Abstract
The field of rare and diffuse pediatric lung disease continues to evolve and expand rapidly as clinicians and researchers make advancements in the diagnosis and treatment of children's interstitial and diffuse lung disease, non-cystic fibrosis bronchiectasis, and primary ciliary dyskinesia. Papers published on these topics in Pediatric Pulmonology and other journals in 2022 describe newly recognized disorders, elucidate disease mechanisms and courses, explore potential biomarkers, and assess novel treatments. In this review, we will discuss these important advancements and place them in the context of existing literature.
| Original language | English |
|---|---|
| Pages (from-to) | 2719-2724 |
| Number of pages | 6 |
| Journal | Pediatric Pulmonology |
| Volume | 58 |
| Issue number | 10 |
| DOIs | |
| State | Published - 2023 |
Funding
Comprised of a group of rare disorders, chILD is generally characterized by diffuse radiographic changes and impaired gas exchange, which are heterogeneous with respect to etiology, natural history, and outcomes. Understanding of disease mechanisms is limited for many types of chILD, and as a result, few directed therapies exist. New forms of chILD are still being discovered and described. Rubinstein-Taybi syndrome (RTS) is caused by genetic alterations affecting the CREBBP or EP300 gene. Affected patients typically have characteristic facial features, broad thumbs and toes, short stature, and intellectual disability. Bradford et al.1 report three patients with RTS, all with computed tomography images that include consolidated densities overlying ground glass opacities. Lung histopathology revealed accumulation of proteinaceous material within alveolar spaces, evidence of fibrosis, and increased alveolar macrophages. Immunofluorescent staining indicated potential disruptions in surfactant metabolism and/or persistent activation of myofibroblasts as mechanism of pathogenicity. Further research is needed for better understanding of pathogenic mechanisms in this newly described type of chILD, which may lead to improved and targeted treatments. Other papers provided improved understanding of mechanisms known disorders. Deficiency of the ATP-binding cassette subfamily A member 3 (ABCA3) transporter is inherited in an autosomal recessive manner, and can present at any age, including with lethal lung disease at birth.2 The reasons for this dramatic variability are incompletely characterized. Previous work by Wambach et al.3 showed genotype-phenotype correlation among 185 children with ABCA3 deficiency. Variants in ABCA3 predicted to lead to production of no functional protein (frameshift or nonsense) were associated with earlier presentation and poorer outcome, whereas those predicted to result in altered protein (missense) were less reliably associated with age of presentation and prognosis. To examine how different types of variants act at the tissue level, Xu et al.4 examined associations between ABCA3 genotype and RNA expression in lung specimens. In 16 patients with lung disease due to compound heterozygous damaging variants in ABCA3, they reported no evidence of allele-specific expression in samples with two missense ABCA3 variants (n = 6) but observed allele-specific expression of missense alleles that were in trans with either frameshift (n = 4) or nonsense (n = 1) variants. The latter was deemed consistent with nonsense-mediated decay. These findings illustrate how expression analysis in lung tissue can be valuable in determining variant-specific mechanisms of pathogenesis. Further studies are needed to explore the roles of modifier genes and environmental influences in the heterogeneity of lung disease due to ABCA3 deficiency. Neuroendocrine cell hyperplasia of infancy (NEHI) is an idiopathic form of chILD characterized clinically by tachypnea, hypoxemia, and crackles presenting in the first year of life.5 Children with NEHI show a characteristic pattern on chest CT and infant pulmonary function testing.6,7 Histologic examination of lung tissue from these patients shows increased numbers of pulmonary neuroendocrine cells (PNECs) in the small airways with minimal other overt pathology.8 Evidence suggests that the hyperplastic PNECs are likely to be causative for the NEHI phenotype,9 rather than representing a reaction to other lung pathology. In one of the most impactful papers in this field from 2022, Xu et al.10 generated the first mouse model of NEHI by inducing a disease-causing variant in the transcription factor gene Nkx2–1 that has been described in a few kindreds with familial NEHI.11 Their results provide compelling evidence that excess