Table 4 Pulmonary disease and treatment experience

Watkin LB. et al., 2015 [3]

21/21 (100%). Various combinations of follicular bronchiolitis, pulmonary hemorrhage, and interstitial lung disease.

Interstitial lymphocyte infiltration with the germinal center formation in lung interstitium and peripheral airway walls. CD20+ B cells within the germinal centers in the lung biopsy specimen on Immunohistochemical staining. Significantly increased CD4+ T cells in the interstitial lung tissue.

Symptomatic partial response to immunosuppression 21 (100).

4/14 (29%) patients had a lung transplant.

3/4 (75%) were in third and fourth decades

1/4 (25%) was in second decade of life.

It is not possible to predict who will need lung transplant with the current level of understanding of the disease.

Lung disease is likely to progress over time despite chronic immunosuppression.

Jensson BO.et al. 2017 [4]

3/3 (100%).

3 (100) presented with a chronic cough, breathlessness and worsening exercise tolerance. No hemoptysis. Diagnosed with chronic follicular bronchiolitis with interstitial lung disease.

Two had progressive restrictive, and one had obstructive lung disease on spirometry test. 1 (33) had recurrent pulmonary hemorrhages on histology.

All had initial low and worsening diffusing capacity for carbon monoxide (DLCO). 2/3 (66) needed a bilateral lung transplant.

open lung biopsy 2/3 (67%).

Hyperplastic lymphoid follicles infiltrating the small airway walls and interstitium with hyperplastic germinal centers. Interstitial lymphoid infiltrate and fibrosis and distal acinar emphysema and cyst formation.

1/3 (33%) had a diffuse intra-alveolar hemorrhage.

Pulse and oral steroids and immunosuppressants.1/3 (33%) were also treated with Bronchodilators. Lung diseases showed a partial response to immunosuppression. (look for supplemental files for immunosuppressants)

2/3 (67%). The index case at 44 years and her son at 28 years, received bilateral lung transplants.

Brennan MA. et al. 2017 [8]

At age 6 years started with a chronic cough, shortness of breath. Diagnosed with progressive restrictive lung disease, ILD and finger clubbing.

Open lung biopsy revealed a mixed picture of inflammation and aspiration.

Pulse and oral steroids, Monthly-six doses of Cyclophosphamide, MTX, Rituximab. Currently on combination therapy: mycophenolate + mofetil+ hydroxychloroquine, prednisolone.

Comorbidities: GERD, Cystic Fibrosis, SLE. Developed MAS.

Partial response to immunosuppression.

0/1 (100%).

The patient is in her teens at the time of publication.

Volpi S. et.al. 2018 [7]

A chronic cough, breathlessness and worsening exercise tolerance. Progressive interstitial lung disease. No pulmonary hemorrhages.

Radiographic

pattern: prominent interstitial

involvement and the presence of the air-filled cysts. Restrictive lung disease.

No lung biopsy but BAL showed Lymphocytic Alveolitis.

Pulse and oral steroids. Poor or no response to Methotrexate and Abatacept. Currently on Mycophenolate Mofetil + Hydroxychloroquine and low dose oral steroids.

Partial response to immunosuppression.

0/1 (100%)

Tsui JL. et al. 2018 [2]

14/14 (100%).

12/14 subjects had spirometry that met ATS criteria. 2/12 (17%) had a mixed obstructive/restrictive,8/12 (67%) had restrictive, 1/12 (8%) had normal spirometry, and 1/12 (8%) had an obstructive lung disease. Initial DLCO was not available for 4/12 patients and was abnormal in 8/8 (100%). 9/10 (90%) patients showed worsening in % predicted FEV1 and FVC over time. Improvement in radiology results did not correlate with spirometry results which worsened with time. CT findings included thin-walled scattered parenchymal cysts, multiple centrilobular nodules, ground-glass opacities, and fibrosis.

10/14 had a lung biopsy. 2/10 had transbronchial, and 8/10 had open lung biopsies.

Follicular bronchiolitis, diffuse alveolar hemorrhage, capillaritis, increased interstitial and alveolar neutrophils. Bronchiolocentric airspace enlargement/cystic change, increased hemosiderin-filled intra-alveolar macrophages. Lymphoid Hyperplasia.

Partial response to immunosuppression. Most patients with diffuse alveolar hemorrhage (DAH) responded to pulse methylprednisolone and monthly-six doses of cyclophosphamide, but few subsequently needed rituximab. Methotrexate, AZA, Etanercept. Most patients are doing better on low dose prednisone+ MMF+ hydroxychloroquine. 2/14 (14%) needed a bilateral lung transplant.

4/14 (29%).

No specific features but the varied presentation and clinical features

Patward A. et.al.

2/2 (100%)

A chronic cough, breathlessness, worsening exercise tolerance, and clubbing, intermittent cyanosis and desaturations. Recurrent pulmonary hemorrhages without hemoptysis. CT Chest: ground glass appearance and interstitial disease. Spirometry: Obstructive lung disease in IC and mixed Obstructive and restrictive lung disease in C2.

Progressively worsening DLCO in C2. DLCO could not be done on Index case.

2/2 (100%) had an open lung biopsy. Histopathology showed pulmonary capillaritis, hemosiderosis with hemosiderin-laden macrophages, extravasation of red blood cells, interstitial inflammation, pulmonary diffuse lymphoid hyperplasia, lymphocytic bronchiolitis, widening of alveolar ducts and distension of air spaces at the periphery, peripheral airways cyst formation. The immunofluorescence staining in case C2 was negative. IC did not have immunofluorescence staining of the biopsy tissue.

Partial response to immunosuppression. Index case: did not respond to Methotrexate, AZA. Good response to pulse steroids followed by low dose oral steroids+ MMF. He had an inadequate response to bronchodilators.

No pulmonary hemorrhages and PICU admission in past one year.

Father of the index case was treated with pulse steroids or oral high and low dose steroids till 18 years of age. He had an inadequate response to bronchodilators. He is on adalimumab 40 mg and … … … for arthritis.

0/2 (100)