Recessive mutations in the ATP-binding cassette transporter A3 (ABCA3) cause lethal neonatal respiratory failure and childhood interstitial lung disease. Most ABCA3 mutations are private.
To ...determine genotype-phenotype correlations for recessive ABCA3 mutations.
We reviewed all published and unpublished ABCA3 sequence and phenotype data from our prospective genetic studies of symptomatic infants and children at Washington and Johns Hopkins Universities. Mutations were classified based on their predicted disruption of protein function: frameshift and nonsense mutations were classified as "null," whereas missense, predicted splice site mutations, and insertion/deletions were classified as "other." We compared age of presentation and outcomes for the three genotypes: null/null, null/other, and other/other.
We identified 185 infants and children with homozygous or compound heterozygous ABCA3 mutations and lung disease. All of the null/null infants presented with respiratory failure at birth compared with 75% of infants with null/other or other/other genotypes (P = 0.00011). By 1 year of age, all of the null/null infants had died or undergone lung transplantation compared with 62% of the null/other and other/other children (P < 0.0001).
Genotype-phenotype correlations exist for homozygous or compound heterozygous mutations in ABCA3. Frameshift or nonsense ABCA3 mutations are predictive of neonatal presentation and poor outcome, whereas missense, splice site, and insertion/deletions are less reliably associated with age of presentation and prognosis. Counseling and clinical decision making should acknowledge these correlations.
A 12‐year‐old male was admitted to the Medical Intensive Care Unit for respiratory failure requiring temporary tracheostomy secondary to an extensive necrotizing methicillin‐resistant Staphylococcus ...aureus pneumonia. Imaging revealed destructive bronchiectasis and multifocal lung abscesses, more advanced in the right lung. He was discharged home after 42‐day hospital admission. 3.5 months after his discharge, he re‐presented to the Emergency Department with a large right pneumothorax and a pneumatocele measuring 10.2 × 6.2 cm2. He was admitted to the hospital and while his pneumothorax resolved in 2 days, the size of the pneumatocele was noted to fluctuate with different phases of respiration. A computed tomography scan of the chest demonstrated a fistula between the pneumatocele and right upper lobe bronchus. Following discussion between Pulmonary medicine and Interventional radiology, transbronchial closure of the air leak was planned. Intubation was done with a dual‐lumen endotracheal tube. Bronchography was performed using a diagnostic catheter. A large air leak was noted from the anterior segment of the right upper lobe bronchus. Embolization of the fistula was performed using n‐butyl cyanoacrylate (nBCA, glue) injected through a second catheter under fluoroscopic guidance. The residual pneumatocele slowly resolved over 2 months. Endobronchial embolization has been described in the literature as a treatment strategy for air leaks, largely in adult patients. Endobronchial embolization of large pneumatoceles and bronchopleural fistulas may offer an alternative treatment option with less morbidity than the classic surgical approach.
ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control ...by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.
Aim
Pulmonary hemorrhage in infancy is rare, with challenges in determining its incidence, causes, and outcomes across diverse groups. Our aim was to better understand the incidence and identified ...causes. We further analyzed the subgroup of patients meeting criteria for acute idiopathic pulmonary hemorrhage of infancy (AIPHI) to determine recurrence, mortality, and treatment.
Methods
We performed a 10‐year retrospective cohort study of infants with pulmonary hemorrhage in a large tertiary care center. One‐hundred fifty‐seven patients overall were identified.
Results
The most common diagnoses in infants with pulmonary hemorrhage were congenital heart disease (36.6%), prematurity/premature lung disease (34.6%), congenital or acquired lung disorders (15.0%), and congenital or acquired coagulopathies (13.7%). Nonaccidental trauma (NAT; n = 3) was also an important cause of pulmonary hemorrhage. All patients diagnosed with NAT had normal retinal examinations and skeletal surveys. Only four patients were identified with AIPHI. There was no mortality in this group of infants. One of four patients with AIPHI had a recurrence. Steroids were the consistent treatment for AIPHI, with a large range of treatment duration.
Conclusion
Diagnostic studies should focus on identifying non‐pulmonary sources of bleeding, infection, underlying lung disease, congenital heart defects, coagulopathies, infection, and NAT, as these were the most frequently identified causes of bleeding. NAT is not adequately identified with ophthalmology exam and skeletal survey. Overall, we found AIPHI to be a rare diagnosis. All of the patients with idiopathic hemorrhage received systemic steroids with varying doses and lengths of treatment.
To describe the etiologies of hemoptysis in patients without pre-existing bronchiectasis or cardiac disease; to assess odds of recurrent hemoptysis by diagnostic category; and to assess odds of ...mortality by diagnostic category.
This retrospective case series included all patients with hemoptysis documented during an admission to Boston Children's Hospital from January 1, 2007 to June 1, 2017. Patients with bronchiectasis, congenital heart disease, primary pulmonary hypertension, bleeding above the glottis, hemoptysis before 38 weeks of corrected gestational age, hematemesis, foreign body, and trauma were excluded. Patients were also characterized by coagulation status. Primary outcomes were recurrent hemoptysis and death. Univariate analysis was performed to determine ORs for recurrence and death per diagnostic category with infection as the reference category.
