Clinical Immunology and Immunopathology
Regular ArticleInvestigation of EB Virus and Cytomegalovirus in Rapidly Progressive Interstitial Pneumonitis in Polymyositis/Dermatomyositis by in Situ Hybridization and Polymerase Chain Reaction
Abstract
In polymyositis/dermatomyositis (PM/DM), a rapidly progressive interstitial pneumonitis (RPIP) which is a fatal complication of unknown etiology has received increasing attention. We have encountered 9 RPIP cases among 150 PM/DM cases in the past 10 years. To investigate the pathogenic role of viruses in RPIP, we examined lung specimens from patients with RPIP in PM/DM for the presence of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) using polymerase chain reaction (PCR) and in situ hybridization (ISH). We analyzed 21 specimens from RPIP in PM/DM (n = 9), collagen diseases (n = 6; 4 had interstitial lung disease), and controls (n = 6). EBV was frequently detected in RPIP (7/9 by PCR, 3/9 by ISH), hut was also detected in other collagen diseases of the lungs. In lung specimens from both patients with RPIP in PM/DM and those with collagen diseases, EBV was significantly detected (13/15 by PCR, 5/15 by ISH, P < 0.005) compared to controls (1/6 by PCR, 0/6 by ISH). CMV was detected by ISH in 2 RPIP patients but in none of the others, though by PCR CMV was detected equally in the three groups studied. These findings indicate that a direct involvement of EBV or CMV in RPIP of PM/DM is unlikely, although it is possible that an immune response to latent viruses or vital products in PM/DM may have a role in the pathogenesis of the RPIP.
References (0)
Cited by (30)
Epstein-Barr virus and breast cancer: Epidemiological and Molecular study on Egyptian and Iraqi women
2012, Journal of the Egyptian National Cancer InstituteCitation Excerpt :Breast cancer may express EBERs less abundantly than other malignancies [9–12]. However, EBERs are not found in all NPCs or in some Burkitt and Hodgkin lymphomas that are LMP-1 positive by PCR [11–23]. Regarding the association of EBV presence with tumor grade, there was no statistical significant relation between EBV presence and tumor grade (p > 0.05) in both populations.
The role of Epstein-Barr virus (EBV) in breast carcinogenesis is still controversial. Unraveling this relationship is potentially important for better understanding of breast cancer etiology, early detection and possibly prevention of breast cancer. The aim of the current study is to unravel the association between EBV and primary invasive breast cancer (PIBC) in two different Arab populations (Egyptian and Iraqi women).
The study was done on paraffin-embedded tissues of 40 Egyptian and 50 Iraqi patients with PIBC in addition to 20 normal breast tissues as controls for each group. Both controls and neoplastic tissues were assessed for the expression of EBV genes and proteins (EBNA-1, LMP-1, and EBER) as well as CD21 marker by immunohistochemistry (IHC), in situ hybridization (ISH) and PCR techniques.
Our gold standard for EBV reactivity in breast cancer cases was positivity of both EBNA1 by PCR and EBER by in situ hybridization. EBV was detected in 18/40 (45%) and 14/50 (28%) of Egyptian and Iraqi women; respectively where p = 0.073, compared to 0/20 (0%) of their control groups (p < 0.05). Regarding the association between EBV positivity and tumor grade, there was not any statistical significant difference between EBV presence and tumor grade in both populations where p = 0.860 and p = 0.976 and the calculated rank biserial correlation coefficient was 0.114 and 0.269 for Egyptian and Iraqi women respectively.
Our findings show that EBV might act as a promoter for the development of PIBC and it might contribute to increased tumor aggressiveness in Egyptian and Iraqi patients.
Polymyositis/dermatomyositis and nasopharyngeal carcinoma: The Epstein-Barr virus connection?
2010, Journal of Clinical VirologyCitation Excerpt :However, the etiopathogenesis of PM/DM remains unclear. Viral infection might induce autoimmunity in susceptible individuals.8,9 The reported seasonal occurrence of PM/DM indicates that viral infection could trigger this rheumatic disease.10,11
Polymyositis (PM) and dermatomyositis (DM) are associated with high risk of nasopharyngeal carcinoma (NPC) in Asian countries. Epstein–Barr virus (EBV) might induce autoimmunity and malignancies in susceptible individuals.
To investigate the association of EBV with PM/DM and NPC in PM/DM patients.
