TABLE 2

Case reports/series and clinical trials of humans with a surfactant-processing mutation involved in fibrotic interstitial pneumonia

	Diagnosis	Drug	Outcome after treatment per drug combination	Overall outcome after treatment	[Ref.]
Adult case reports and series
SFTPC p.I73T	Adult with CPFE	Prednisone	No effect	No effect	[55]
SFTPA2 p.G231V	1 adult with hypersensitivity pneumonitis	Prednisone and avoidance of birds	Improvement	1 improvement/1 no effect	[7]
SFTPA2 p.G231V	1 adult with pulmonary fibrosis and bronchoalveolar carcinoma	Prednisone	No effect	1 improvement/1 no effect	[7]
ABCA3 p.G964D	Adult with pulmonary fibrosis	Antibiotics	No effect	Stabilisation	[10]
ABCA3 p.G964D	Adult with pulmonary fibrosis	Prednisone and azithromycin	Stabilisation	Stabilisation	[10]
ABCA3 p.G964D	Adult with restrictive lung disease	Steroids and azithromycin	(Short-term) improvement	Stabilisation	[85]
HPS^#	Adult with HPS	Antibiotics and oxygen inhalation	No effect	No effect	[92]
HPS1 IVS5+5 G>A	Adult with HPS	Prednisolone, cyclosporine A	No effect		[91]
HPS1 IVS5+5 G>A	Adult with HPS	+ pirfenidone	Short-term stabilisation	Short-term stabilisation	[91]
HPS4 p.Q620X	Adult with HPS	Corticosteroids, pirfenidone	Stabilisation	Stabilisation	[90]
HPS1 p.L668P	Adult with HPS	Prednisolone, pirfenidone, azathioprine	No effect	No effect	[93]
HPS^#	Adult with HPS	Oral corticosteroids	No effect	No effect	[94]
HPS4 p.685delC	Adult with HPS	High-dose steroids and azathioprine	No effect	No effect	[95]
HPS^#	Adult with HPS and pulmonary sarcoidosis	Prednisone	Improvement	Improvement	[89]
HPS^#	Adult with HPS	Prednisolone and pirfenidone	No effect	No effect	[96]
*Paediatric case reports/series with SFTPC* mutations**
SFTPC p.I73T p.I38F, p.V39L	4 children with DIP, 1 child with chronic interstitial pneumonitis (p.V39L)	1/5 systemic steroids	No effect	2 short-term improvement/3 improvement	[36]
SFTPC p.I73T p.I38F, p.V39L		5/5 hydroxychloroquine	2 short-term improvement, 3 improvement	2 short-term improvement/3 improvement	[36]
SFTPC p.A116D	Child with NSIP	Hydroxychloroquine and supplemental oxygen	Improvement	Improvement	[37]
SFTPC p.I73T	Child with ILD	Corticosteroids and supplemental oxygen	Improvement	Improvement	[55]
SFTPC c.460+1 G → A	Child with cellular or NSIP	Corticosteroids and supplemental oxygen	Improvement	Improvement	[5]
SFTPC p.I73T	5 children with chronic ILD	5/5 methylprednisolone, 4/5 hydroxychloroquine, 5/5 supplemental oxygen	5 improvement	5 improvement	[38]
Different SFTPC BRICHOS/non-BRICHOS	17 children with ILD (NSIP, PAP or DIP)	14/17 hydroxychloroquine	12/14 improvement 2/14 no effect	7 improvement/7 stabilisation/3 no effect	[39]
		15/17 systemic steroids	14/15 improvement 1/15 no effect
		7/17 surfactant	2/7 improvement, 5/7 no effect
		3/17 colchicine	3 no effect
SFTPC 14 non-BRICHOS, 6 BRICHOS	22 children with chronic ILD at diagnosis	18/22 methylprednisolone, 11/22 hydroxychloroquine, 5/22 azithromycin, 20/22 supplemental oxygen	6/22 no effect, 16/22 improvement	16 improvement/6 no effect	[40]
SFTPC p.G97S	Child with CPI pattern with globular alveolar proteinosis	Home ventilator support, oxygen_, pulse methylprednisolone, azithromycin, hydroxychloroquine	Improvement	Improvement	[41]
SFTPC p.I73T, p.I38F	2 children with CPI	Hydroxychloroquine, prednisone, ranitidine, TMP-SMX; 2 months after therapy began, pulse therapy of methylprednisolone; later, hydroxychloroquine alone	2 improvement	2 improvement	[42]
