hydroxychloroquin (hcq) in child of genetic defect

Conditions: Surfactant Dysfunction

Summary: the purpose of this proposed research is to investigate the efficacy and safety of hydroxychloroquine sulfate (hcq, quensyl) for pediatric ild(child) caused by pulmonary surfactant-associated genes mutations.

children interstitial lung disease (child) is a heterogeneous group of rare respiratory disorders of known and unknown etiologies that are mostly chronic and associated with high morbidity and mortality. ild are characterized by inflammatory and fibrotic changes of the lung parenchyma structure that typically result in the presence of diffuse infiltrates on lung imaging, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect and/or impaired gas exchange. genetic factors are important contributors to child. genetic variations have been mainly described in genes encoding (or interacting with) the surfactant proteins (sp): sp-c (sftpc) and the atp-binding cassette-family a-member 3 (abca3) (abca3), and less frequently in the genes encoding nkx homeobox 2 (nkx2)-1 (nkx2-1), sp-b (sftpb), sp-a (sftpa) and other genes. to date, the therapeutic managements of such child remain limited and are mainly based of the use of corticosteroids, however, their efficacy is highly variable. an alternative approach to treatment was originally described by tooley who reported a good response to treatment with chloroquine in a girl with ild, and several case reports have shown a positive response to hydroxychloroquine(hcq) alone or in combination with systemic steroids of the children with ild. the exact mechanism of action of hcq is unknown, but is probably due to its anti-inflammatory properties, hcq have lysosomal activities such as diminished vesicle fusion, diminished exocytosis, decreased digestive efficiency of phagolysosomes and reversible "lysosomal storage disease. this may be the mechanism by which hcq tend to help in child, especially in those cases related to surfactant protein deficiency. sp-b and sp-c are synthesized in the endoplasmic reticulum (er) of alveolar type ii cells as large precursor proteins, are cleaved by proteolytic enzymes and transported through golgi apparatus to multivesicular bodies that fuse with lamellar bodies. in child related to sp-c gene mutations, there is misfolding of prosp-c that accumulates within er and golgi apparatus in alveolar type ii cells, resulting in cellular injury and apoptosis. treatment with hcq may interfere with this accumulation of pro-surfactant proteins within alveolar cells. the investigators propose to study the efficacy and safety of the therapy with hcq for children with child suffered with genetic mutations, and its long-term effects. through this study the investigators hope to confirm the benefits of hcq in the treatment of this rare disease.

Eligibility criteria:
inclusion criteria: * patients should be clinically stable for inclusion into the study * mature newborn ≥ 37 weeks of gestation, infants and children (≥2month and \< 18y) or previously preterm (≤ 37 weeks of gestation) babies or children(≥2month and \<18y) if child genetically diagnosed * child genetically diagnosed surfactant dysfunction disorders including patients with mutations in sftpc, sftpb, abca3, ttf1 (nkx2-1), foxf1 further extremely rare entities with specific mutations, for example in tbx4, npc2, npc1, npb, copa, lrba and other genes * no hcq treatment in the last 3 months * ability of subject or/and legal representatives to understand character and individual consequences of clinical trial * signed and dated informed consent of the subject (if subject has the ability) and the representatives (of underaged children) must be available before start of any specific trial procedures exclusion criteria: subjects presenting with any of the following criteria will not be included in the trial: * child primarily related to developmental disorders * child primarily related to growth abnormalities reflecting deficient alveolarization * child related to chronic aspiration * child related to immunodeficiency * child related to abnormalities in lung vessel structure * child related to organ transplantation/organ rejection/gvhd * child related to recurrent infections * acute severe infectious exacerbations * known hypersensitivity to hcq, or other ingredients of the tablets * proven retinopathy or maculopathy * glucose-6-phosphate-dehydrogenase deficiency resulting in favism or hemolytic anemia * myasthenia gravis * hematopoetic disorders * participation in other clinical trials during the present clinical trial or not beyond the time of 4 half-lives of the medication used, at least one week * hereditary galactose intolerance, lactase deficiency or glucose-galactose- malabsorption * simultaneous prescription of other potentially nephrotoxic or hepatotoxic medication at the discretion of the treating physician

Keywords: interstitial lung disease hydroxychloroquine