Fibrosing mediastinitis complicating prior histoplasmosis is associated with human leukocyte antigen DQB1*04:02 − a case control study

Abstract

BackgroundFibrosing mediastinitis (FM) is an idiosyncratic reaction to infection with Histoplasma capsulatum with a prevalence of 3:100,000 people infected. The rarity of post-histoplasmosis fibrosing mediastinitis (PHFM) in areas where H. capsulatum is endemic suggests that an abnormal immunological host response may be responsible for the development of fibrosis. Our group previously reported an association between subjects with PHFM and human leukocyte antigen (HLA)-A*02. We sought to confirm or extend those findings with application of high resolution HLA typing in a cohort of subjects with PHFM.MethodsHigh-resolution HLA typing was performed on DNA samples from a new cohort 34 patients with PHFM. Control cohorts included 707 subjects from the “European American” subset of the National Marrow Donor Program® (NMDP) and 700 subjects from Dialysis Clinic, Inc. (DCI). The carriage frequencies of the HLA alleles identified in the PHFM, NMDP, and DCI cohorts were calculated and then all were compared.ResultsWe found an increase in the carriage frequency of HLA-DQB1*04:02 in PHFM subjects relative to the controls (0.15 versus 0.07 in DCI and 0.05 in NMDP; p = 0.08 and 0.03). Multiple logistic regression showed that DQB1*04:02 was statistically significant (p = 0.04), while DQB1*03:02 and C*03:04 had point estimates of OR > 1, though they did not reach statistical significance. The HLA-A*02 association was not replicated.ConclusionsHLA-DQB1*04:02 is associated with PHFM, which supports the premise that an aberrant host immune response contributes to the development of PHFM.

Fibrosing Mediastinitis: Uncommon Life-threatening Complication of Histoplasmosis

“…It is reported as abnormal host immunological response to histoplasma responsible for fibrosis. The study by Strock et al reported an association of major histocompatibility complex, class II, DQ beta 1 *04:02 subtype with post histoplasmosis fibrosing mediastinitis [ 2 ]. Histoplasmosis involving mediastinum is very rare which can present as a mediastinal mass or fibrosing mediastinitis [ 3 ].…”

Fibrosing mediastinitis: a rare complication of histoplasmosis

“…Urgent thoracotomy is indicated in cases of massive haemoptysis (>300 mL) in order to control haemorrhage of lung parenchyma 1. Less severe haemorrhage may be treated with endobronchial laser coagulation or transcatheter embolisation 6. Resection of fibrous tissues, however, is considered a last resort given the high risk of haemorrhage, damage to involved mediastinal structures and intraoperative mortality 2.…”

“…A limited number of case reports and case series have investigated the role of antifungal, antifibrotic and anti-inflammatory medications in treating FM 4. Itraconazole, the current drug of choice for treating mild to moderate histoplasmosis, has demonstrated extensive anecdotal efficacy in symptomatic improvement for patients with FM 6 8 13. Therefore, our patient was started on 200 mg of itraconazole two times a day for 3 months.…”

“…Focal granulomatous and diffuse non-granulomatous forms of FM have been described, although work up for both is identical 1 7. Granulomatous FM is more frequently reported in North America, where it is most commonly associated with infection by Histoplasma capsulatum 6 8 9. FM is incidentally diagnosed in about 40% of cases but, when symptomatic, it can mimic malignancy and cause pulmonary and/or vascular compromise, including superior vena cava (SVC) syndrome 1 2.…”

Sarcoidosis and Histoplasmosis: Is One a Consequence of the Other? A Case Report and Review of the Literature

“…There were 3 separate case reports discussing fibrosing mediastinitis in patients with sarcoidosis developing complications such as pulmonary edema, pulmonary hypertension, and pulmonary artery occlusion [ 14 – 16 ]. Strock recently found that certain HLA typing within histoplasmosis could carry a higher predisposition towards development of fibrosing mediastinitis [ 17 ]. This suggests that an aberrant host immune response could be contributing to its pathogenesis.…”