Serum levels of anti-EBV viral capsid antigens (VCA) and anti-EBV-coded nuclear antigens-1 (EBNA-1) antibodies were measured by ELISA, and EBV DNA loads were determined using real-time PCR for 98 PM/DM patients, 94 systemic lupus erythematosus (SLE) patients and 370 healthy controls (HC). Anti-transfer-RNA synthetase antibodies (ASA) were determined by radioimmunoprecipitation for PM/DM patients.
Thirteen (13.3%) of PM/DM patients vs. none of SLE patients had detectable NPC. ASA were detectable in 31.7% of PM/DM without malignancy, while lack of ASA in any PM/DM patient with NPC. IgA anti-EBNA-1 were detectable in 30.6% of PM/DM patients and 31.9% of SLE patients, but only in 4.1% of HC (odds ratio [OR] 10.44 and 11.12 respectively, both p < 0.001). Significantly higher positivity for IgA anti-EBNA-1 were observed in PM/DM with NPC than in those without malignancy (OR 44.7, p < 0.01). Significantly higher positivity for EBV genome were observed in PM/DM with NPC than in those without malignancy (OR 43.9, p < 0.01), in SLE patients (OR 13.2, p < 0.05) and in HC (OR 99.4, p < 0.001). EBV DNA loads were significantly higher in PM/DM with NPC compared with those without malignancy and HC.
Our results showed a positive association of EBV with PM/DM and NPC. PM/DM patients who have IgA anti-EBNA-1 or increased EBV DNA loads should be highly suspected to have occult NPC.
Pulmonary damage during polymyositis and dermatomyositis: Interstitial lung disease
2006, Presse MedicaleLa pneumopathie interstitielle est une complication grave des polymyosites/dermatomyosites, dont elle représente l’une des premières causes de mortalité, aboutissant au décès par insuffisance respiratoire chronique dans 30 à 66% des cas. De fait, elle constitue un critère de mauvais pronostic de la maladie.
Sa date de survenue est variable dans le cours évolutif des polymyosites/dermatomyosites, mais elle précède l’apparition des polymyosites/dermatomyosites dans la moitié des cas. Son mode de présentation peut revêtir différentes formes: aiguë (25%), insidieuse (60%), ou infraclinique de découverte fortuite (15%).
Les examens complémentaires de choix pour la dépister précocement sont la tomodensitométrie haute résolution et les explorations fonctionnelles respiratoires, qui devraient être réalisées lors du bilan initial et de la surveillance des polymyosites/dermatomyosites. De plus, la tomodensitométrie haute résolution permet également d’apprécier la nature des lésions histologiques de pneumopathie interstitielle. Le diagnostic de pneumopathie interstitielle n’impose pas aujourd’hui, en règle générale, une confirmation anatomopathologique, la pneumopathie interstitielle non spécifique semblant constituer l’atteinte histologique la plus habituelle au cours des polymyosites/dermatomyosites (40 à 80%).
L’anticorps anti-Jo1 étant un marqueur sensible de la pneumopathie interstitielle au cours des polymyosites/dermatomyosites, une surveillance étroite des paramètres pulmonaires est préconisée chez les patients ayant cet autoanticorps. La recherche systématique des anticorps anti-Jo1 est aussi justifiée chez les patients présentant une pneumopathie interstitielle d’allure idiopathique, afin d’éliminer une polymyosite/dermatomyosite sous-jacente.
Le traitement de la pneumopathie interstitielle n’est pas clairement établi au cours des polymyosites/dermatomyosites. Il repose en premier lieu sur la corticothérapie. L’association du cyclophosphamide et des corticoïdes pourrait être la plus efficace dans les formes de polymyosites/dermatomyosites corticorésistantes, ce d’autant qu’elle est instituée précocement; il pourrait également être licite de l’instaurer d’emblée lorsque des facteurs prédictifs du pronostic péjoratif de la pneumopathie interstitielle sont décelés.
Interstitial lung disease is a serious complication of polymyositis/dermatomyositis and leads to death from chronic respiratory insufficiency in 30 to 66% of cases. It is a criterion of poor prognosis in these disorders.
Its onset occurs at variable points in the course of polymyositis/dermatomyositis, and precedes them in half of all cases. Presentation may also vary: acute (25%), insidious (60%), or infraclinical, discovered fortuitously (15%).
The examinations of choice for early screening are high-resolution computed tomography (CT) and pulmonary function tests, which should be performed during the initial work-up and during ongoing surveillance. Moreover, high-resolution CT also makes it possible to determine the type of histologic lesions in the interstitial lung disease. Today, diagnosis of this disease does not generally require histological confirmation; nonspecific interstitial lung disease seems to be the most common histologic form of lung damage in polymyositis/dermatomyositis (40 to 80%).
