A necrotizing vasculitis with epithelial pustulation was seen in 2 patients. Interstitial GA-like infiltrates were seen in 5 cases. Immunofluorescent (IF) testing revealed a positive lupus band test (LBT) and epidermal nuclear and vascular staining for IgG and C5b-9 in the SLE patient. One DM patient had a negative LBT in concert with C5b-9 deposition along the dermoepidermal junction (DEJ) and within blood vessels while the other showed endomysial vascular Cs5b-9 deposition. In all patients, skin biopsy material contained B19 genome, which was absent in the serum of 4 patients analyzed. Symptomatic relief followed immunosuppressive and immunomodulatory therapy with agents including prednisone, cyclophosphamide, hydroxychloroquine, non-steroidal anti-inflammatory drugs and etanercept, but no patient has had complete symptom resolution.
CONCLUSIONS: Persistent B19 infection may be of pathogenetic importance in certain prototypic CTD syndromes, to which underlying immune dysregulation associated with a blunted IgM response to viral antigen may predispose. Anti-viral therapy might be worthy of consideration since traditional immunosuppressive therapy was unsuccessful in our cases.
HENOCH-SCHONLEIN PURPURA
Parvovirus B19 and parvovirus V9 are not associated with Henoch-Schonlein purpura in children.Heegaard ED, Taaning EB.
Department of Clinical Microbiology, University State Hospital, Rigshospitalet, Copenhagen, Denmark.
Pediatr Infect Dis J 2002 Jan;21(1):31-4 Abstract quote BACKGROUND: Based on single case reports, parvovirus B19 (B19) has repeatedly been proposed as an etiologic agent in patients with Henoch-Schonlein purpura (HSP), perhaps causing vasculitis by direct invasion of vascular endothelial cells because of the tissue distribution of the cellular B19 receptor. A cohort of children with HSP and other vasculitic diseases was investigated and compared with healthy control children to assess the role of B19 as well as parvovirus V9 (a putative emerging B19-like virus).
PATIENTS AND METHODS: Serum samples from 36 children with HSP (n = 29) or other vasculitic diseases (n = 7) were examined, and 38 healthy bone marrow donors were used as controls. The presence of specific B19 and V9 IgM and IgG antibodies was determined with a recently developed enzyme-linked immunosorbent assay, and viral DNA was detected by a novel nested PCR.
RESULTS: Specific IgM was not present in any of the patient or control serum samples. B19 DNA was detected in one patient, a previously healthy 8-year-old boy diagnosed with HSP, whereas none of the controls was B19-positive. V9 was not detected in any of the clinical or control samples. It seems likely that B19 infection might have triggered the development of HSP in the B19-positive patient, because B19 viremia is otherwise uncommon.
CONCLUSIONS: Although causality is difficult to construe in single cases, the data indicate that B19 is not a common contributing factor in the pathogenesis of vasculitis and that this pathogen is only rarely associated temporally with HSP or vasculitic diseases in children.
Parvovirus B19 associated adult Henoch Schonlein purpura.Cioc AM, Sedmak DD, Nuovo GJ, Dawood MR, Smart G, Magro CM.
Department of Pathology, Ohio State University, Columbus, OH, USA, Cadham Provincial Laboratories, Winnipeg, Manitoba, Canada.
J Cutan Pathol 2002 Nov;29(10):602-7 Abstract quote BACKGROUND: Parvovirus B19 has recently been implicated in various vasculitic syndromes including Henoch Schonlein purpura (HSP), Wegener's granulomatosis and microscopic polyarteritis. The association was established through serology, the identification of DNA in the peripheral blood and affected tissues and more recently by RNA localization to cutaneous capillary endothelium. However, direct localization of the viral DNA to the glomerular and cutaneous endothelium in HSP in correlation with the histopathologic findings has not been demonstrated.
METHODS: Skin and kidney biopsy tissues were processed for hematoxylin and eosin, immunofluorescent, polymerase chain reaction (PCR) and reverse transcriptase in situ PCR studies.
CASE PRESENTATION: A 64-year-old-female presented with palpable purpura and nephrotic range proteinuria. Kidney and skin biopsies showed IgA-associated mesangioproliferative glomerulonephritis and IgA-associated leukocytoclastic vasculitis, respectively. A diagnosis of HSP was rendered. Her clinical course was refractory to prednisone. Parvovirus B19 DNA and tumor necrosis factor alpha DNA were identified in the dermal and glomerular capillary endothelial cells and surrounding dermal inflammatory cells.
CONCLUSION: This is the first documentation of B19 localization to dermal and glomerular capillary endothelium in HSP. It is important to recognize parvovirus B19-associated adult HSP cases, as the treatment of choice is intravenous gamma globulin in concert with anti-TNFalpha therapy. In contrast immunosuppressive therapy may lead to a persistent and/or worsening disease course.
