Discussion

DPLD due to ABCA3 deficiency is rare and of poor prognosis. The largest study reporting seven cases with homozygous or compound heterozygous ABCA3 mutations highlighted the severity of the respiratory disease.3 Although in the present case we cannot exclude some spontaneous improvement of the patient condition, the impressive rapidity of the beneficial response to AZM observed after several years of sustained management with steroids provides some evidence of macrolide therapy efficacy in this pathological situation. This is further supported by a recent publication documenting benefit of AZM associated with hydroxychloroquine in a young patient with a severe respiratory insufficiency due to ABCA3 deficiency.4

The effectiveness of macrolides in the treatment of various forms of chronic lung diseases has been discussed in several reports.2 ,5 ,6 In addition to their antibacterial effect, there is growing evidence that these molecules also exert beneficial effects through anti-inflammatory actions. Several experimental and clinical reports have documented an anti-inflammatory action associated with a decreased synthesis of proinflammatory molecules such as interleukin (IL)-8 in a number of pathological conditions including surfactant deficiency. Recent studies also suggest that macrolides could interfere with cellular processes associated with lung epithelial function and alveolar parenchymal repair.7

In the present case of DPLD linked to ABCA3 mutations, the documented long-term efficacy of AZM is more likely to be due to its anti-inflammatory action rather than its antimicrobial property. Several molecular mechanisms can be discussed. ABCA3 plays an important role in alveolar epithelium homeostasis as a transporter of phospholipids, a step required for a proper surfactant assembly and secretion. In situation of abnormal ABCA3 proteins, AZM may exert its beneficial effect by targeting the altered surfactant metabolism. Indeed, the abnormal lamellar structures documented in the patient lung tissue biopsy are evocative of intracellular phospholipids accumulation, with, as a consequence, an increased AEC stress and injury. Through its capacity to modulate phospholipidosis, AZM may improve alveolar lipid metabolism and surfactant trafficking, contributing to stimulate the defence process against cellular stress.8 Anti-inflammatory actions of AZM may also be proposed, such as downregulation of IL-8 whose exaggerated production has been observed in cells harbouring ABCA3 mutations.3 Other possible explanations include epigenetic modulation, as epigenetic alterations can contribute to various forms of chronic inflammatory lung disorders including DPLD.9 Among the molecular targets is histone deacetylase (HDAC) 2, with a decrease in its level and activity documented in situations of lung parenchymal injury similar to those observed in surfactant disorders. Of interest, recent studies have documented a role of macrolides on restoring HDAC2 activity, thus providing the potential to regenerate lung tissue.10

The present observation is the first documenting a rapid, impressive and sustained clinical improvement of low-dose AZM in a young patient with DPLD associated with ABCA3 mutations. Of importance, the careful monitoring during the follow-up did not document any complications or side effects. This report is of tremendous interest for the lung paediatric community considering the limited efficacy of systemic steroids in the majority of young patients with DPLD. Clinical studies gathering patients with DPLD associated with various forms of surfactant deficiency have been started, under the coordination of the National Reference Center for rare lung diseases in France (Respirare, http://www.respirare.fr).11 They should provide information on the types of paediatric DPLD that may benefit from AZM. Cellular and molecular studies are also ongoing to progress in the understanding of the mechanisms involved.