Rare diffuse lung diseases of genetic origin



Interstitial lung disease in children younger than 2 yearsPaolo Spagnolo MD, PhD1, Andrew Bush MD2Affiliations: 1 Medical University Clinic, Canton Hospital Baselland, and University of Basel, Liestal, Switzerland; 2 Royal Brompton Hospital and Harefield NHS Foundation Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom.Address correspondence to: Paolo Spagnolo, Medical University Clinic, Canton Hospital Baselland, and University of Basel, Rheinstrasse 26, 4410 Liestal, Switzerland, paolo.spagnolo@ksbl.ch, +41 (0)61 925 25 25Short title: Childhood interstitial lung diseaseAbbreviations: ABCA3: Adenosine Triphosphate Binding Cassette family member 3 ACDMPV: alveolar capillary dysplasia associated with misalignment of pulmonary veins BAL: bronchoalveolar lavage chILD: childhood interstitial lung diseaseCT: computed tomography DIP: desquamative interstitial pneumoniaFLNA: filamin AGGO: ground glass opacityHD-chILD: humidifier disinfectant-associated chILD HRCT: high-resolution CT IPH: idiopathic pulmonary hemosiderosis ITGA3: integrin α3 NEHI: neuroendocrine cell hyperplasia of infancy NKX2.1: NK2 homeobox 1NSIP: nonspecific interstitial pneumoniaPIG: pulmonary interstitial glycogenosis PH: pulmonary hypertensionPNH: periventricular nodular heterotopia RDS: respiratory distress syndrome SP-B: Surfactant Protein BSP-C: Surfactant Protein CTTF-1: thyroid-transcription-factor 1 Funding source: AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, and the FP7 chILD-EU grant.Financial disclosure: the authors have no financial relationships relevant to this article to disclose.Conflict of interest: the authors have no conflicts of interest to disclose.Contributor’s Statement: Paolo Spagnolo: Dr. Spagnolo conceptualized the review article, drafted the initial manuscript, and approved the final manuscript as submitted. Andrew Bush: Dr. Bush developed the review article, reviewed and revised the manuscript, and approved the final manuscript as submitted.AbstractChildhood interstitial lung disease (chILD) represents a highly heterogeneous group of rare disorders associated with substantial morbidity and mortality. Disease definition and diagnosis are difficult due to both the large variety of entities and nonspecific presenting clinical manifestations, which largely overlap those of more common airway and diffuse lung diseases. Indeed, most cases present with combinations of tachypnea, hypoxemia, crackles, cough, poor growth, diffuse infiltrates on chest radiographs, restrictive ventilatory defect and impaired gas exchange on pulmonary function tests in children old enough to perform these. Although our current understanding of chILD remains limited, important advances have recently been made, the most important being probably the appreciation that disorders that present in early life are ILD in infants is distinct from ILD those occurring in older children and adults, albeit with some overlap. chILD manifests with diffuse pulmonary infiltrates and nonspecific respiratory signs and symptoms, making exclusion of more common conditions presenting in a similar fashion an essential preliminary step. Subsequently, a systematic approach to diagnosis includes a careful history and physical examination, computed tomography of the chest, and some or all of bronchoscopy with bronchoalveolar lavage, genetic testing, and if diagnostic uncertainty persists, lung biopsy. This review will focus on chILD presenting in infants younger than 2 years of age and discuss recent advances in In addition, evidence-based guidelines on the classification, diagnostic approach, and management of chILD in this age range. children less than 2 years of age, and a European perspective on standardized investigation of chILD have recently been developed. Lung biopsy is no longer essential in all cases as an increasing number of chILD are able to be diagnosed noninvasively using genetic testing and chest computed tomography imaging. While obtaining a specific diagnosis We will describe novel genetic entities, along with initiatives that aim at collecting clinical data and biologic samples from carefully characterized patients in a prospective and standardized fashion . Early referral to expert centers and timely diagnosis may has have important implications for patient management and prognosis, but effective therapies are often lacking. Following massive efforts, international collaborations among the key stakeholders with the aim of collecting large cohorts of carefully and uniformly characterized patients are finally starting to be in place. These have allowed the setting up and conducting of the first randomized controlled trials of therapeutic interventions in patients with chILD. IntroductionChildhood interstitial lung disease (chILD) comprises a large and heterogeneous group of rare disorders characterized by diffuse pulmonary infiltrates, restrictive lung physiology and impaired gas exchange, which are associated with substantial morbidity and mortality.1-3 (Nathan N, Thouvenin G, Fauroux B, Corvol H, Clement A. Interstitial lung disease: physiopathology in the context of lung growth. Paediatr Respir Rev. 2011;12(4):216–222; Vece TJ, Fan LL. Diagnosis and management of diffuse lung disease in children. Paediatr Respir Rev. 2011;12(4):238–242)The term “interstitial” is however misleading as most of these conditions are associated with abnormalities that are not limited to the lung interstitium but extend to the alveolar and airway compartments. Although it could be argued that ‘diffuse lung disease’ is a better term, the term ‘chILD’ is in fact now well established in the literature. Historically, terminology and classification of ILD in children have mirrored those of adult disease, but this is generally not helpful. Indeed, there are major differences in disease etiology, natural history and management between the pediatric age group - in whom ILD most often develops primarily because of an underlying developmental or genetic abnormality4 - and adults. For instance, adult desquamative interstitial pneumonia (DIP) is a relatively benign smoking-related condition, whereas pediatric cases are often associated with Surfactant Protein C (SP-C) and Adenosine Triphosphate Binding Cassette family member 3 (ABCA3) mutations and have a very poor prognosis, particularly if they present in the neonatal period.1, 5-7 Similarly, idiopathic pulmonary fibrosis, the most common and severe of the idiopathic interstitial pneumonias in adults,8, 9 is not found in children. On the other hand, there are forms of ILD, which are unique to infants and children younger than 2 years of age,5 hence the use of adult terminology and classification does not adequately address pediatric entities. Therefore, new appropriate codes have recently been added for several chILD disorders in the International Classification of Diseases, Ninth Revision (ICD-9) (Popler J, Lesnick B, Dishop MK, Deterding RR. New coding in the International Classification of Diseases, Ninth Revision, for children's interstitial lung disease. Chest 2012;142(3):774–780). Moreover, the multi-institutional ChILD Research Cooperative has recently developed a classification system specifically for young children.5, 10 Despite some conceptual and practical limitations (e.g., it focuses exclusively on young children who underwent diagnostic lung biopsy, thus providing little guidance in cases without a confirmatory lung biopsy, and does not address properly those cases showing features of more than one entity), this classification system groups disorders with similar clinical and/or pathologic features, and provides consensus terminology, diagnostic criteria as well as a useful framework for approaching childhood ILD, particularly entities unique to young children (Table 1). The ChILD scheme is also applicable to patients in the 2-18-year-old group, although additional entities, such as lymphoproliferative disorders, hypersensitivity pneumonitis, or pulmonary hemorrhage syndromes, need to be included.11 Signs and symptoms of chILD are very nonspecific, and the diagnosis of chILD may not be considered initially. In fact, the rarity of these conditions hampers hugely the acquisition of adequate knowledge, which almost invariably results in delayed diagnosis. Compared to adult disease,12 chILD occurs far less frequently, with a prevalence of idiopathic ILD among immunocompetent children aged 0 to 16 years being estimated at 3.6 cases per million,13 although this is likely to be an underestimate.14Our understanding of chILD remains incomplete. However, important advances in disease mechanisms, diagnostic approach and management have been recently made. In this review, we summarize and discuss these with special attention to conditions that are unique to infants. Diagnostic approachThe primary diagnostic step is to identify children who require further investigation for chILD. To this end, more common causes of diffuse lung disease (e.g., cystic fibrosis, immunodeficiency, or congenital heart disease) sharing a common presentation with chronic respiratory symptoms (e.g., tachypnea, cough and hypoxemia) and diffuse radiographic infiltrates should be excluded. Once major non-chILD disorders have been excluded, the term “chILD syndrome” is used to refer to children who meet at least three of the four following criteria: (1) respiratory symptoms (cough, rapid breathing, or exercise intolerance), (2) signs (resting tachypnea, adventitious sounds, retractions, digital clubbing, failure to thrive, or respiratory failure), (3) hypoxemia, and (4) appropriate diffuse abnormalities on chest imaging.1A systematic approach to patients with chILD is crucial in establishing the diagnosis [ref] . Clinical context can provide valuable differential diagnostic clues. For instance, neonates presenting acutely with respiratory distress and hypoxemia are more likely to have developmental lung disorders, whereas a family history of siblings with similar lung conditions may suggest a genetic or familial lung disease such