Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children.

BACKGROUND: Mutations in the T-Box 4 (TBX4) gene are a lesser-known cause of heritable pulmonary arterial hypertension (PAH). Patients with heritable PAH typically have worse outcomes when compared with patients with idiopathic PAH, yet little is known about the phenotypical presentation of this mutation. OBJECTIVE: This article reviews the pattern of chest CT findings in pediatric patients with PAH and TBX4 mutations and compares their radiographic presentation with those of age-matched patients with PAH but without TBX4 mutations. MATERIALS AND METHODS: A retrospective chart review of the pulmonary arterial hypertension database was performed. Pediatric patients with PAH-confirmed TBX4 mutations and an available high CT were included. Fifteen (9 females) patients met the inclusion criteria. Fourteen (8 females) age-matched controls with diagnosed PAH but without TBX4 mutations were also evaluated. The median age at diagnosis was 7.4 years (range: 0.1-16.4 years). Demographic information and clinical outcomes were collected. CTs of the chest were reviewed for multiple airway, parenchymal, and structural abnormalities (16 imaging findings in total). Chi-square tests were used to compare the prevalence of each imaging finding in the TBX4 cohort compared to the control group. RESULTS: Patients with TBX-4 mutations had increased presence of peripheral or subpleural irregularity (73% vs 0%, P < 0.01), cystic lucencies (67% vs 7%, P < 0.01), and linear or reticular opacity (53% vs 0%, P < 0.01) compared to the control group. Ground glass opacities, bronchiectasis, and centrilobular nodules were not significantly different between the two patient groups (P > 0.05). CONCLUSION: TBX4 mutations have distinct imaging phenotypes in pediatric patients with PAH. Compared to patients without this mutation, patients with TBX-4 genes typically present with peripheral or subpleural irregularity, cystic lucencies, and linear or reticular opacity.

Imaging of pulmonary fibrosis in children: A review, with proposed diagnostic criteria.

Computed tomography (CT) imaging findings of pulmonary fibrosis are well established for adults and have been shown to correlate with prognosis and outcome. Recognition of fibrotic CT findings in children is more limited. With approved treatments for adult pulmonary fibrosis, it has become critical to define CT criteria for fibrosis in children, to identify patients in need of treatment and those eligible for clinical trials. Understanding how pediatric fibrosis compares with idiopathic pulmonary fibrosis and other causes of fibrosis in adults is increasingly important as these patients transition to adult care teams. Here, we review what is known regarding the features of pulmonary fibrosis in children compared with adults. Pulmonary fibrosis in children may be associated with genetic surfactant dysfunction disorders, autoimmune systemic disorders, and complications after radiation, chemotherapy, transplantation, and other exposures. Rather than a basal-predominant usual interstitial pneumonia pattern with honeycombing, pediatric fibrosis is primarily characterized by reticulation, traction bronchiectasis, architectural distortion, or cystic lucencies/abnormalities. Ground-glass opacities are more frequent in children with fibrotic interstitial lung disease than adults, and disease distribution appears more diffuse, without clearly defined axial or craniocaudal predominance. Following discussion and consensus amongst a panel of expert radiologists, pathologists and physicians, distinctive disease features were integrated to develop criteria for the first global Phase III trial in children with pulmonary fibrosis.

Radiation dose reduction using spectral shaping in pediatric non-contrast sinus CT.