PNEC-derived neuropeptides, such as calcitonin gene-related peptide (CGRP) activate receptors enriched on pulmonary endothelial cells, leading to increased vascular permeability, excess lung fluid, and impaired gas exchange.10 This makes treatment of NEHI patients with a CGRP receptor antagonist a strategy worth further exploration. Having a specific therapeutic strategy would advance the field tremendously since currently NEHI is treated only with supportive and preventive measures.5 It is unclear how generalizable such an approach might be, however, as NEHI likely represents a phenotype rather than a single discrete disease, and potentially has multiple different upstream causes. The Nkx2-1 variant used to generate this model has only been found in a handful of NEHI cases, thus the mechanisms observed here may not hold true for NEHI due to other causes. This paper nonetheless is important as the first preclinical model of this poorly understood condition. Biomarkers present an opportunity to enhance diagnosis and disease monitoring in patients with many different types of chILD, including the inborn errors of surfactant metabolism. Patients heterozygous for damaging variants in the surfactant protein C gene (SFTPC) develop lung disease with variable clinical presentation and course. Otsubo et al.12 reported a case of chILD due to a damaging SFTPC variant, with elevated serum thymus and activation-regulated chemokine/C-C motif chemokine ligand 17 (TARC/CCL17) levels. The TARC/CCL17 levels decreased after clinical improvement with treatment, which included two courses of pulse methylprednisolone, hydroxychloroquine, and azithromycin. A known disease marker for atopic dermatitis, TARC/CCL17 may be associated with idiopathic pulmonary fibrosis.13 Although this report is limited by a lack of normative values of TARC/CCL17, biomarkers are needed for monitoring disease progression and response to treatment in many forms of chILD. Bronchiolitis obliterans (BO) is a fixed, obstructive lung disease resulting from small airway injury leading to fibrosis and obliteration of the bronchioles. Although the pathophysiology differs from asthma, both present with obstructive lung disease. Using proteomics to identify unique biomarkers between the two diseases, Kang et al.14 compared plasma samples from 30 healthy controls, 18 patients with asthma, and 15 patients with postinfectious BO (PIBO). Mass spectrometry was used to identify proteins in the samples, with 48 determined to be significantly different between the three groups. Analysis suggested that transforming growth factor beta 1 in PIBO and periostin in asthma were negatively correlated with several pulmonary function measures. Currently, diagnosis of PIBO requires clinical suspicion, reliable pulmonary function data, and expertize to interpret imaging and/or lung histology findings. Biomarkers could provide supportive diagnostic data and an additional means for monitoring disease progression. Histopathologic diagnosis remains an important tool in chILD, as imaging, biomarkers, and genetic testing cannot sufficiently evaluate for all forms. Dhochak et al.15 describe use of transbronchial cryobiopsy via flexible bronchoscopy to diagnose chILD in five children 9−15 years of age. Cryobiopsy involves rapid freezing through a cryoprobe to obtain a larger sample of lung tissue without the crush that typically occurs in transbronchial lung biopsy (TBLB) with forceps, while being less invasive than open surgical lung biopsy (OSLB).16,17 In the study, the procedure was well-tolerated and led to management changes in all five patients. While TBLB and OSLB approaches will likely remain the standard for obtaining diagnostic lung tissue specimens in children, a role may develop for cryobiopsy. In younger children this may be limited by probe sizes and risk of bleeding. An epidemic emerged in 2019 due to lung injury associated with use of electronic cigarettes, also known as e-cigarettes. The clinical presentation of electronic cigarette/vaping associated lung injury (EVALI) is heterogeneous.18 Diagnosis requires a history of e-cigarette use within 90 days of the development of pulmonary infiltrates.19 Vitamin E acetate (VEA) was found in brochoalveolar lavage fluid in many patients with EVALI,20 yet approximately 20% reported using only nicotine e-cigarettes that were unlikely to include VEA.21 With most labs unable to isolate VEA, its use as a biomarker is limited. McGraw et al.22 sought a blood-based biomarker for EVALI by comparing five e-cigarette users without EVALI, five e-cigarette users with EVALI, and five controls. Using untargeted lipidomics, the investigators