as inborn errors of surfactant metabolism. However, further diagnostic testing is always required; the pace of testing depends on the clinical situation – in an ill child, a lung biopsy may be performed urgently, but if the child is stable, it may be appropriate to await the results of genetic testing. It is important to plan investigations so as to minimize the number of general anaesthetics for the child; so for example, unless it is very likely that bronchoscopy will be diagnostic, and obviate the need for a lung biopsy, the procedure should probably be better combined with lung biopsy under the same anaesthetic.Lung function tests. Most experience is in older children, while data in infants are limited. The biggest dataset is in neuroendocrine cell hyperplasia of infancy (NEHI) which is characterized by airflow obstruction and hyperinflation.15 At school age, lung function tests typically show a restrictive ventilatory defect with reduced total lung capacity (TLC), forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) with a normal or elevated FEV1/FVC ratio.16 An elevated residual volume (RV) and RV/TLC ratio suggest air trapping.Imaging. Chest computed tomography (CT), compared to plain chest radiographs, provides more precise information about extent and distribution of parenchymal abnormalities. It is used to confirm that chILD is indeed the underlying problem and to guide the site of a biopsy; in addition, it can sometimes be used to make specific diagnoses (below). Common radiographic patterns include ground glass opacity (GGO), geographic hyperlucency, consolidation, septal thickening, lung cysts, and nodules.17, 18 In some cases, CT findings are highly suggestive or even characteristic, thus obviating the need for invasive procedures.19 CT may also provide prognostic information (e.g., NEHI has a favorable prognosis, whereas growth abnormalities and surfactant mutations carry substantial mortality). Bronchoalveolar lavage (BAL). The most common indication for pediatric BAL is detection of infection both in immunocompromised and immunocompetent hosts.20 Occasionally, this procedure may also provide useful information in children with suspected chILD.21 For example, in the appropriate clinical setting, BAL may help to identify diffuse alveolar hemorrhage or aspiration by the presence of hemosiderin-laden or lipid-laden macrophages, respectively.4 Other patterns of BAL cellularity (e.g., lymphocytosis or eosinophilia) are less indicative of specific conditions.Genetic testing. If positive, genetic testing may allow the diagnosis of known single-gene disorders. However, at present, a genetic cause has been identified for only a minority of chILD (e.g., mutations in surfactant protein genes SP-B and SP-C, the gene encoding the surfactant processing protein ABCA3 and thyroid-transcription-factor 1 [TTF-1]).10 In addition, as the results of genetic tests may not be available for several weeks, a lung biopsy may still be necessary to make a secure diagnosis in severe or progressive cases.Lung biopsy. Lung biopsy remains the gold standard for chILD when less invasive tests have failed to secure a diagnosis.5 Open lung biopsy and video-assisted thoracoscopy are the most reliable way to obtain adequate tissue for diagnosis.5, 22 Whatever technique is used, adequate processing of lung biopsies is essential to ensure optimal diagnostic yield.23 Similarly important is that such biopsies are interpreted by a pathologist with expertise in pediatric lung disease. Management Treatment options and outcomeTreatment is largely empirical mirroring the poorly understood pathogenesis of many forms of chILD. The majority of patients with chILD require treatment of some sort. Management is generally supportive, including supplemental oxygen for chronic hypoxemia, adequate nutrition, proper immunization, avoidance of environmental pollutants, and treatment of intercurrent infections. Further treatments can be divided into specific therapies (for example, Etanercept for sarcoidosis, inhaled GM-CSF for pulmonary alveolar proteinosis due to circulating anti-GM-CSF autoantibodies) and non-specific Despite limited evidence of efficacy, corticosteroids remain the treatment of choice for most patients with chILD, with as many as 40% of treated children improving in terms of clinical status, lung function and oxygen requirement in a retrospective study.16 Hydroxychloroquine and azithromycin have been used as adjuvants. Nevertheless, treatment decisions are highly individual, after careful consideration of the benefit and potential steroid-related side effects. pharmacological treatment which is based on small case series and low-quality evidence with treatment decisions being made on a case-by-case basis.10 There are currently no randomized controlled trials of any treatment for chILD. Systemic steroids and hydroxychloroquine remain the treatment of choice for most patients with chILD, based on the assumption that suppressing inflammation may prevent evolution to fibrosis (Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Interstitial lung diseases in children. Orphanet J Rare Dis. 2010;5:22). European treatment protocols have recently been published [Bush, Thorax 2015].Systemic steroids. Steroids can be administered orally or intravenously depending on disease severity.2 Oral prednisolone is generally administered at a dose of 1-2 mg/kg/day, whereas methylprednisolone is usually given at a dose of 10-30 mg/kg/day for 3 consecutive days, followed by single monthly pulses for a minimum of 3 cycles (Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland. Pediatr Pulmonol. 