Treatment
Treatment strategies in SPDS are varied and not standardized given its heterogeneity and rarity. Two major clinical practice guidelines exist based on the consensus of clinicians. The first is the European treatment guideline that was developed though a Delphi consensus process and provides a consensus between clinicians from Europe and Australasia for children up to the age of 16[70, 79]. The second guideline was developed by the American Thoracic society for children under the age of two years[71]. Treatment of SPDS is often through immunosuppression as an attempt to reduce pulmonary fibrosis[12] and the need for lung transplant in severe cases[80].
Through the Delphi consensus process, the use of corticosteroids whether enterally or parenterally with subsequent consideration of other adjunct add-on therapies for example hydroxychloroquine and azithromycin was recommended. [79]The rationale of using pulse methylprednisolone stems from the postulate that glucocorticoids increase the expression of ABCA3 in vitro . Nevertheless, there is limited evidence of any benefits in the use of glucocorticoid in clinical practice. The decision to trial glucocorticoids should then be made on an individual basis and more importantly these patients should be monitored for the notorious side effects of steroids. Surveillance with long term steroid use should include serial ophthalmological review for cataracts, bone mineral density scanning and growth monitoring. The next option is hydroxychloroquine which also requires close monitoring in terms of retinal toxicity, bone marrow suppression and cataract formation[81, 82]. Retinal toxicity is a serious side effect that is relates to the total accumulated dose. The risk of developing retinal toxicity is ~40% following use for 20 years[83, 84]. At present, there is an international, prospective, randomized controlled phase 2a trial ongoing to evaluate the efficacy, risks and benefits of hydroxychloroquine in children with chILD[85]. Azithromycin has also been used in to provide immunomodulation in SFTPC and ABCA3 deficiencies[86].
Studies into amino acid sequence of surfactant protein has enabled studies into the production of recombinant surfactant. Synthetic surfactants have been modelled from the structures of SP-B and SP-C for example KL4, an amphipathic peptide which is modelled after SP-B was approved for the use of respiratory distress syndrome in the USA by Food and Drug Administration[87]. Similarly, SP-B and SP-C like peptides has managed to improve lung function in animal models[88]. The clinical application in surfactant protein deficiency is yet to be clearly explored.
Supportive therapy is essential towards the management of SPDS. The use of supplemental oxygen should be evaluated in these children and in more severe cases of SPDS non-invasive ventilation may also have a role. Therefore, continuous saturation monitoring or performing overnight oximetry and capnography is important to elucidate requirement.
Nutrition also likely plays an important role in the prognosis of SPDS and is taken in the assumption that nutritional rehabilitation helps in children with cystic fibrosis and bronchiectasis. Increased work of breathing leading to increased calorie expenditure is fairly common in these chronic conditions and long-term nutritional support may be necessary[89].
Vaccination plays an important role in the supportive care of these children with suggestions of annual flu vaccination. In view of the severe RSV bronchiolitis that occurs in patients with SPDS, in infants with severe SPDS it has been recommended for the use of palivizumab. Additionally, prophylaxis for Pneumocystis jeroveci should be given to children on immunosuppressants.
Although the psychological aspects of the management of SPDS in both patients and families is limited and often underappreciated in view of its rarity[90], evidence from families affected by other chronic lung diseases e.g. cystic fibrosis and bronchiectasis may benefits from psychological support both before and after diagnosis is made. In cases of more severe SPDS, the involvement of the palliative care service where available and socially accepted is also an important aspect in managing the psychosocial aspects of this disease.
Timing of lung transplant in SPDS is dependent on the age of the child, for infants they are most commonly transplanted for SP-B or ABCA3 deficiency while children were more commonly transplanted for SP-C or ABCA3 deficiency[91]. For infants, they were more likely to be mechanically ventilated at time of transplant and were less likely to develop bronchiolitis obliterans post- transplant, which is a feared complication particularly in children beyond 1 year from transplant[91]. Regardless of this however, studies have shown that there is no significant difference in the mortality rate of transplant either occurring in infancy or during childhood[92]. The 5 year survival rates are approximately 50% in patients undergoing lung transplant[93]. Although transplant permits for short term survival in an otherwise lethal disease, there is significant burden of care of these children post lung transplant which includes regular clinic reviews, admission, repeated blood test, bronchoscopies and CT scan in addition to medications that has significant side effect profiles[91]. The significant challenges and impact on families in this aspect must be properly evaluated. Discussion with families and allowing them to have a say in this decision is imperative and a review on decisions to transplant these children has shown that up to 50% of families have actually refused lung transplant[94].
Given the rarity of SPDS and the heterogeneity of this condition, it is important that the management is approached in a multidisciplinary perspective. This multidisciplinary team should include paediatric pulmonologists, cardiologist, geneticist, pathologists, genetics counsellor and other members of the allied health team[86]. Multiple such platforms exists worldwide; for example chILD-EU[79], chILD research network (chILDRN)[95] and chILD Research Australia and New Zealand (chILDRANZ)[96] and chILD network[97] to facilitate discussions, provide support for diagnosis and management of these conditions.