found that median levels of phosphatidylethanolamines (PEs) were reduced by 37% in EVALI versus nonusers and 31% in EVALI versus e-cigarette users (p = 0.0029). Because PEs are classified as plasmalogens and play a role in surfactant homeostasis,23,24 the authors hypothesized that reduced plasmalogen levels predispose EVALI subjects to alveolar collapse. While promising, this study is small and needs validation in a larger cohort. As specific causes of chILD disorders are better understood, more targeted therpaies can be employed. This was illustrated by Wobma et al.25 who report three cases of distinct primary immune regulatory disorders, each with different causative mechanisms which informed different targeted therapeutic approaches. The first case was a 23-year-old with a gain-of-function variant in STAT3 leading to lung fibrosis, who was successfully treated with an IL-6 blocker, Janus kinase (JAK) inhibitor, and hematopoietic stem cell transplant (HSCT). The second case was a 22-year-old with STING-associated vasculopathy with onset in infancy that was treated with tofacitinib, subsequently allowing a wean off systemic corticosteroids. The final case was a 13-year-old with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) haploinsufficiency, presenting with hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenias, and lung disease, who was successfully treated with HSCT.25 As our understanding of these rare diseases expands, we are more likely to use targeted therapies and less likely to use nonspecific anti-inflammatory medications like systemic corticosteroids or other immunosuppressant agents. Plastic bronchitis (PB) is characterized by the formation of airway casts that can cause life-threatening obstruction. Typically, PB occurs in congenital heart disease patients who have undergone surgical palliation. Liptzin et al.26 described 11 patients with PB due to congenital heart disease and proposed a novel classification scheme to describe composition of airway casts based on the presence of fibrin and inflammation. Treatment suggestions provided are based on cast characterization. If fibrin is present, alteplase is recommended for treatment and heparin for prevention; with inflammation, targeted therapies such dornase alfa or steroids are recommended. Protocols for inhaled fibrinolytic and anticoagulant therapy developed at Children's Hospital Colorado are provided. Further investigations into prevention and treatment of cast formation in PB will help improve outcomes in this rare but potentially fatal condition. Dysfunctional surfactant clearance can lead to chronic pulmonary alveolar proteinosis (PAP), in which proteinaceous material accumulates in the alveoli. Whole lung lavage has been used in patients with various forms of PAP to clear the alveolar spaces, temporarily improving gas exchange.27 In a patient with heterozygous OAS1 mutation leading to hypogammaglobulinemia and PAP, whole lung lavage was successfully used starting at 2 years of age to bridge the patient to curative treatment with HSCT.28 This report emphasizes the utility of whole lung lavage as a temporizing measure, as well as the importance of establishing the underlying cause of PAP, so that definitive treatment can be employed. Finally, in a landmark paper, Deterding et al.29 reported results from the first international multicenter clinical trial for chILD. They reported results from the InPedILD trial of nintedanib in pediatric lung fibrosis, which may occur as a common end point in many forms of chILD, including surfactant dysfunction mutations, systemic sclerosis, hypersensitivity pneumonitis, and toxic pneumonitis. Investigators randomized 39 children aged 6−17 years old 2:1 to receive nintedanib or placebo in a blinded fashion for 24 weeks with subsequent open label dosing. The weight-based dosing regimen employed produced pharmacokinetics comparable to what is seen in adults. Although patients in treatment and placebo group experienced adverse events at the same rate, diarrhea and vomiting were reported more frequently in the nintedanib group. There was no difference in forced vital capacity, 6-min walk test, or quality of life measures between the groups. Although further trials are needed to determine the efficacy of nintedanib in children with fibrotic lung disease, this study produced critical dosing and safety data. Perhaps most importantly, it provided a blueprint for how to perform large-scale clinical trials in patients with chILD.
Keywords
- bronchiectasis
- congenital abnormalities
- interstitial lung disease
- primary ciliary dyskinesia
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