2002;34(1):23–29; Fan LL, Deterding RR, Langston C: Pediatric interstitial lung disease revisited. Pediatr Pulmonol. 2004;38(5):369–378). Dosage and duration of treatment depend on disease severity and clinical response, and should be weighed against the morbidity of steroid treatment. Broadly speaking, conditions that tend to respond to steroid therapy include DIP and nonspecific interstitial pneumonia (NSIP) (when no underlying diagnosis has been made) and idiopathic pulmonary hemosiderosis (IPH).3 Hydroxychloroquine. It is an anti-malarial agent with a number of immunological effects that may be beneficial in chILD (van der Heijden JW, Dijkmans BA, Scheper RJ, et al. Drug insight: resistance to methotrexate and other disease-modifying antirheumatic drugs – from bench to bedside. Nat Clin Pract Rheumatol. 2007;3(1):26–34). Recently, Braun and colleagues performed an extensive literature search and identified 85 case reports or small case series of children with ILD treated with either chloroquine or hydroxychloroquine published between 1984 and 2013 (Braun S, Ferner M, Kronfeld K, Griese M. Hydroxychloroquine in children with interstitial (diffuse parenchymal) lung diseases. Pediatr Pulmonol. 2015;50(4):410–419). Clinical response varied widely, although, overall, a positive treatment effect was more likely to be seen in cases of lymphocytic interstitial pneumonia, IPH, or cellular interstitial pneumonia. An ophthalmologic examination at the start of treatment is recommended due to the known risk of ocular toxicity, (Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):415–422). A number of other treatments have been used in various chILDs, including azithromycin, methotrexate, azathioprine, cyclosporine and Rituximab. The evidence base for efficacy is even less than for corticosteroids and hydroxychloroquine. Lung transplantation is an option for children with end-stage disease, with long-term outcomes comparable to lung transplant recipients with cystic fibrosis and pulmonary vascular disease.24 The prognosis for children with ILD is highly variable, with pulmonary hypertension (PH) being the single greatest clinical predictor of mortality.5 Infants with NEHI generally have a favorable prognosis, although they may remain symptomatic and require long-term oxygen. At the other end of the spectrum, children with growth failure, PH and severe fibrosis have a poor prognosis. Indeed, in the ChILD Research Cooperative study of children less than 2 years of age, mortality was highest (100%) in developmental disorders and ABCA3 mutations, and lowest in NEHI, pulmonary interstitial glycogenosis (PIG), and SP-C mutations,5 although fatal cases of PIG and SP-C mutations have also been described.25, 26 Disorders more prevalent in infants age 0-2 yearsThe initial classification [Deutsch], although an excellent first attempt, can be criticized. It is based only on biopsies, thus excluding conditions not requiring a tissue diagnosis; newer work has highlighted other disorders not covered by the original classification [Rose, Histopathology] and it includes conditions (obliterative bronchiolitis and bronchopulmonary dysplasia for example) which many would not consider as chILD; and the fact that the same condition can cause more than one type of abnormality was not really appreciate [Rose, Histopathology]. Clearly chILD classification is an ongoing work in progress; nonetheless, the initial manuscript has given us a very useful framework.Diffuse developmental disorders. Diffuse developmental disorders, which include acinar dysplasia, congenital alveolar dysplasia and alveolar capillary dysplasia associated with misalignment of pulmonary veins (ACDMPV), are a group of poorly understood primary disorders that occur during the earliest stages of lung development. Accordingly, biopsies from these patients display arrest in lobular development, reduced alveolar capillary density, and hypertensive arterial remodeling.5 ACDMPV is also characterized by markedly dilated bronchial veins due to prominent right-to-left intrapulmonary vascular shunt (e.g., pulmonary artery-bronchial artery anastomoses, which by-pass the alveolar capillary bed; the pulmonary veins themselves are not in fact misplaced, what is seen are the hypertrophied bronchial veins).27 In addition, ACDMPV is often accompanied by cardiovascular, gastrointestinal, or genitourinary system anomalies. Without lung transplant, diffuse developmental