BACKGROUND: CT is the standard imaging technique to evaluate pediatric sinuses. Given the potential risks of radiation exposure in children, it is important to reduce pediatric CT dose and maintain image quality. OBJECTIVE: To study the utility of spectral shaping with tin filtration to improve dose efficiency for pediatric sinus CT exams. MATERIALS AND METHODS: A head phantom was scanned on a commercial dual-source CT using a conventional protocol (120 kV) and a proposed 100 kV with a 0.4-mm tin filter (Sn100 kV) protocol for comparison. Entrance point dose (EPD) of eye and parotid gland region was measured by an ion chamber. Sixty pediatric sinus CT exams (33 acquired with 120 kV, 27 acquired with Sn100 kV) were retrospectively collected. All patient images were objectively measured for image quality and blindly reviewed by 4 pediatric neuroradiologists for overall noise, overall diagnostic quality, and delineation of 4 critical paranasal sinus structures, using a 5-point Likert scale. RESULTS: Phantom CTDIvol from Sn100 kV is 4.35 mGy, compared to CTDIvol of 5.73 mGy from 120 kV at an identical noise level. EPD of sensitive organs decreases in Sn100 kV (e.g., right eye EPD 3.83±0.42 mGy), compared to 120 kV (5.26±0.24 mGy). Patients in the 2 protocol groups were age and weight (unpaired T test P>0.05) matched. The patient CTDIvol of Sn100 kV (4.45±0.47 mGy) is significantly lower than 120 kV (5.56±0.48 mGy, unpaired T test P<0.001). No statistically significant difference for any subjective readers' score (Wilcoxon test P>0.05) was found between the two groups, indicating proposed spectral shaping provides equivalent diagnostic image quality. CONCLUSION: Phantom and patient results demonstrate that spectral shaping can significantly reduce radiation dose for non-contrast pediatric sinus CT without compromising diagnostic quality.

Computed tomographic parenchymal lung findings in premature infants with pulmonary vein stenosis.

BACKGROUND: Developmental pulmonary vein pulmonary vein stenosis in the setting of prematurity is a rare and poorly understood condition. Diagnosis can be challenging in the setting of chronic lung disease of prematurity. High-resolution non-contrast chest computed tomography (CT) is the conventional method of evaluating neonates for potential structural changes contributing to severe lung dysfunction and pulmonary hypertension but may miss pulmonary venous stenosis due to the absence of contrast and potential overlap in findings between developmental pulmonary vein pulmonary vein stenosis and lung disease of prematurity. OBJECTIVE: To describe the parenchymal changes of pediatric patients with both prematurity and pulmonary vein stenosis, correlate them with venous disease and to describe the phenotypes associated with this disease. MATERIALS AND METHODS: A 5-year retrospective review of chest CT angiography (CTA) imaging in patients with catheterization-confirmed pulmonary vein stenosis was performed to identify pediatric patients (< 18 years) who had a history of prematurity (< 35 weeks gestation). Demographic and clinical data associated with each patient were collected, and the patients' CTAs were re-reviewed to evaluate pulmonary veins and parenchyma. Patients with post-operative pulmonary vein stenosis and those with congenital heart disease were excluded. Data was analyzed and correlated for descriptive purposes. RESULTS: A total of 17 patients met the inclusion criteria (12 female, 5 male). All had pulmonary hypertension. There was no correlation between mild, moderate, and severe grades of bronchopulmonary dysplasia and the degree of pulmonary vein stenosis. There was a median of 2 (range 1-4) diseased pulmonary veins per patient. In total, 41% of the diseased pulmonary veins were atretic. The right upper and left upper lobe pulmonary veins were the most frequently diseased (n = 13/17, 35%, n = 10/17, 27%, respectively). Focal ground glass opacification, interlobular septal thickening, and hilar soft tissue enlargement were always associated with the atresia of an ipsilateral vein. CONCLUSION: Recognition of the focal parenchymal changes that imply pulmonary vein stenosis, rather than chronic lung disease of prematurity changes, may improve the detection of a potentially treatable source of pulmonary hypertension, particularly where nonangiographic studies result in a limited direct venous assessment.

Unexpected extracardiac findings in cardiac computed tomography from neonates to young adults.

BACKGROUND: Modern CT scanners with lower radiation doses have resulted in large numbers of cardiac CTs being performed in children. As seen in adults, pediatric cardiac CT has the potential to demonstrate extracardiac variants and pathology that can occur in conjunction with congenital heart disease (CHD). Prior publications demonstrated a high incidence of extracardiac findings in various locations but the prevalence of urgent unexpected extracardiac findings in children is unknown. OBJECTIVE: The purpose of this study was to describe the incidence, distribution and clinical significance of the extracardiac findings on pediatric cardiac CT at a tertiary referral center. MATERIALS AND METHODS: We reviewed all reports (n = 648) for 554 children through young adults who received a cardiac CT study between Jan. 2, 2018, and March 10, 2020, at our tertiary referral pediatric hospital. We interrogated CT reports for extracardiac findings and categorized them by system (airway, pulmonary, abdomen, malpositioned lines and musculoskeletal). We then subclassified each of these findings by level of clinical importance based upon the need for intervention or treatment into low, medium or high importance. High-importance findings were confirmed with a focused chart review. If a patient had more than one CT with a persistent extracardiac finding, the finding was only counted once. RESULTS: We identified 562 individual extracardiac findings, with one or more extracardiac findings present in 91% of the study population. Extracardiac findings with high clinical importance, requiring urgent attention or intervention, were present in 10% (57/554) of cases. The most common location of extracardiac findings was pulmonary (50%; 280/562), followed by airway (22%; 125/562) and abdomen (9%; 52/562). CONCLUSION: Unexpected highly important extracardiac findings were found in 10% of patients. Therefore, extracardiac structures should be scrutinized for the timely identification of potentially highly important findings.