Anti-Jo1 antibodies are a sensitive marker of interstitial lung disease during polymyositis/dermatomyositis, and close surveillance of lung function is recommended in patients with these autoantibodies. Systematic testing for them is also justified in patients with apparently idiopathic interstitial lung disease, to rule out underlying polymyositis/dermatomyositis.
No clear treatment protocols have been established for interstitial lung disease during polymyositis/dermatomyositis. Corticosteroid treatment is the first choice. Its combination with cyclophosphamide may be most effective in corticosteroid-resistant forms of polymyositis/dermatomyositis, especially when begun early; it may also be appropriate to begin corticosteroids as soon as factors predicting poor prognosis are detected.
Interstitial lung disease in polymyositis and dermatomyositis
2001, Revue de Medecine InternePropos. – La pneumopathie interstitielle constitue l’une des plus fréquentes manifestations pulmonaires au cours des polymyosites et des dermatomyosites. Elle demeure une complication grave de la maladie, dont elle représente à l’heure actuelle l’une des premières causes de mortalité aboutissant au décès par insuffisance respiratoire dans 30 à 66 % des cas.
Actualités et points forts. – Sa date de survenue est variable, mais elle précède l’apparition des polymyosites et des dermatomyosites dans la moitié des cas. De plus, son mode de présentation clinique peut revêtir des formes différentes : aiguë, insidieuse et infraclinique de découverte fortuite. Les examens complémentaires de choix pour la dépister précocement sont la tomodensitométrie haute résolution et les explorations fonctionnelles respiratoires, qui devraient être réalisées lors du bilan initial et de la surveillance des polymyosites et des dermatomyosites. De plus, l’anticorps anti-JO1 étant un marqueur de la pneumopathie interstitielle au cours des polymyosites et des dermatomyosites, une surveillance étroite des paramètres pulmonaires est également indiquée chez les patients ayant cet anticorps. Par ailleurs, l’histologie pulmonaire a montré son intérêt pour déterminer la nature des lésions pulmonaires qui constitue un paramètre pronostique en termes de survie ; les patients porteurs d’une BOOP (bronchiolitis obliterans organizing pneumoniae) auraient ainsi un taux de survie supérieur à ceux ayant une pneumonie interstitielle usuelle et des dommages alvéolaires diffus. Les indications des autres examens, et notamment du lavage bronchoalvéolaire, restent à déterminer.
Perspectives et projets. – Le traitement spécifique de la pneumopathie interstitielle n’est pas clairement établi au cours des polymyosites et des dermatomyosites. Il repose en premier lieu sur la corticothérapie. L’association du cyclophosphamide et des corticoïdes pourrait être la plus efficace dans les formes de pneumopathies interstitielles corticorésistantes. En définitive, l’accent doit être mis, à l’heure actuelle, sur l’importance du diagnostic et de la prise en charge thérapeutique précoce des pneumopathies interstitielles.
Purpose. – Interstitial lung disease is one of the most common respiratory manifestations in polymyositis and dermatomyositis. It still remains a severe complication of the disease, leading to death related to ventilatory insufficiency in 30–66% of patients.
Current knowledge and key points. – Time onset of interstitial lung disease is variable, although interstitial lung disease onset precedes initial manifestations of polymyositis/dermatomyositis in roughly half of the patients. Moreover, clinical presentation of interstitial lung disease can be dichotomized, according to patients’ pulmonary manifestations, into: 1) both acute and aggressive lung disease similar to Hamman-Rich syndrome; 2) slowly progressive lung disease; and 3) an asymptomatic pattern. The methods of choice adopted for early diagnosis of interstitial lung disease are high-resolution computed tomography scan and pulmonary function tests, which should be performed during both initial evaluation of polymyositis/dermatomyositis and follow-up. Because anti-JO1 antibody is considered to be a marker of interstitial lung disease in polymyositis/dermatomyositis, close pulmonary follow-up of anti-JO1-positive patients with polymyositis is therefore required for early detection of subclinical impairment. Furthermore, histological lung findings provide prognostic data; patients with bronchiolitis obliterans organizing pneumonia (BOOP) indeed appear to have a more favorable outcome than those with usual interstitial pneumonia or diffuse alveolar damage. Finally, as a guide to both the severity and progress of interstitial lung disease, the significance of other investigations, notably bronchoalveolar lavage, remains controversial.