PITYRIASIS LICHENOIDES Pityriasis lichenoides: a cytotoxic T-cell-mediated skin disorder. Evidence of human parvovirus B19 DNA in nine cases.
Tomasini D, Tomasini CF, Cerri A, Sangalli G, Palmedo G, Hantschke M, Kutzner H.
Department of Dermatology, Hospital of Busto Arsizio, Busto Arsizio, Italy.
J Cutan Pathol. 2004 Sep;31(8):531-8. Abstract quote
Background: Pityriasis lichenoides et varioliformis acuta (PLEVA) and pityriasis lichenoides chronica (PLC) probably represent the polar ends of the same pathologic process, i.e. pityriasis lichenoides (PL), with intermediate forms in between. Previous studies have demonstrated that the inflammatory infiltrate in PLEVA is composed of cytotoxic suppressor T cells, whereas in PLC the helper/inducer T-cell population drives the immunological answer. Furthermore, monoclonal rearrangement of the T-cell receptor-gamma (TCR-gamma) genes was repeatedly found both in PLEVA and PLC.
Methods: Forty-one formalin-fixed, paraffin-embedded tissue specimens of 40 cases of PL were retrieved from the files of the authors. Immunophenotyping for cytotoxic granular proteins (Tia-1/GMP-17 and Granzyme B) and T-cell-related antigens (n = 41), TCR-gamma chain gene analysis (n = 30) and molecular investigations for parvovirus B19 (PVB19) DNA (n = 30) were performed.
Results: Overlapping immunophenotypes were observed in PLEVA and PLC. The dermal and epidermal T cells predominantly expressed CD2, CD3, CD8, and Tia-1 with a variable positivity for CD45RA, CD45RO, and Granzyme B. A monoclonal rearrangement pattern of the TCR-gamma genes was detected in three cases (10%). PVB19 DNA was found in nine cases (30%). T-cell monoclonality in conjunction with genomic PVB19 DNA was present in one case.
Conclusions: Our results demonstrate that PL is a skin disorder mediated by the effector cytotoxic T-cell population. The identification of PVB19 DNA in nine cases may be interpreted ambiguously: PVB19 as a true pathogen or as an innocent bystander.
PATHOGENESIS CHARACTERIZATION Tropism of the virus to erythroid precursors
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION General VARIANTS Erythema infectiosum Papular-purpuric gloves and socks syndrome (PPGSS) J Am Acad Dermatol 1990;23:850-854
Closely associated with parvovirus but other viruses including HHV-6 and CMV have been implicatedIntense erythema and edema of the palms and soles which progresses to petechial or purpuric lesions with sharp demarcation at the wrists or ankles
Enanthem may be present with vesicles and small erosions of the hard and soft palate, pharynx, tounge, and inner lips
Papular-purpuric "gloves and socks" syndrome: polymerase chain reaction demonstration of parvovirus B19 DNA in cutaneous lesions and sera.Grilli R, Izquierdo MJ, Farina MC, Kutzner H, Gadea I, Martin L, Requena L.
Department of Dermatology, Fundacion Jimenez-Diaz, Universidad Autonoma, Madrid, Spain.
J Am Acad Dermatol 1999 Nov;41(5 Pt 1):793-6 Abstract quote We report a typical case of papular-purpuric "gloves and socks" syndrome (PPGSS) in which primary infection by parvovirus B19 was demonstrated by seroconversion to this virus; parvovirus B19 DNA was also identified by polymerase chain reaction (PCR) methods in the sera of the patient and in the cutaneous biopsy specimen, both taken 4 days after the onset of clinical manifestations.
To our knowledge, this is the fourth published case in which parvovirus B19 DNA has been recovered from the skin by PCR. Serologic studies and PCR investigations in cutaneous biopsy for other viruses including herpes simplex virus types 1 and 2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, and human herpesvirus 6, 7, and 8 were negative.
Clinically, our case presented some additional features, which have not been previously described in cases of PPGSS, namely dysuria with vulvar edema and erythema, and unilateral petechial rash on the breast. The histopathologic findings of our case were nonspecific and consisted of an interface dermatitis with slight vacuolar degeneration at the dermoepidermal junction and a superficial perivascular inflammatory infiltrate mostly composed of lymphocytes, with numerous extravasated erythrocytes.
We review the cases of PPGSS published in the literature with respect to the different viruses that have been proposed as etiologic agents and conclude that acute infection by parvovirus B19 is the only one that has been adequately proved.
Gloves and socks syndrome: Early and late histopathologic features.Smith SB, Libow LF, Elston DM, Bernert RA, Warschaw KE.
San Antonio Uniformed Services Health Education Consortium at Brooke Army Medical Center and Wilford Hall Medical Center, Fort Sam Houston, and the Mayo Clinic, Scottsdale.
