Figures
- FIGURE 1
Serial imaging while on immunosuppressive therapy (two subjects). Axial computed tomography images from subject 5 demonstrate radiographic stability (a) baseline and b) 6 years later) in contrast to subject 4, who developed more cysts and ground-glass opacities over time (c) baseline and d) 14 years later). Yellow arrows indicate cysts and blue arrows indicate ground-glass opacity.
- FIGURE 2
Lung histopathology from two subjects demonstrating either capillaritis or prior alveolar haemorrhage. Subject 2: a) low-power view shows diffuse alveolar haemorrhage with filling of alveolar spaces by red blood cells. Focal lymphoid hyperplasia is present. Scale bar=500 µm. b) High-power view shows alveolar haemorrhage and prominent septal neutrophils (arrows) consistent with alveolar capillaritis. Scale bar=100 µm. Subject 4: c) low-power view shows bronchiolocentric airspace enlargement/cystic change, prominent lymphoid hyperplasia and increased haemosiderin-filled intra-alveolar macrophages. Scale bar=1 mm. d) High-power view shows lymphoid hyperplasia and haemosiderin-filled macrophages, indicative of prior alveolar haemorrhage. Scale bar=200 µm.
- FIGURE 3
Impact of immunosuppressive therapy on pulmonary function, recurrence of diffuse alveolar haemorrhage (DAH) and chest computed tomography (CT) findings over time (four subjects). a) Subject 5 demonstrated decline in pulmonary function as indicated by % predicted forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) but had radiographic stability while on treatment, while in contrast, her sibling, b) subject 4, struggled with medication noncompliance and developed multiple episodes of DAH as well as radiographic decline based on serial CT scans. Both c) subject 6 and d) subject 11 experienced physiological decline but radiographic stability and/or improvement with immunosuppression. Time axis is years from initial study. Vertical arrows within the plots indicate episodes of DAH; numbers in boxes indicate the episode number. Major chest CT scan findings and treatment regimen are indicated below. Dotted line represents 80% predicted FEV1, FVC and DLCO, which are the cut-offs for normal.
Tables
- TABLE 1
Subject characteristics
Characteristics Patients Subjects 14 Sex Male 3 (21%) Female 11 (79%) Age at presentation years <1 1 (7%) 2–9 10 (71%) 10–12 3 (21%) Disease manifestations Lung disease Diffuse alveolar haemorrhage 7 (50%) DPLD 14 (100%) Arthritis 14 (100%) Renal disease 3 (21%) DPLD: diffuse parenchymal lung disease.
- TABLE 2
Initial pulmonary function tests (PFTs)
Subject Age years FEV1 % predicted FVC % predicted FEV1/FVC % TLC % predicted PFT pattern DLCO % predicted 1 31 55 61 72 68 Restrictive 37 3 23 35 48 62 56 Mixed 17 4 20 56 58 83 62 Restrictive 45 5 13 57 72 75 67 Restrictive 69 6 5 58 56 95 NA Restrictive NA 7 35 32 43 63 63 Mixed NA 8 7 67 64 98 67 Restrictive NA 10 8 82 76 91 NA Normal NA 11 28 67 69 83 76 Restrictive 68 12 35 69 69 80 69 Restrictive 41 13 15 89 91 79 101 Obstructive 58 14 9 59 61 89 72 Restrictive 48 FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusing capacity of the lung for carbon monoxide; NA: not available.
- TABLE 3
Lung histopathological findings
Features Subjects (n with finding/n tested) Number of biopsies available for review 10 (10/11) Type of biopsy Open lung biopsy 8 (8/10) Transbronchial biopsy 2 (2/10) Follicular bronchiolitis 7 (7/10) Alveolar haemorrhage 4 (4/10) Airspace enlargement/cystic changes 2 (2/10) Acute lung injury with capillaritis 2 (2/10)# Interstitial fibrosis 2 (2/10)¶ Nondiagnostic 1 (1/10) #: both subjects with this finding were related (father and daughter); ¶: both biopsies demonstrated non-usual interstitial pneumonitis.
- TABLE 4
Current immunosuppression maintenance regimens
Type of immunomodulation Subjects# Low-dose corticosteroids 9 (75%) Mycophenolate mofetil 5 (42%) Hydroxychloroquine 4 (33%) Azathioprine 3 (25%) Rituximab 2 (16%) Etanercept 2 (16%) Methotrexate 2 (16%) IVIG 2 (16%) Combination therapies One agents 4 (33%) Two agents 3 (25%) More than two agents 5 (42%) IVIG: intravenous immunoglobulin. #: N=12.
- TABLE 5
When to consider genetic testing for COPA syndrome
Pulmonary features Evidence of follicular bronchiolitis or cysts Diffuse alveolar haemorrhage Extrapulmonary features Early age of onset (<12 years) Family history of disease Positive for ANA or ANCA, ±RF Arthritis Consider targeted sequencing for exons 8–9 of COPA in patients with one pulmonary feature and two extrapulmonary features, and strongly consider sequencing in patients with one pulmonary and three extrapulmonary features. ANA: anti-nuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody; RF: rheumatoid factor.
Supplementary Material
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TABLE S1 Subject characteristics (detailed) 00017-2018_tableS1