Future prospects and projects. – Specific therapy of interstitial lung disease has not yet been clearly established in polymyositis/dermatomyositis patients. Corticosteroid therapy is considered the first line of therapy for polymyositis/dermatomyositis patients with interstitial lung disease. The association of cyclophosphamide and corticosteroids may be the most effective in patients with steroid-resistant interstitial lung disease. Early diagnosis and management of this disease is therefore of the utmost importance.
Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy
2001, Kidney InternationalCitation Excerpt :PVB19 DNA thus obtained was biotinylated using BioPrime DNA labeling system (GIBCO BRL, Grand Island, NY, USA). A biotinylated probe was used for in situ detection of PVB19 DNA by the Enzo pathoGene DNA probe assay protocol (Enzo Diagnostics, Inc., Farmingdale, NY, USA)22. Slides containing one to three sections were deparaffinized, dehydrated, and postfixed in neutral-buffered formalin for 20 minutes.
Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy.
Collapsing glomerulopathy (CG), a disorder with severe glomerular and tubular involvement, occurs either as an idiopathic lesion or in some patients with human immunodeficiency virus (HIV) infection known as HIV-associated nephropathy (HIVAN). We previously reported a renal transplant recipient with de novo CG and red cell aplasia in association with persistent parvovirus B19 (PVB19) infection. This prompted us to look for an association between PVB19 infection and CG.
DNA from archived biopsies of patients with CG was analyzed for PVB19 by polymerase chain reaction (PCR). Results were compared with HIVAN, idiopathic focal segmental glomerulosclerosis (FSGS), and controls. In situ hybridization (ISH) was done to localize PVB19 in renal biopsies. Peripheral blood specimens of patients with CG, HIV infection, healthy controls, and randomly selected hospitalized patients (sick controls) were also analyzed for PVB19.
PVB19 DNA was detected in renal biopsies of 18 out of 23 (78.3%) patients with CG, 3 out of 19 (15.8%) with HIVAN, 6 out of 27 (22.2%) with FSGS, and 7 out of 27 (25.9%) controls (P < 0.01, CG vs. HIVAN, FSGS, and controls). PVB19 was detected in peripheral blood of 7 out of 8 (87.5%) CG patients, 3 out of 22 (13.6%) with HIV infection, 4 out of 133 (3%) healthy controls, and 2 out of 50 (4%) sick controls (P < 0.001, CG vs. HIV infected, healthy, and sick controls). PVB19 was identified in glomerular parietal and visceral epithelial and tubular cells by ISH.
The significantly higher prevalence of PVB19 DNA in renal biopsies and peripheral blood of CG patients suggests a specific association between PVB19 infection and CG. In susceptible individuals, renal epithelial cell infection with PVB19 may induce CG.
The lung in polymyositis
1998, Clinics in Chest MedicinePolymyositis (PM) is an idiopathic inflammatory myopathy with systemic manifestations and mediated by autoimmune and cellular mechanisms. It results in proximal muscle weakness and often chronic disability. Systemic complications, in particular, lung involvement, are responsible for increased morbidity and mortality. In the United States 5 to 10 new cases of PM or its related disorder dermatomyositis (DM) per million population is discovered yearly.58 Women are more apt to be affected than men, and there is a predilection for African-American women.52 There are two disease peaks: one in children and the other in young to middle-aged adults.28 A classification of PM follows54:
Adult polymyositis
Adult dermatomyositis
Childhood polymyositis/dermatomyositis
Association with an underlying malignancy
Complicating an established collagen vascular disease
Polymyositis and DM are similar except for the prominent dermatologic rash and less muscle involvement in DM. The onset of PM or DM in an elderly patient may be the result of an underlying malignancy. Although sometimes disputed, Manchel et al, using strict criteria, found malignancy in 15 of 71 patients with PM or DM.45 These subjects were over 50 years with primaries in either the colon, breast, prostate, lung, or uterus. The neoplasm either predated, appeared concomitantly with, or became apparent at some point following the diagnosis of PM or DM. Neoplasms that preceded the onset were present for up to 20 years before the episode of PM or DM. In malignancies that appeared after the diagnosis of PM or DM, there was a 1- to 4-year delay. Two other studies indicated that DM but not PM is associated with an increased incidence of malignancy.1, 88
Polymyositis can also complicate the course of another collagen vascular disease and myositis can be a prominent manifestation of systemic lupus erythematosus, scleroderma, mixed connective tissue disease, and less frequently rheumatoid arthritis. This form of the inflammatory myopathy invariably occurs in women.52