disorders are almost universally fatal due to rapidly progressive respiratory failure and PH, which develop within days of birth.28 However, longer survivors have also been reported.29 Recently, inactivating deletions and point mutations within the FOX transcription factor gene cluster on 16q24.1 have been identified in cases of ACDMPV with distinct congenital malformations,30 suggesting the utility of genetic testing in neonates presenting with respiratory failure and PH, especially when gastrointestinal, cardiovascular, or genitourinary abnormalities coexist.Alveolar growth abnormalities. Alveolar growth abnormalities are the most common cause of chILD in infants.4, 5, 31 Unlike diffuse developmental disorders, in infants with alveolar growth abnormalities abnormal pulmonary development is secondary and may be seen in a variety of settings, including pulmonary hypoplasia associated with prenatal conditions (e.g., oligohydramnios, abdominal wall defects, or neuromuscular disease), prematurity (e.g., chronic neonatal lung disease), chromosomal abnormalities (e.g., trisomy 21; Figure 1A, 1B, 1C, 1D), congenital heart diseases, and, in term infants, postnatal lung injury. Affected children present with varying degrees of respiratory distress and hypoxemia. Though rarely diagnostic, characteristic imaging findings are seen in specific conditions. For instance, chronic neonatal lung disease of prematurity (which many would doubt is a true chILD) is characterized by hyperlucent areas corresponding to alveolar enlargement and reduced distal vascularization, and linear opacities, which reflect fibrotic changes.32 Histologically, disorders in this category are characterized by variable lobular simplification with alveolar enlargement and deficient septation. Mortality rate, at 34%, is substantial with prematurity and severity of the growth abnormality representing the strongest predictors of poor outcome.5 NEHI. This is a disorder of unknown etiology that typically manifests in the first year of life with chronic tachypnea, retractions, hypoxemia, and crackles on chest auscultation.33 Chest X-ray almost invariably shows hyperinflation, whereas high-resolution CT (HRCT) imaging typically shows air trapping in a mosaic attenuation pattern affecting at least 4 lobes; geographic GGO is most conspicuous in the right middle lobe and lingula.32 When interpreted by experienced pediatric thoracic radiologists, the sensitivity and specificity of HRCT for NEHI is 78%-83% and 100%, respectively (Fig), thus obviating the need for a confirmatory lung biopsy.19 Diagnosis on biopsy is based on essentially normal histology on standard staining, with an increase in Bombesin-positive cells on specific staining. However, while hyperplasia of neuroendocrine cells within bronchioles (as demonstrated by immunohistochemistry), the only consistent pathologic finding, may be seen in a variety of disorders, including bronchopulmonary dysplasia, bronchiolitis, and PH,11, 34, 35 neuroendocrine cell prominence with otherwise normal histopathology is a distinguishing feature of NEHI.36 These other conditions all have specific features, which would preclude diagnostic confusion with NEHI. Reported familial cases suggest that NEHI may have a genetic basis,37 although to date no mutation has been consistently identified.38 Long-term outcome is generally favorable with most patients gradually improving over time, although persistent airway obstruction mimicking severe asthma,39 and relapse with respiratory infection have also been reported.40 PIG. This is a rare disorder that manifests within the first few weeks of life with respiratory distress and diffuse interstitial infiltrates.41, 42 Histologically, PIG is characterized by interstitial thickening by immature vimentin-positive mesenchymal cells containing abundant monoparticulate glycogen, without inflammation or fibrosis (Figure). Imaging findings vary considerably based on whether PIG occurs as an isolated condition (diffuse PIG), or associated with an underlying lung growth disorder (patchy PIG).43, 44 Typical HRCT features include GGO, reticular changes and hyperinflated areas in a predominantly subpleural distribution.31 In patchy PIG, these abnormalities overlap with those of the underlying lung growth disorder. Long-term use of corticosteroids is not recommended, particularly in PIG occurring in the setting of lung growth abnormalities, due to their negative effect on post-natal alveolarization and neurological development, and lack of efficacy. Unlike diffuse PIG, which has an excellent prognosis, the outcome of PIG associated with growth abnormality is variable, being related to the severity of the primary lung disorder. Surfactant dysfunction disorders. The identification of mutations within genes encoding proteins involved in surfactant function and metabolism has dramatically improved our understanding of these disorders, which cause significant morbidity and mortality in neonates, older infants, children and adults.45 Because surfactant