In total, 257 patients met study criteria and were analyzed. The most common causes of hemoptysis were infection (n = 122), neoplasm (n = 58), and other diagnoses (n = 49). Of the patients with infection, recurrence was 28% and all-cause mortality was 12%. Neoplasm had lower odds of recurrence (OR 0.3, P = .012) but higher odds of mortality (OR 15.8, P < .001). Thrombocytopenia had lower odds of recurrence (OR 0.2, P = .005) but higher odds of mortality (OR 5.9, P < .001). Patients with a tracheostomy had higher odds of recurrence (OR 6.3, P < .001), but lower odds of death (OR 0.4, P = .042).
This study confirms that infection is the most common cause of hemoptysis in patients without severe underlying pulmonary or cardiac disease. Hemoptysis associated with neoplasm and/or thrombocytopenia confers mortality risk. Tracheostomy confers risk of recurrence. Future prospective research on diagnoses associated with hemoptysis is warranted.
A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting ...at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.
Although interleukin-1 (IL-1)/IL-6 inhibitors are effective therapies for systemic juvenile idiopathic arthritis (JIA), some patients develop eosinophilia and lung disease during treatment. This ...study was undertaken to retrospectively evaluate incidence and risk factors for eosinophilia and describe lung disease outcomes in IL-1/IL-6 inhibitor-exposed patients with systemic JIA.
Among JIA patients at our institution exposed to interleukin-1 (IL-1)/IL-6 inhibitors (1995-2022), we compared incidence rate of eosinophilia in systemic JIA compared to other JIA, stratified by medication class (IL-1/IL-6 inhibitors, other cytokine inhibitors, methotrexate). We used Cox models to identify predictors of eosinophilia during IL-1/IL-6 inhibitor use and summarized treatment changes and outcomes after eosinophilia, including lung disease. HLA typing was performed on a clinical or research basis.
There were 264 new medication exposures in 75 patients with systemic JIA and 41 patients with other JIA. A total of 49% of patients with systemic JIA with HLA typing (n = 45) were positive for HLA-DRB1*15 alleles. Eosinophilia was common during IL-1/IL-6 inhibitor use and did not differ by systemic JIA compared to other JIA (0.08 and 0.07 per person-year, respectively; P = 0.30). Among systemic JIA patients, pretreatment macrophage activation syndrome (MAS) was associated with a higher rate of subsequent eosinophilia on biologic therapy (unadjusted hazard ratio 3.2 95% confidence interval 1.2-8.3). A total of 4 of 5 patients who switched therapy within 10 weeks of eosinophilia experienced disease flare compared to none of the patients who continued the original therapy. A total of 8 of 25 patients with pulmonary evaluations had lung disease, and all had severe manifestations of systemic JIA (MAS, intensive care unit stay). One death was attributed to systemic JIA-lung disease.
Eosinophilia is common in JIA patients using IL-1/IL-6 inhibitors. Severe disease may be associated with eosinophilia and lung disease in systemic JIA.
Children's interstitial and diffuse lung diseases are a diverse group of rare lung disorders that present in childhood with diffuse pulmonary infiltrates and respiratory signs and symptoms. Children ...with these disorders face high morbidity and mortality and their families must cope with overwhelming uncertainty. Physicians caring for these patients are challenged by a paucity of directed therapies, or even understanding of natural history. Through the establishment of the Children's Interstitial Lung Disease Foundation Research Network and the Children's Interstitial Lung Disease Foundation significant progress has been made through collaboration and research. This review outlines the past and current successes in the new and rapidly growing field of Children's Interstitial and Diffuse Lung Disease.
Neuroendocrine cell hyperplasia of infancy (NEHI) is an important form of children's interstitial and diffuse lung disease for which the diagnostic strategy has evolved. The prevalence of ...comorbidities in NEHI that may influence treatment has not been previously assessed.
To evaluate a previously unpublished NEHI clinical score for assistance in diagnosis of NEHI and to assess comorbidities in NEHI.
We performed a retrospective chart review of 199 deidentified patients with NEHI from 11 centers. Data were collected in a centralized Research Electronic Data Capture registry and we performed descriptive statistics.
The majority of patients with NEHI were male (66%). The sensitivity of the NEHI Clinical Score was 87% (95% confidence interval CI, 0.82-0.91) for all patients from included centers and 93% (95% CI, 0.86-0.97) for those with complete scores (e.g., no missing data). Findings were similar when we limited the population to the 75 patients diagnosed by lung biopsy (87%; 95% CI, 0.77-0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35% had aspiration or were at risk for aspiration, and 17% had evidence of immune system abnormalities.
The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however, its specificity has not yet been addressed. Clinicians should consider evaluating patients with NEHI for comorbidities, including gastroesophageal reflux, aspiration, and immune system abnormalities, because these can contribute to the child's clinical picture and may influence clinical course and treatment.
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