Early Anti-Tumor-Necrosis-Factor Therapy for Crohn's Disease-Related Abdominal Abscesses and Phlegmon in Children.

BACKGROUND: Internally penetrating Crohn's Disease complications, including abscesses and phlegmon, represent a high-risk Crohn's Disease phenotype. Anti-tumor-necrosis-factor-α (Anti-TNF) therapies are effective in treating penetrating Crohn's Disease and early initiation has shown unique benefits. However, timing of anti-TNF initiation in the setting of internally penetrating Crohn's Disease complications is typically heterogenous due to concern over precipitating serious infections. Recent studies demonstrate such an association may not exist. AIMS: We aimed to describe the multidisciplinary management of pediatric patients with internally penetrating Crohn's Disease complications, focusing on the utilization and timing of anti-TNF therapy relative to complication resolution and adverse events. METHODS: We performed a single-center retrospective cohort study of pediatric patients with internally penetrating Crohn's Disease complications from 2007 to 2021. The safety and effectiveness of anti-TNF therapy initiation prior to complication resolution was assessed by comparing rates of infectious and Crohn's Disease-related adverse events between those who received anti-TNF therapy prior to complication resolution, versus those who did not. RESULTS: Twenty-one patients with internally penetrating Crohn's Disease complications were identified. 7/21 received anti-TNF therapy prior to complication resolution. Infectious adverse events within 90 days of complication occurred in 0/7 patients initiating anti-TNF therapy prior to complication resolution and 10/14 patients who did not (p = 0.004). Crohn's Disease-related surgeries and hospitalizations within 1 year of complication occurred in 12/20 patients, with similar frequency between groups. CONCLUSIONS: Initiating anti-TNF therapy prior to internally penetrating Crohn's Disease complication resolution may be a safe and effective strategy to improve clinical outcomes.

Computed Tomographic Angiography Provides Reliable Coronary Artery Evaluation in Infants With Pulmonary Atresia Intact Ventricular Septum.

Evaluate the use of coronary CTA as an initial assessment for determining Right Ventricle Dependent Coronary Circulation (RVDCC) in neonates with Pulmonary Atresia with Intact Ventricular Septum (PA IVS). Retrospective review of cases with coronary CTA and compare with available catheter angiography, pathology, surgical reports, and outcomes from Mar 2015 to May 2022. In our cohort of 16 patients, 3 were positive for RVDCC, confirmed by pathologic evaluation, and there was concordance for presence or absence of RVDCC with catheter angiography in 5 patients (4 negatives for RVDCC, 1 positive). Clinical follow up for the 8 patients that underwent RV decompression had no clinical evidence of myocardial ischemia. Our findings suggest that coronary CTA is reliable as first-line imaging for determination of RVDCC in neonates with PA IVS. These findings, if supported by further prospective study, may reserve invasive coronary angiography for cases with diagnostic uncertainty or at the time of necessary transcatheter interventions.

Computed tomography evaluation of pediatric pulmonary hypertension.

Although rare in the pediatric population, pulmonary hypertension is a significant cause of morbidity and mortality in affected individuals. In addition to evaluating potential causes and severity of parenchymal lung diseases, non-contrast high-resolution CT of the chest can aid in the diagnosis of heritable and acquired causes. In addition to evaluating parenchymal lung disease, CT angiography can help to confirm findings of pulmonary hypertension using criteria similar to echocardiography, and provide detailed assessment of the pulmonary vascularity in specific causes.

Chest computed tomography findings of ground-glass nodules with enhancing central vessel/nodule in pediatric patients with BMPR2 mutations and plexogenic arteriopathy.