J Am Acad Dermatol 2002 Nov;47(5):749-54 Abstract quote BACKGROUND: Gloves and socks syndrome (GSS) is a recently described exanthem, most commonly caused by parvovirus B19.
OBJECTIVE: Our purpose was to describe both early and late histopathologic features of GSS.
METHODS: We performed histopathologic examination of biopsy specimens from a case of GSS and reviewed all the English-language literature reports of GSS to compare the reported histologic descriptions.
RESULTS: A total of 46 cases of GSS have been reported in the English-language literature. In 18 of those, the pathologic features were described. The histologic features of the current case evolved from a nonspecific superficial perivascular lymphocytic infiltrate to a vacuolar interface dermatitis with necrotic keratinocytes, erythrocyte extravasation, and a superficial perivascular and interstitial lymphocytic infiltrate.
CONCLUSION: Early lesions of GSS show nonspecific features common to viral exanthems. The late features, of a fully evolved exanthem, demonstrate a vacuolar interface dermatitis with necrotic keratinocytes, a superficial perivascular and interstitial infiltrate, and dermal hemorrhage. These late pathologic features, together with the clinical appearance of GSS, may help distinguish it from other entities.
Arthropathy/arthritis Transient aplastic crisis Chronic anemia Hydrops fetalis Intrauterine fetal demise J Infect Dis 1995;171:1360-1363
1610 pregnant women <28 weeks gestation were screened for infection3.7% incidence of acute infection
1.6% incidence of B19 related fetal lossGreatest risk when infection is acquired before 20 weeks gestation and most fetal loss occured between 20-28 weeks gestation
Neurologic disease Rheumatologic disease Lab Invest 2000;80:61A
Hum Pathol 2000;31:488
Vasculitis Myocarditis
Prevalence of the parvovirus B19 genome in endomyocardial biopsy specimens.Pankuweit S, Moll R, Baandrup U, Portig I, Hufnagel G, Maisch B.
Hum Pathol. 2003 May;34(5):497-503 Abstract quote Although enteroviruses have long been considered the most common cause of inflammatory heart muscle diseases, parvovirus B19 (PVB19) is emerging as a new and important candidate for myocarditis and dilated cardiomyopathy with inflammation (DCMi) and without inflammation (DCM).
We investigated left ventricular endomyocardial biopsy specimens from 110 patients with suspected inflammatory heart disease for the presence of PVB19, Coxsackie virus (CVB), and adenovirus (Ad2) genome by polymerase chain reaction. Diagnosis of myocarditis (36 patients), DCM (18 patients), DCMi (13 patients), and perimyocarditis (12 patients) was made by immunohistochemical and histopathological investigation of endomyocardial biopsy specimens. A control group consisting of patients with arterial hypertension was also investigated. Prevalence of the PVB19 genome in endomyocardial biopsy specimens was highest in patients with DCMi (3 of 13) and patients with myocarditis (7 of 36); in patients with DCM and perimyocarditis, prevalence was 3 of 13 and 2 of 12, respectively.
In patients with resolved myocarditis, no PVB19 DNA was detected; in patients with no inflammation and controls, prevalence was only 4% and 7%, respectively. CVB-RNA was detected in endomyocardial biopsy specimens from 3 of 37 patients with myocarditis; Ad2-DNA was found in 1 patient with DCM and 1 patient with perimyocarditis.
These findings suggest an association of the PVB19 genome in endomyocardial biopsy specimens of adults with the development of DCM, DCMi, and chronic myocarditis more frequently than previously expected. PVB19 should therefore be recognized as a potential cardiotropic pathogen in patients of all ages.Fatal parvovirus myocarditis in a 5-year-old girl
Charles E. Murry, etal
Hum Pathol 2001;32:342-345. (Abstract quote)
Infection with parvovirus B19 is common in children and typically causes mild illness. We report here the case of a 5-year-old girl who died suddenly, 2 weeks after the clinical diagnosis of a parvoviral infection (erythema infectiosum).
Microscopic examination of the heart showed severe myocarditis with extensive T-cell and macrophage infiltration. Cultures, serology, and molecular analyses of serum for enteroviridae, adenovirus, influenza, varicella zoster, cytomegalovirus, and herpes simplex viruses were negative. Quantitative polymerase chain reaction (PCR) analysis for parvovirus B19 in peripheral blood, however, showed active infection (91,000 genomes/mL serum; 2.4 genomes/mononuclear cell). Despite the presence of myocarditis, immunostaining for parvoviral surface antigens was negative in the heart. Quantitative PCR analysis of paraffin sections showed that myocardial parvoviral content was significantly less than that of the normal appearing kidney and within the range predicted simply by tissue blood content.
Thus, parvovirus B19 infection can be complicated by fatal myocarditis. Because the virus does not appear to have infected the heart, per se, we speculate that myocarditis arose from immunological cross-reaction to epitopes shared between the virus and the myocardium.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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