SFTPC p.I73T	Child with CPI, pneumatoceles after biopsy	Methylprednisolone, hydroxychloroquine, azithromycin	Improvement	Improvement	[43]
SFTPC p.I73T	Child with ILD	Hydroxychloroquine, oxygen supplementation	Improvement	1 improvement/1 stabilisation/1 no effect	[44]
	Child with ARDS/DIP	Supplemental oxygen and steroids	No effect
		Steroids pulse therapy	Short-term improvement
		Hydroxychloroquine	Improvement
		Hydroxychloroquine replaced by azithromycin	Stabilisation
	Child with DIP	Hydroxychloroquine and steroids	No effect
SFTPC p.I73T	Child with chILD	Bronchodilators, inhaled corticosteroids and antileukotrienes, azathioprine, hydroxychloroquine and i.v. immunoglobulins, exogenous surfactant	No effect	No effect	[52]
SFTPC p.I73T	Child with PAP and NSIP	Supplemental oxygen, whole-lung lavages, systemic corticosteroids and azathioprine	Short-term improvement	Short-term improvement	[45]
SFTPC p.I73T	Child with PAP and NSIP	Additional corticosteroid pulse therapy plus azathioprine	No effect	Short-term improvement	[45]
SFTPC Δexon 4	Child with respiratory distress	Oral and i.v. corticosteroids, hydroxychloroquine, supplemental oxygen	Improvement	Improvement	[51]
SFTPC p.E66K, p.I73T, p.V102M, p.A155P	8 children with idiopathic diffuse lung diseases	2 children supplemental oxygen, pulse steroids and hydroxychloroquine	2 limited effect	2 limited effect/6 stabilisation	[46]
		Supplemental oxygen, pulse steroids, hydroxychloroquine	Stabilisation
		Supplemental oxygen, hydroxychloroquine	Stabilisation
		Supplemental oxygen, steroids, hydroxychloroquine, azithromycin	Stabilisation
		Supplemental oxygen, pulse steroids, hydroxychloroquine	Stabilisation
		Supplemental oxygen, pulse steroids, bronchodilators, antibiotics	Stabilisation
		Steroids, supplemental oxygen	Stabilisation
SFTPC p.L188Q	2 children with respiratory distress (NSIP-like pattern)	Methylprednisolone and hydroxychloroquine	2 no effect	2 no effect	[53]
SFTPC^#	Child with CPI	Corticosteroids, hydroxychloroquine and continuous oxygen	Short-term improvement	Short-term improvement	[47]
SFTPC p.I73T	Child with NSIP/PAP	Supplemental oxygen, antibiotics and oral corticosteroids	No effect	No effect	[54]
SFTPC p.I73T	Child with PAP/ILD	Whole-lung lavages, systemic corticosteroids and azathioprine	Improvement	Improvement	[48]
SFTPC p.G182R, p.L188Q, p.C189W	1 child with PAP/NSIP	Clearance, steroids, hydroxychloroquine, mechanical ventilation	Improvement	3 improvement	[49]
	1 child with respiratory failure	Clearance, steroids, azathioprine, mechanical ventilation	Improvement
	1 child with respiratory failure	Steroids, azithromycin, hydroxychloroquine, mechanical ventilation	Improvement
SFTPC p.L81V	Child with surfactant protein C deficiency	Hydroxychloroquine, oxygen therapy	Improvement	Improvement	[87]
SFTPC^#	Child with NSIP	Systemic steroids, azathioprine, hydroxychloroquine	Improvement	Improvement	[88]
Different SFTPC mutations	15 children with interstitial chronic lung disease	All methylprednisolone 5/15 azithromycin 8/15 hydroxychloroquine	11 no effect/4 improvement	11 no effect/4 improvement	[50]
*Paediatric case reports/series with ABCA3* mutations**
ABCA3^#/SFTPC	Child with DPLD/surfactant dysfunction	Surfactant	Improvement	2 short-term improvement/1 no effect	[88]
ABCA3^#/SFTPC	Child with DPLD/surfactant dysfunction	Systemic steroids	No effect
