Pulmonary granulomatosis of genetic origin

Abstract

Granulomatous inflammation of the lung can be a manifestation of different conditions and can be caused by endogenous inflammation or external triggers. A multitude of different genetic mutations can either predispose patients to infections with granuloma-forming pathogens or cause autoinflammatory disorders, both leading to the phenotype of pulmonary granulomatosis. Based on a detailed patient history, physical examination and a diagnostic approach including laboratory workup, pulmonary function tests (PFTs), computed tomography (CT) scans, bronchoscopy with bronchoalveolar lavage (BAL), lung biopsies and specialised microbiological and immunological diagnostics, a correct diagnosis of an underlying cause of pulmonary granulomatosis of genetic origin can be made and appropriate therapy can be initiated. Depending on the underlying disorder, treatment approaches can include antimicrobial therapy, immunosuppression and even haematopoietic stem cell transplantation (HSCT). Patients with immunodeficiencies and autoinflammatory conditions are at the highest risk of developing pulmonary granulomatosis of genetic origin. Here we provide a review on these disorders and discuss pathogenesis, clinical presentation, diagnostic approach and treatment.

FIGURE 1

Alveolar haemorrhage: partly epithelioid cellular interstitial inflammation in the affected lung, suggestive of a mild granulomatous-lymphocytic interstitial lung disease (GLILD). Airspaces are filled with erythrocytes (a), as indicated by an exemplar asterisk), some cluster forming alveolar macrophages (a) and c), as indicated by arrowheads, the latter using CD68⁺ stain) and small non-necrotising interstitial granulomas (b), as indicated by arrowheads) consisting of a few epithelioid cells and lymphocytes. Interstitial lymphocytic infiltrate mainly consists of CD4⁺ T-cells, partly clustered d) and partly scattered e). CD8⁺ T-cells are scattered f) and form the minority of the lymphocytic infiltrations. Scale bars: a–c, e, f) 50 μm; d) 200 μm.

FIGURE 2

Granulomatous-lymphocytic interstitial lung disease (GLILD). a) A 9-year old girl with atypical and confluent, partly spot-shaped infiltrates on chest computed tomography (CT) scan. b) A 20-year old woman showing nodules with adjacent ground-glass infiltrates. c) A chest CT scan of a 6-year old boy with cytotoxic T-lymphocyte-associated protein 4 deficiency. Multiple round infiltrates resembling “reversed halo” (or “atoll”) signs are evidence of GLILD. d) The same patient as in c) but 6 months after allogenic haematopoietic stem cell transplantation. Marked regression of GLILD is shown with mild residual, streaky interstitial consolidations. Scale bars: a, c, d) 15 mm; b) 20 mm.

FIGURE 3

Pulmonary granulomas in a 4-year old boy with chronic granulomatous disease. A subpleural granuloma with a surrounding fuzzy rim is indicated (arrow). Scale bar: 10 mm.

FIGURE 4

Proposed algorithm to differentiate between early onset sarcoidosis and Blau syndrome. HRCT: high-resolution computed tomography; BAL: bronchoalveolar lavage; NOD2: nucleotide-binding oligomerisation domain-containing protein 2. Data from [103].