Vertex Pharmaceuticals.

BackgroundIdiopathic pulmonary hemosiderosis (IPH) is a rare cause of alveolar hemorrhage in children and its pathophysiology remains obscure. Classically, diagnosis is based on a triad including hemoptysis, diffuse parenchymal infiltrates on chest X-rays, and iron-deficiency anemia. We present the French pediatric cohort of IPH collected through the French Reference Center for Rare Lung Diseases (RespiRare®, http://www.respirare.fr).MethodsSince 2008, a national network/web-linked RespiRare® database has been set up in 12 French pediatric respiratory centres. It is structured as a medical recording tool with extended disease-specific datasets containing clinical information relevant to all forms of rare lung diseases including IPH.ResultsWe identified 25 reported cases of IPH in children from the database (20 females and 5 males). Among them, 5 presented with Down syndrome. Upon diagnosis, median age was 4.3 [0.8-14.0] yrs, and the main manifestations were: dyspnea (n = 17, 68%), anemia (n = 16, 64%), cough (n = 12, 48%), febrile pneumonia (n = 11, 44%) and hemoptysis (n = 11, 44%). Half of the patients demonstrated diffuse parenchymal infiltrates on chest imaging, and diagnosis was ascertained either by broncho-alveolar lavage indicating the presence of hemosiderin-laden macrophages (19/25 cases), or lung biopsy (6/25). In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%). All the patients were initially treated by corticosteroids. In 13 cases, immunosuppressants were introduced due to corticoresistance and/or major side effects. Median length of follow-up was 5.5 yrs, with a satisfactory respiratory outcome in 23/25 patients. One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage.ConclusionThe present cohort provides substantial information on clinical expression and outcomes of pediatric IPH. Analysis of potential contributors supports a role of auto-immunity in disease development and highlights the importance of genetic factors.

Capsule summary 55This article demonstrates that JAK inhibition represents a highly promising and well-tolerated 56 therapy for STING-associated vasculopathy, and which may also be relevant to the treatment 57 of other type I interferonopathies. 58 59Key words: Stimulator of Interferon genes, TMEM173, Janus kinase 1/2 inhibitor, type I 60 interferonopathy, interstitial lung disease, vasculopathy. 61 To the Editor: 62Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) 63 underlie a novel type I interferonopathy, 1 termed SAVI (STING-associated vasculopathy with 64 onset in infancy). 2,3 This disease is associated with high childhood morbidity and mortality. 65 STING is a central component of DNA sensing that leads to the induction of type I 66 interferons (IFN), which in turn drives the expression of IFN-stimulated genes (ISGs) through 67 the engagement of a common receptor and subsequent activation of Janus kinase 1 (JAK1) 68 and tyrosine kinase 2 (TYK2). 69We describe, for the first time, the use and efficacy of ruxolitinib, a selective oral JAK1/2 70 inhibitor, in three children with TMEM173-activating mutations over 6 to 18 months of 71 follow-up. The patients, aged between 5 and 12 years, exhibited the phenotypic variability 72 associated with TMEM173-activating mutations, 2,3,4 with lung disease and systemic 73 inflammation being the major features in P1 and P3, whilst in P2 skin involvement was most 74 prominent (Fig 1 and see Supplemental Text, Fig E3, and Table E1 in the Online Repository). 75There was minimal response to a broad spectrum of immunosuppressive therapies including 76 steroids, methotrexate and anti-CD20 monoclonal antibodies. 77 78An increased expression of ISGs, a so-called type I IFN signature, 5 was observed in all three 79 patients (see Fig E1, A in the Online Repository). Increased levels of STAT1 phosphorylation 80 were recorded in patient T lymphocytes (P1, P2, P3), T cultured lymphoblasts (P1) and 81 primary fibroblasts (P3) compared to controls (see Fig E2, A in the Online Repository). Liu et 82 al. demonstrated that, in vitro, three JAK1 inhibitors (ruxolitinib, tofacitinib and baricitinib) 83 were able to block the constitutive phosphorylation of STAT1 in lymphocytes from 84 TMEM173-mutated patients, 2 and we saw that exposure to ruxolitinib inhibited the 85 constitutive phosphorylation of STAT1 and decreased the expression of IL-6 and 3 ISGs 86 tested in T lymphoblasts from P1 (see Fig E2, B, C in the Online Repository). Considering the 87 severity of the phenotype and the poor response to conventional immunosuppressive 88 therapies, we hypothesized that JAK1 inhibition would block IFN signaling in the context of 89 activating mutations in TMEM173. 90 91We observed a marked positive effect on all aspects of the phenotype in all three treated 92 children. There was a general improvement in patient-reported well-being, a reduction of 93 febrile episodes, an almost complete resolution of the associated cutaneous lesions and a 94 major impr...

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

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We report three cases of pulmonary disease suggesting fibrosis in two familial and one sporadic case. Pulmonary symptoms were associated with various clinical features of systemic inflammation and vasculitis involving the skin, and appeared at different ages. A strong interferon signature was found in all three cases. Disease was not responsive to corticosteroids, and lung transplantation was considered for all three subjects at an early age. One of them underwent double-lung transplantation, but she immediately experienced a primary graft dysfunction and died soon after. Recognized causes of familial interstitial lung disease were all excluded. All three subjects had a mutation in the previously described autoinflammatory disease called SAVI (stimulator of interferon genes [STING]-associated vasculopathy with onset in infancy). These cases emphasize the need to consider this possibility in children and young adults with lung fibrosis after common causes have been ruled out.

Initial diagnosis is based on clinical presentation, radiological features and BALF analysis, but the definitive diagnosis requires genetic analysis. Although progressive improvement was seen in most patients, the development of new therapeutic strategies with minimal side effects is needed.

Although spirometric results indicate normal lung function, the mean VDI in patients (5.1) found in this study is well above the VDI in healthy subjects (1.6) reported in the literature. A single CPT session induces disparate changes in the distribution and extent of ventilation defects.