ABCA3^#	Child with CPI	Systemic steroids, surfactant	Improvement
	Child with CPI	Chloroquine	No effect
	Child with DIP	Systemic steroids, hydroxychloroquine	No effect
ABCA3 c.358_359del	Child with ABCA3 deficiency	Methylprednisolone, oxygen therapy	Limited effect	Limited effect	[87]
ABCA3 p.W1148X and p.T1114A	Child with PAP-like features	Methylprednisolone, antibiotics, antivirals and antifungals, oxygen, mechanical ventilation	No effect	Improvement	[76]
		BAL with bovine surfactant	Improvement
		Hydroxychloroquine	Improvement
ABCA3 p.G964D	Child with (possible) IPF	Prednisone and macrolides	Improvement	Improvement	[10]
ABCA3 p.A307V	Child with respiratory distress	Dexamethasone and surfactant, CPAP	Short-term improvement	Improvement	[75]
ABCA3 p.A307V	Child with respiratory distress	Methylprednisolone, azithromycin, hydroxychloroquine	Improvement	Improvement	[75]
ABCA3 p.Y1515X	Child with RDS	Pulse steroids, antibiotics	No effect	No effect	[77]
ABCA3 p.R194G and V1615GfsX15	2 children with IRDS	CPAP, corticosteroids and hydroxychloroquine	2 limited effect	2 limited effect	[78]
ABCA3 p.D253H	Child with DPLD	Methylprednisolone, oral prednisone, oxygen therapy	No effect	Improvement	[74]
ABCA3 p.D253H	Child with DPLD	Azithromycin	Improvement	Improvement	[74]
ABCA3 p.R280C and p.E690G	Child with DIP	Oxygen supplementation, surfactant therapy, corticosteroids	No effect	Improvement	[73]
ABCA3 p.R280C and p.E690G	Child with DIP	Hydroxychloroquine	Improvement	Improvement	[73]
ABCA3 p.D507del CA Ter 508, p.D696N	Child with DIP	Dexamethasone, supplemental oxygen, surfactant therapy	Short-term improvement	Improvement	[72]
ABCA3 p.D507del CA Ter 508, p.D696N	Child with DIP	Methylprednisolone, azithromycin, hydroxychloroquine	Improvement	Improvement	[72]
ABCA3 p.K914R, p.L1238_E1239insGG	Child with ILD	Methylprednisolone, antibiotics	Limited effect	Improvement	[71]
ABCA3 p.K914R, p.L1238_E1239insGG	Child with ILD	+ hydroxychloroquine	Improvement	Improvement	[71]
ABCA3 c.59G>T and c.2646_2647insC	Child with severe RDS	Home ventilator, methylprednisolone, hydroxychloroquine, azithromycin	Improvement	Improvement	[70]
ABCA3 p.H778R, p.L1252P	Child with DIP-like pattern	Methylprednisolone, prednisone and hydroxychloroquine, clarithromycin	Improvement	Improvement	[69]
Different ABCA3 mutations	9 children with PAP pattern, DIP pattern and NSIP pattern	All corticosteroids, 7/9 hydroxychloroquine	4 no effect, 2 stabilisation, 3 improvement	4 no effect, 2 stabilisation, 3 improvement	[68]
ABCA3, p.L798P, p.R1612P	Child with DIP	Antibiotics, supplemental oxygen, exogenous surfactant, methylprednisolone, hydroxychloroquine	No effect	No effect	[79]
ABCA3 p.R1561Stop	Child with respiratory distress with cyanosis	Antibiotics, surfactant, dexamethasone, inhaled nitric oxide, methylprednisolone, hydroxychloroquine	Short-term improvement	Short-term improvement	[67]
ABCA3 large deletion exon 2–5	Child with IRDS	N-CPAP, surfactant therapy, dexamethasone	No effect	No effect	[80]
ABCA3 ΔF1203 and c.1375ins15	Child with IRDS	Supplemental oxygen and systemic corticosteroids and diuretics	No effect	No effect	[81]
ABCA3 p.R20L and c.4483del25	Child with ILD	Prednisolone and supplemental oxygen	No effect	No effect	[82]
ABCA3 heterozygous p.E292V	Child with cerebropulmonary dysgenetic syndrome	CPAP, mechanical ventilation and antibiotics	No effect	No effect	[84]