BACKGROUND: Germline mutation in bone morphogenetic protein type II (BMPR2) is the most common cause of idiopathic/heritable pulmonary hypertension in pediatric patients. Despite the discovery of this gene there are no known descriptions of the CT or CT angiography findings in these children. OBJECTIVE: To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene. MATERIALS AND METHODS: We performed a search to identify pediatric patients with a BMPR2 mutation and CT or CT angiography with the clinical history of pulmonary hypertension. Three pediatric radiologists reviewed the children's CT imaging findings and ranked the dominant findings in order of prevalence via consensus. RESULTS: We identified three children with pulmonary hypertension and confirmed germline BMPR2 mutations, two of whom had undergone lung biopsy. We then correlated the imaging findings with histopathology and clinical course. CONCLUSION: All of our patients with BMPR2 mutations demonstrated a distinct CT pattern of ground-glass nodules with a prominent central enhancing vessel/nodule. These findings correlated well with the pathological findings of plexogenic arteriopathy.

High-Altitude Pulmonary Edema in Colorado Children: A Cross-Sectional Survey and Retrospective Review.

Kelly, Timothy D., Maxene Meier, Jason P. Weinman, Dunbar Ivy, John T. Brinton, and Deborah R. Liptzin. High-altitude pulmonary edema in Colorado children: a cross-sectional survey and retrospective review. High Alt Med Biol. 23:119-124, 2022. Introduction: Few studies of high-altitude pulmonary edema (HAPE) are specific to the pediatric population. The purpose of this investigation was to further characterize the radiographic patterns of pediatric HAPE, and to better understand ongoing risk following an initial pediatric HAPE episode. Methods: This study uses both a retrospective chart review and cross-sectional survey. Pediatric patients with HAPE at a single quaternary referral center in the Rocky Mountain Region were identified between the years 2013 and 2020. Patients were eligible if they presented with a clinical diagnosis of HAPE and had a viewable chest radiograph (CXR). Surveys were sent to eligible patients/families to gather additional information relating to family history, puberty, and HAPE recurrence. Results: Forty-two individuals met criteria for clinical diagnosis of HAPE with a viewable CXR. A majority of CXRs (24/42, 57.1%) demonstrated predominant right-sided involvement. Similarly, 24 CXRs (24/42, 57.1%) demonstrated predominant upper lobe involvement. Twenty-one (21/42, 50%) surveys were completed. A minority of individuals went on to experience at least one other HAPE episode (8/19, 42.1%). Conclusion: The most common radiographic pattern seen in pediatric HAPE is pulmonary edema that favors the right lung and upper lobes. After an initial HAPE presentation, some children will experience additional HAPE episodes.

Women, men and COVID-19.

BACKGROUND: There is often gender bias in access and provision of care. Women fall through the cracks of the healthcare system due to gender-biased norms and poorer socioeconomic status. METHODS: This study uses COVID-19 sex-disaggregated data from 133 countries. Using bootstrapping and imputation methods and heteroscedastic linear regression model, it investigates the effect of biological factors and gender norms on reported differences in male and female COVID-19 case and death rates. RESULTS: Gender norms are significant factors explaining such differences. Countries, where women experience more discrimination in families and have less access to resources, education and finance, report larger differences between male and female rates of COVID-19 cases and deaths. CONCLUSION: Women's lower access to healthcare due to social norms, financial and non-financial barriers may affect women's testing for COVID-19 and access to adequate care, and result in underreported female cases and deaths from COVID-19.

Vaping and diffuse alveolar hemorrhage: All EVALI is not created equal.

E-cigarette, or vaping product, use associated lung injury (EVALI) refers to respiratory illness in patients with recent vaping and no signs of infection or underlying illness. EVALI can cause severe acute respiratory distress syndrome and death. A spectrum of diagnoses can fit the description of EVALI since it relies heavily on nonspecific, radiographic findings. We present a rare case of EVALI in which a patient with a history of vaping presented with acute hypoxemia and was diagnosed with diffuse alveolar hemorrhage (DAH). The mechanism of injury of DAH due to vaping is unknown, and further research into the topic is required.

Diffuse alveolar hemorrhage in children with trisomy 21.

