TABLE 1.

Immunodeficiencies and autoinflammatory disorders associated with pulmonary granulomatosis

Condition	Exemplary clinical features	Exemplary laboratory features	Radiologic presentation	Histology
CVID	Recurrent bronchopulmonary Infections Lymphoproliferation	Hypogammaglobulinaemia	GLILD Small and large nodules Round infiltrates (“reversed halo” or “atoll” signs) GGOs (mainly in the lower lobes) Lymphadenopathy	Interstitial pneumonitis Follicular bronchiolitis Non-caseating granulomas Lymphoid infiltration
LRBA/CTLA-4 deficiency	Autoimmunopathies (lymphoproliferation, enteropathy, cytopenias)  Respiratory infections  CNS involvement	Hypogammaglobulinaemia Cytopenias Functional T-cell defects	See CVID	See CVID
CGD	Recurrent infections Skin and organ abscesses	Reduced “respiratory burst”	Infiltrates Abscesses Pneumatoceles Bronchiectasis obliterative bronchiolitis Chronic fibrosis	Changes associated with inflammatory infiltrates, abscesses and fibrosis Non-caseating granulomas
STAT3 loss of function (AD HIES)	Dermatitis, skin abscesses Tooth retention Coarse facial features Bronchopulmonary infections	↑ IgE (>2.000 units·mL−1) ↓ Th17 cells ↓ Memory B cells ↓ Production of inflammatory cytokines (IL-17/IL-22)	Abscesses Pneumatoceles Chronic pneumothorax Granulomas	Changes associated with inflammatory infiltrates, abscesses and fibrosis Non-caseating granulomas
STAT3 gain of function	Autoimmunopathies (cytopenias, lymphoproliferation, enteropathy, diabetes)	Cytopenias Hyperglycaemia Impaired T-cell signalling	Lymphocytic interstitial pneumonitis  Granulomas  Pulmonary fibrosis  Cryptogenic organising pneumonia	Lymphocytic interstitial pneumonia  Non-necrotising granulomas  Fibrosis
MSMD	Mycobacterial infections Infection by intracellular pathogens Chronic mucocutaneous candidiasis	Reduced IFN-γ production	Focal infiltration of upper lobes, middle lobes, or lingula Pulmonary granulomas as in mycobacterial infection Cavernas Lymphadenopathy	Necrotising granulomas in Mycobacterium tuberculosis  Varying histology in non-M. tuberculosis mycobacteria (necrotising and non-necrotising)  Random or bronchocentric location of granulomas
Blau syndrome/early onset sarcoidosis	Classical triad (granulomatous polyarthritis, dermatitis, uveitis)  50% fever, lymphadenopathy, vasculitis	↑ Inflammatory cytokines ↑ ACE, sCD25, neopterin BAL (lymphocytosis, CD4:CD8 ratio >3.5:1)	GGOs Micronodules Granulomas	Non-necrotising granulomas
NOD2-associated autoinflammatory disease	Recurrent fever Weight loss Non-erosive arthritis Granulomatous dermatitis Granulomatous colitis	Anaemia Leukocytosis Elevated inflammatory cytokines	GGOs Micronodules Granulomas	Non-necrotising granulomas
Chronic beryllium disease	Dry cough Shortness of breath Malaise Fatigue	Positive beryllium lymphocyte proliferation test	Nodules GGOs, thickened septal lines Bronchial wall thickening Lymphadenopathy	Non-necrotising granulomas Mononuclear cell infiltrates
SAVI	Constant fever in infancy Vasculitis Lymphadenopathy Cutaneous manifestations	Constantly ↑ acute phase/inflammation parameters	Nodules Cavities Fixed infiltrates	Mixed lymphocytic infiltrate   Interstitial fibrosis   Emphysema
Granulomatosis with polyangiitis	Rhinitis, otitis Cough Stridor Obstruction Dyspnoea	↑ Cytoplasmic ANCAs	Nodules/granulomas Cavities Pleural effusions Lymphadenopathy	Necrotising granulomas Necrotising vasculitis
Eosinophilic granulomatosis with polyangiitis	Asthma Vasculitis Cutaneous, intestinal, cardial granulomas	↑ Perinuclear ANCAs Eosinophilia	Nodules/granulomas GGOs Bronchial wall thickening Consolidations	Necrotising granulomatous inflammation   Eosinophilic infiltration
Hypersensitivity pneumonitis	Acute onset (fever, cough, tachydyspnea) Subacute/chronic (productive cough, fatigue, malaise, chronic cyanosis)	↑ Specific IgGs against organic compounds	Centrilobular GGOs Nodular opacities air-trapping Mosaic attenuation Septal thickening Bronchiectasis Honeycombing	Poorly-formed non-caseating granulomas Bronchiolitis with lymphocytic infiltration Fibrotic nonspecific interstitial inflammation Lymphocytic infiltrates Poorly-formed granulomas

CVID: common variable immunodeficiency; GLILD: granulomatous-lymphocytic interstitial lung disease; GGO: ground-glass opacity; LRBA: lipopolysaccharide-responsive beige-like anchor protein; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; CNS: central nervous system; CGD: chronic granulomatous disease; STAT-3: signal transducer and activator of transcription 3; Ig: immunoglobulin; AD: autosomal-dominant; HIES: hyper IgE syndrome; IL: interleukin; MSMD: Mendelian-susceptibility to mycobacterial disease; IFN: interferon; ACE: angiotensin-converting enzyme; BAL: bronchoalveolar lavage; NOD2: nucleotide-binding oligomerisation domain-containing protein 2; STING: stimulator of interferon genes; SAVI: STING-associated vasculopathy with onset in infancy; ANCA: anti-neutrophil cytoplasmic antibody.