ABCA3 p.S1116F	Child with RDS	Supplemental oxygen, mechanical ventilation, exogenous surfactant, antibiotics and inhaled nitric oxide	No effect	No effect	[83]
ABCA3 mutation^#	19 children (14 RDS, 4 RDS/PAP, 1 PAP)	16/19 surfactant	7 no effect, 9 improvement/short-term improvement	29 no effect/3 improvement/3 stabilisation	[85]
		19/19 systemic steroids	14 no effect, 5 improvement/short-term improvement
		9/19 hydroxychloroquine	5 no effect, 4 improvement/short-term improvement
		2/19 azithromycin	2 no effect
Heterozygous ABCA3 mutation^#	16 children (9 with RDS, 4 with RDS/PAP, 1 PAP, 2 chILD)	12/16 surfactant	8 no effect, 4 improvement/short term improvement
		12/16 systemic steroids	8 no effect, 4 improvement/short-term improvement
		8/16 hydroxychloroquine	3 no effect, 5 improvement/short-term improvement
ABCA3 p.M1227R and Ins1510fs/ter1519	Child with DIP	Macrolides, dexamethasone, mechanical ventilation	No effect	Short-term improvement	[66]
ABCA3 p.M1227R and Ins1510fs/ter1519	Child with DIP	Surfactant	Short-term improvement	Short-term improvement	[66]
ABCA3 heterozygous R288K (7 patients) p.R43L, R288K + c.4751delT (1 patient), R288K, P766S (heterozygous, 1 patient), R288K, S693L (heterozygous, 1 patient), R288K, Q215K (1 patient)	11 children with ILD	5/11 prednisolone, surfactant, oxygen or corticosteroids	No effect	5 no effect/6 improvement	[65]
	11 children with ILD	6/11 oxygen, aspirin, surfactant, dexamethasone, montelukast, salbutamol, steroids, hydroxychloroquine, azathioprine, azithromycin or antibiotics	Improvement
*Paediatric case report with AP3B1* mutation**
AP3B1 p.R509X and p.E659X	Child with HPS2	Oxygen, systemic corticosteroids, G-CSF	Stabilisation	Stabilisation	[13]
Clinical trials
HPS1^¶	21 adults with HPS	11 treated with pirfenidone, 10 placebo	Pirfenidone superior to placebo: ΔFVC of 0.46% per month (p=0.587) Restricted group including only patients with initial FVC values >50% pred: difference in pulmonary function ∼0.7% per month (p=0.02)		[97]
HPS1 or 4⁺	35 adults with HPS	23 treated with pirfenidone, 12 placebo	No statistically significant difference in lung function		[98]

ABCA3 mutations were compound heterozygous or homozygous mutations, unless otherwise stated. CPFE: combined pulmonary fibrosis and emphysema; HPS: Hermansky–Pudlak syndrome; DIP: desquamative interstitial pneumonia; NSIP: nonspecific interstitial pneumonia; ILD: interstitial lung disease; PAP: pulmonary alveolar proteinosis; CPI: chronic pneumonitis of infancy; ARDS: acute respiratory distress syndrome; chILD: childhood ILD; DPLD: diffuse parenchymal lung disease; BAL: bronchoalveolar lavage; IPF: interstitial pulmonary fibrosis; (N)-CPAP: (nasal)-continuous positive airway pressure; RDS: respiratory distress syndrome; IRDS: infant respiratory distress syndrome; G-CSF: granulocyte colony-stimulating factor; ΔFVC: change in forced vital capacity. ^#: specific mutation not mentioned in the article, diagnosis based on absence of platelet dense bodies under electron microscopy or genetic testing; ^¶: 20 of these patients were Puerto Ricans homozygous for a 16-bp duplication in exon 15 of the HPS1 gene, which leads to a frameshift. The other patient was a Puerto Rican with a 3904-bp deletion in the HPS3 gene; ⁺: 33 of these patients were Puerto Ricans homozygous for the known 16-bp duplication in exon 15 of the HPS1 gene. Two patients were non-Puerto Rican, and the mutations in these patients are not reported.