BACKGROUND: Respiratory conditions are the leading cause of hospitalization and death in children with Trisomy 21 (T21). Diffuse alveolar hemorrhage (DAH) occurs at higher frequency in children with T21; yet, it is not widely studied nor is there a standardized approach to diagnosis or management. The objective of this study was to identify children with T21 and DAH in order to understand contributing factors and identify opportunities to improve outcomes. We identified 5 children with T21 at a single institution with histology-proven DAH over 10 years and discuss their presentation, evaluation, management, and outcomes. We also reviewed the cases in the literature. CASE PRESENTATION: Patient 1 died at age seven due to secondary hemophagocytic lymphohistiocytosis. DAH was seen on autopsy. Patient 2 was a three-year-old with systemic-onset juvenile idiopathic arthritis diagnosed with DAH after presenting for hypoxia. Patient 3 was diagnosed with DAH at age nine after presenting with recurrent suspected pneumonia and aspiration. Patient 4 was diagnosed with DAH at age eight after presenting with pallor and fatigue. She had additional ICU admissions for DAH with infections. Patient 5 developed hemoptysis at age three and had recurrent DAH for 10 years. Four patients responded positively to immune-modulation such as intravenous immunoglobulin, glucocorticoids, and rituximab. Of the 19 patients identified in the literature, only one was from the United States. The majority had anemia, respiratory distress, autoantibodies, and recurrences. Very few patients had hemoptysis. Idiopathic pulmonary hemosiderosis was the most common diagnosis. Almost all received glucocorticoids with or without additional immunosuppression. The majority of our patients and those in the literature had positive auto-antibodies such as anti-neutrophil cytoplasmic antibodies and anti-nuclear antigen antibodies. Diagnostic clues included respiratory distress, hypoxia, anemia, recurrent pneumonia, and/or ground glass opacities on imaging. We identified four contributors to DAH: structural lung abnormalities, pulmonary arterial hypertension, infection/aspiration, and autoimmune disease/immune dysregulation. CONCLUSION: These cases demonstrate the need for an increased index of suspicion for DAH in children with T21, particularly given the low frequency of hemoptysis at presentation, enrich the understanding of risk factors, and highlight the favorable response to immunosuppressive therapies in this vulnerable population.

Stevens-Johnson Syndrome in Children: Consider Monitoring for Bronchiolitis Obliterans.

We reviewed patients with Stevens-Johnson syndrome (SJS) evaluated at Children's Hospital Colorado and investigated the occurrence of bronchiolitis obliterans (BO). Approximately 9% of patients with SJS developed BO. Pediatricians should consider monitoring patients with SJS for BO, especially those with recurrent SJS and patients treated with mechanical ventilation.

Ground glass and fibrotic change in children with surfactant protein C dysfunction mutations.

INTRODUCTION: Therapeutics exist to treat fibrotic lung disease in adults, but these have not been investigated in children. Defining biomarkers for pediatric fibrotic lung disease in children is crucial for clinical trials. Children with surfactant protein C (SFTPC) dysfunction mutations develop fibrotic lung disease over time. We evaluated chest computed tomography (CT) changes over time in children with SFTPC dysfunction mutations. METHODS: We performed an institutional review board-approved retrospective review of children with SFTPC dysfunction mutations. We collected demographic and clinical information. Chest CT scans were evaluated using visual and computerized scores. Chest CT scores and pulmonary function tests were reviewed. RESULTS: Eleven children were included. All children presented in infancy and four children suffered from respiratory failure requiring mechanical ventilation. Those who performed pulmonary function tests had stable forced vital capacities over time by percent predicted, but increased forced vital capacity in liters. CT findings evolved over time in most patients with earlier CT scans demonstrating ground glass opacities and later CT scans with more fibrotic features. In a pilot analysis, data-driven textural analysis software identified fibrotic features in children with SFTPC dysfunction that increased over time and correlated with visual CT scores. DISCUSSION: We describe 11 children with SFTPC dysfunction mutations. Increases in forced vital capacity over time suggest that these children experience lung growth and that therapeutic intervention may maximize lung growth. Ground glass opacities are the primary early imaging findings while fibrotic features dominate later. CT findings suggest the development of and increases in fibrotic features that may serve as potential biomarkers for antifibrotic therapeutic trials.