dysfunction disorders display considerable overlap in their clinical and histologic features, genetic analysis is essential for establishing a specific diagnosis. However, immunohistochemical and ultrastructural examination may also provide valuable diagnostic clues.SP-B deficiency. It is a rare autosomal recessive disorder that most frequently presents with rapidly progressive neonatal respiratory distress syndrome (RDS),46 although partial SP-B deficiency may be associated with a milder phenotype and longer survival (Table 2).47 Over 40 loss-of-function mutations within the SP-B gene - resulting in partial to complete absence of SP-B protein - have been identified thus far. The most common one - a GAA substitution for C at genomic position 1549 in codon 121 (the “121ins2” mutation), which accounts for approximately 70% of cases of SP-B deficiency - results in an unstable transcript and absent pro- and mature SP-B protein.48 The absence of SP-B disrupts the formation and structure of lysosome-related secretory organelles called lamellar bodies (e.g., on electron microscopy, the well-organized concentric rings of phospholipid membranes that characterize lamellar bodies are replaced by large, disorganized multivesicular bodies), thus leading to abnormal surfactant composition and function. Abnormal lamellar bodies on electron microscopy are a strong pointer to SP-B mutations. Histologically, SP-B deficiency is characterized by alveolar accumulation of granular, eosinophilic, periodic acid-Schiff-positive, lipoproteinaceous material.Clinical estimates suggest an incidence of 1 per million live births. Most infants with SP-B deficiency present within hours of birth with respiratory failure requiring mechanical ventilation. Chest radiograph and HRCT appearances mimic that of hyaline membrane disease in premature infants with diffuse haziness and air bronchograms. However, infants with SP-B deficiency are only transiently or minimally responsive to surfactant replacement and, with rare exceptions, all patients succumb without lung transplantation. The very rare infants with mutations that allow for partial expression of the SP-B protein appear to survive longer and go on to develop chronic ILD.47SP-C deficiency. It was originally described in an infant and mother with nonspecific interstitial pneumonia (NSIP) and DIP, respectively. Both carried a heterozygous guanine to adenine substitution leading to skipping of exon 4 and deletion of 37 amino acids.49 A large five generation kindred was later identified with 14 affected family members, including four adults with histologic usual interstitial pneumonia and three children with NSIP, all carrying a rare heterozygous missense mutation predicted to hinder processing of SP-C precursor protein.50 Over 35 dominantly expressed SP-C mutations have been identified, half of which arise spontaneously, thus resulting in sporadic disease, whereas the remainder is inherited. The most common mutation, a T to C transition at genomic position 1295, leads to a threonine substitution for isoleucine in codon 73 (I73T), and accounts for a quarter of cases.51 The pathophysiology of lung disease due to SP-C mutations is thought to involve aberrant surfactant protein folding, decreased endogenous SP-C secretion, endoplasmic reticulum stress and apoptosis of alveolar type II cells.52 Age at presentation and natural history of lung disease are highly variable: a large proportion of patients present in late infancy/early childhood; a minority present acutely in early infancy (Figure 2A and 2B); while others are discovered in adulthood. SP-C mutations account for a large minority of familial cases of pulmonary fibrosis,53 whereas they are a rare cause of sporadic forms of idiopathic interstitial pneumonia.54 Whether the nature and location of SP-C mutations impact on the severity of lung disease is unknown. However, affected family members harboring the same SP-C mutation display considerable variability in the onset and severity of lung disease.50 In this regard, it is well established that viral infection may trigger the disease and affect negatively its clinical course.55, 56 Successful treatment with either cloroquine or hydroxychloroquine and prolonged survival of children with SP-C mutations and ILD has been described reported (Figure 2C) (Avital A, Hevroni A, Godfrey S, et al. Natural history of five children with surfactant protein C mutations and interstitial lung disease. Pediatr Pulmonol. 2014;49(11):1097–1105).ABCA3 deficiency. The membrane transporter ABCA3 facilitates the translocation of phospholipids from the cytosol into lamellar bodies for the production of surfactant in type II alveolar epithelial cells. Mutations within ABCA3 are the most common genetic cause of respiratory failure in full-term infants.7, 57 In fact, affected infants present in the neonatal period with severe and progressive RDS despite medical treatment.58 There is a genotype-phenotype correlation; patients homozygous for severe mutations invariably have a neonatal presentation and death in the first year of life, whereas milder mutations permit prolonged survival.7 However, ABCA3 mutations have been identified also in older children and even young adults with ILD, usually with DIP.59 Distinctive ultrastructural abnormalities observed in the alveolar type II cells of patients with of ABCA3 mutations include small, markedly abnormal lamellar bodies with densely packed phospholipid membranes and electron-dense inclusions. Notably, the family history is usually negative as the disease is inherited in an autosomal recessive fashion. NK2 homeobox 1/Thyroid transcription factor-1 (NKX2.1/TTF-1) mutations. NKX2.1/TTF-1 is critical for lung development, surfactant homeostasis and innate immune responses. It is a transcription factor for SP-B, SP-C, and ABCA3. Deletions or loss-of-function mutations on one copy (“haploinsufficiency”) of NKX2.1 gene can result in severe RDS and chronic ILD,60 classically in the form of “brain-thyroid-lung syndrome” - which is characterized by hypothyroidism, muscular hypotonia, developmental delay and choreoathetosis - as the gene is also expressed in the thyroid gland and central nervous system.61 However, patients with NKX2.1 mutations may also present in the newborn period or during childhood with isolated lung involvement as well as with a spectrum of pulmonary manifestations, including alveolar proteinosis and severe neonatal RDS, pulmonary fibrosis, PH and recurrent respiratory infections.62 Moreover, mutations within NKX2.1 may be associated with NEHI.38 Lung disease in this setting is thought to result from decreased amounts of several gene products in combination or reduced amounts of a key protein, particularly SP-B or ABCA3, below a critical level. Incidence and prevalence of lung disease due to NKX2.1 haploinsufficiency are unknown. As with other surfactant dysfunction disorders, histological abnormalities include prominent alveolar type II epithelial cell hyperplasia, thickening of the interstitium by mesenchymal cells, and accumulation of foamy macrophages along with granular, eosinophilic proteinaceous material within the air spaces.5 Clinical availability of genetic testing and improved recognition of disease patterns on imaging studies have allowed many cases to be diagnosed noninvasively. No specific therapies have been demonstrated to be effective in these disorders. Recent advances in childhood ILDNovel genetic entitiesIntegrin α3 mutations. Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. They are also involved in signal transduction, and cell survival, proliferation and differentiation.68, 69 Loss-of-function mutations within the integrin α3 (ITGA3) gene have been associated with a fatal recessive multiorgan disorder consisting of congenital nephrotic syndrome, early onset ILD and skin fragility.70-72 Lung involvement was the primary cause of death in all cases, and lung biopsy revealed abnormal alveolarization, consistent with distorted morphogenesis. ITGA3 mutations are probably under recognized as both the full spectrum of clinical manifestations and genotype-phenotype correlations are poorly characterized. Nevertheless, ITGA3 gene sequencing is strongly recommended in newborns presenting with severe RDS and/or congenital nephrotic syndrome of unknown etiology. Filamin A mutations. Loss-of-function mutations in FLNA, which encodes the actin cross-linking protein Filamin A, cause X-linked periventricular nodular heterotopia (PNH), one of the most common brain malformations (Ek?io?lu YZ, Scheffer IE, Cardenas P, et al. Periventricular heterotopia: an X-linked dominant epilepsy locus causing aberrant cerebral cortical development. Neuron 1996;16:77–87). However, FLNA mutations have also been associated with severe diffuse lung disease (characterized on HRCT by GGO, thickened interlobular septa, atelectasis, areas of hyperinflation and cysts), tracheobronchomalacia and severe PH (Lord A, Shapiro AJ, Saint-Martin C, Claveau M, Melan?on S, Wintermark P. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care. 2014;59(11):e171–7; Masurel-Paulet A, Haan E, Thompson EM, et al. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet. 2011;54(1):25–28; de Wit MC, Tiddens HA, de Coo IF, Mancini GM. Lung disease in FLNA mutation: confirmatory report. Eur J Med Genet. 2011;54(3):299–300). Lung pathology reveal alveolar simplification. FLNA mutations are inherited in an X-linked dominant manner, with high perinatal mortality in affected males, whereas in females the prognosis depends on the severity of the associated cardiovascular abnormalities (de Wit MC, de Coo IF, Lequin MH, Halley DJ, Roos-Hesselink JW, Mancini GM. Combined cardiological and neurological abnormalities due to filamin A gene mutation. Clin Res Cardiol. 2011;100(1):45–50). In premature infants with diffuse lung disease and respiratory course atypical for chronic neonatal lung disease in terms of timing, severity and response to treatment, FLNA mutations should be suspected. Humidifier disinfectant-associated chILD (HD-chILD). This is a unique chILD syndrome caused by inhalation of humidifier disinfectants in the home environment. HD-chILD, outbreaks of which were originally observed among Korean children in spring 2006,73-75 is characterized by spontaneous air leak, rapid progression and high mortality.76, 77 Radiological abnormalities include diffuse or patchy GGO, dense consolidation, and diffuse centrilobular nodules. Lung biopsy reveals a temporally homogeneous pathologic process characterized by variable degrees of bronchiolar injury associated with bronchiolocentric acute lung damage and relative sparing of the lobular periphery, consistent with an inhalation injury.76 HD-chILD has been eradicated upon withdrawal of humidifier disinfectants from the market in November 2011. However, thousands of potentially toxic chemicals (to which children are far more vulnerable than adults) are used worldwide. Therefore, in cases of unusually acute and progressive disease an environmental hazard should be suspected.Parent experiences and perspectives. A broader understanding of the experiences and expectations of families of children diagnosed with ILD is crucial for improving current delivery and future planning of healthcare in this setting. A recent web-based survey conducted in UK identified a number of areas for development, which included feeding problems (an issue previously not fully appreciated); written information sharing; written communication between shared care hospitals; training for less experienced hospitals; and psychological support.78 Some of these issues will be addressed by the currently on-going FP-7 chILD program, a European project, which aims at increasing awareness of chILD across Europe, setting up a pan-European database and bio-bank compatible with others worldwide, increasing diagnostic accuracy through international panels of clinicians, radiologists, geneticists and pathologists; and implementing evidence-based guidelines and treatment protocols.66American Thoracic Society clinical practice guideline on chILDThe American Thoracic Society has recently published a clinical practice guideline that provides a comprehensive approach to the evaluation and management of childhood ILD, focusing on neonates and infants <2 years of age.10 Some of the key messages of the guideline can be summarized as follows:Owing to their rarity, more common causes of diffuse lung diseases should be excluded prior to testing for specific forms of chILD;Achieving a specific diagnosis is critically important as disease behavior, management and outcomes are highly variable;While many patients still require tissue sampling, in the appropriate clinical setting genetic testing may obviate the need for lung biopsy,63 although the guideline also emphasizes limitations of current sequencing modalities and challenges in interpretation of results. Nevertheless, as many as one-third of cases can be classifiable based on clinical, genetic, and/or radiographic criteria without histological information;64Referral of patients to highly specialized centers is highly recommended as multidisciplinary discussion between pediatric pulmonologists, radiologists and pathologists with expertise in chILD greatly enhances the likelihood of accurate diagnosis;Because no controlled clinical trials of therapeutic interventions have been performed for childhood ILD, recommendations on management derive from observational evidence and clinical experience. Accordingly, the guideline emphasizes the need for decisions to be made on a case-by-case basis. The chILD-EU collaborationILD in children are very rare and it has been estimated that the average European hospital will see no more than 5 cases/year.65 The chILD-EU collaboration has brought together centers from across Europe with the aim of 1. creating a pan-European registry; 2. peer reviewing all potential diagnoses of chILD; 3. collecting prospective longitudinal data from well-defined groups of patients; and 4. setting up and performing the first randomized controlled trial of treatment.66 In order to achieve this, it is essential diagnostic and therapeutic approaches be harmonized across Europe. To this end, a sequence of diagnostic procedures - along with standard operating procedures for performing such investigations - and therapeutic interventions and protocols have recently been proposed and agreed upon using the Delphi study methodology, a consensus-building process among experts through a series of carefully designed questionnaires.67Summary and ConclusionChildhood ILD encompasses a large spectrum of rare and heterogeneous disorders, which differ substantially from adult ILD. In the past decade, genetic discoveries and multicenter collaborative efforts have resulted in the publication of a guideline document that provides systematic diagnostic approaches and standardized nomenclature. In addition, an increasing proportion of cases can be diagnosed without lung biopsy through chest CT patterns and genetic testing. 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