Cryoprobe for endoscopic enucleation in children with pulmonary tuberculosis - effective but not without danger: Case report and review of literature.

INTRODUCTION: Tuberculosis (TB) in children under 15 years often results in airway compression, with bronchus intermedius (BI) being the most common site. Endoscopic enucleations can be used to remove lymph nodes and establish an airway in severe cases. Both rigid and flexible bronchoscopy are suitable, with alligator forceps being preferred for its ability to extract tissue. Recent studies have also explored cryoprobe enucleation. CASE PRESENTATION: An HIV-positive boy with persistent symptoms after 9 months of TB treatment was diagnosed based on his mother's and sister's Xpert MTB/RIF positive status. He was started on 4-drug TB treatment, but the child remained clinically symptomatic with abnormal chest X-ray and unconfirmed TB. Bronchoscopy was performed, revealing complete obstruction of BI due to caseating granulomas causing collapse of the right middle and lower lobes. Cryotherapy was used to recanalise the airway, and follow-up bronchoscopy confirmed patent BI. CONCLUSION: While cryotherapy was effective in the restoration of airway patency in this case, there is a lack of knowledge about its use in children.

Location-specific pathology analysis of the monopodial pulmonary vasculature in a rabbit model of bronchopulmonary dysplasia-A pilot study.

The mammalian pulmonary vasculature consists of functionally and morphologically heterogeneous compartments. When comparing sets of lungs, for example, in disease models or therapeutic interventions, local changes may be masked by the overall heterogeneity of the organ structure. Therefore, alterations taking place only in a sub-compartment may not be detectable by global analysis. In the monopodial lung, the characterization of distinct vessel groups is difficult, due to the asymmetrical branching pattern. In this pilot study, a previously established method to classify segments of the monopodial pulmonary arterial tree into homogeneous groups was employed. To test its suitability for experimental settings, the method was applied to a hyperoxia (HYX, ≥95% oxygen) rabbit model of bronchopulmonary dysplasia and a normoxic control group (NOX, 21% oxygen). The method allowed the identification of morphological differences between the HYX and the NOX groups. Globally visible differences in lumen diameter were pinpointed to specific lung regions. Furthermore, local changes of wall dimension and cell layers in single compartments, that would not have been identifiable in an unfocused analysis of the whole dataset, were found. In conclusion, the described method achieves a higher precision in morphological studies of lung disease models, compared to a common, global analysis approach.

Prematurity and Hyperoxia Have Different Effects on Alveolar and Microvascular Lung Development in the Rabbit.

Bronchopulmonary dysplasia (BPD) is a developmental disorder of infants born prematurely, characterized by disrupted alveolarization and microvascular maturation. However, the sequence of alveolar and vascular alterations is currently not fully understood. Therefore, we used a rabbit model to evaluate alveolar and vascular development under preterm birth and hyperoxia, respectively. Pups were born by cesarean section 3 days before term and exposed for 7 days to hyperoxia (95% O2) or normoxia (21% O2). In addition, term-born rabbits were exposed to normoxia for 4 days. Rabbit lungs were fixed by vascular perfusion and prepared for stereological analysis. Normoxic preterm rabbits had a significantly lower number of alveoli than term rabbits. The number of septal capillaries was lower in preterm rabbits but less pronounced than the alveolar reduction. In hyperoxic preterm rabbits, the number of alveoli was similar to that in normoxic preterm animals; however, hyperoxia had a severe additional negative effect on the capillary number. In conclusion, preterm birth had a strong effect on alveolar development, and hyperoxia had a more pronounced effect on capillary development. The data provide a complex picture of the vascular hypothesis of BPD which rather seems to reflect the ambient oxygen concentration than the effect of premature birth.

'Miliary metastasis' in a child with papillary thyroid cancer.

Lung disease with diffuse nodules has a broad differential diagnosis. We present a case of childhood papillary thyroid carcinoma with diffuse lung metastases in which the diagnosis was delayed due to fact that the diffuse nodules were considered to be pathognomonic of miliary tuberculosis. Diffuse nodular lung disease in children requires a careful diagnostic approach. The role of multidisciplinary involvement in these rare cases is invaluable.

Foreign body aspiration in two young infants: The devil in the carpet.

Foreign body aspiration is rare in children below 6 months of age. Very young children presenting with stridor, atypical croup presentation, and not responding accordingly, subglottic foreign body aspiration should be considered. These may not always be visible with bedside flexible endoscopy and may need investigation under anesthesia. We report two cases of devil's thorn aspiration in young infants. These children were left on the floor to play and devils thorn may be a danger lurking as the they have been deposited unknowingly by the shoes people wear and pick up by these young infants.

Pulmonary Echinococcus in children: A descriptive study in a LMIC.

BACKGROUND: Echinococcus granulosus is a major public health problem in lower middle-income countries (LMIC). Children are commonly diagnosed with cysts in the lungs and/or the liver. OBJECTIVES: The purpose of this study was to describe a pediatric cohort diagnosed with pulmonary Cystic Echinococcus (CE) and treated with a combination of medical and surgical therapy. METHODS: This was a retrospective study performed between July 2017 and December 2020 at Tygerberg Hospital, South Africa. Clinical, laboratory, radiological, medical, and surgery-related outcomes were reviewed. RESULTS: The cohort consisted of 35 children, 17 (49%) were male, with a mean age of 9 ± 5.4 years. The most frequently encountered presenting symptom was cough (93%) followed by fever (70%). Isolated pulmonary CE accounted for the majority of cases (74%) with left lower lobe predominance. A significant proportion of the cohort exhibited chest computed tomography (CT) characteristics consistent with complicated pulmonary CE. Eighteen (58%) children had a positive indirect hemagglutination assay (IHA) test result. All children received medical treatment whilst 30 (86%) of children required surgery. Children with complicated pulmonary CE stayed a mean of 12.5 ± 6.6 days, while those with simple cysts stayed 6.8 ± 1.5 days. CONCLUSION: Isolated pulmonary CE is common in children, whereas extrapulmonary cysts are uncommon. Pulmonary CE is diagnosed using chest X-ray and, CT imaging. IHA serology has limited diagnostic utility for pulmonary CE. Combined surgery and chemotherapy remains the gold standard for treating pulmonary CE.

Ventilation and respiratory outcome in extremely preterm infants: trends in the new millennium.

Ventilation and respiratory care have substantially changed over the last decades in extremely premature neonates but the impact on respiratory health remains largely unclear. To determine changes in respiratory care and disease frequency in extremely premature infants, a retrospective single-centre cohort study of extremely preterm infants was performed. All infants born alive between 24 + 0 and 27 + 6 weeks of gestation in 2000-2001 (Epoch 1), 2009-2010 (Epoch 2), and 2018-2019 (Epoch 3) were included. The primary outcome of this study was the incidence of bronchopulmonary dysplasia (BPD, diagnosed according to three different criteria) or death. Secondary outcomes included the usage of different ventilation modes, changes in pharmacotherapy, and the incidence of significant extra-pulmonary morbidities. A total of 184 neonates were included of whom 151 survived until 36 weeks of corrected GA (cGA). Oxygen or positive pressure dependence increased over time (26.1%, 41.7%, and 56.1% respectively), with higher adjusted odds in Epoch 3 for the composite outcome "BPD or death" (adjusted odds ratio: 2.55 [95%CI 1.19-5.61]). Severity-based definitions showed increasing trends in survivors only. Time spent on invasive mechanical ventilation was similar throughout the years, but the use of non-invasive ventilation significantly increased in Epoch 3 (32.0 [95%CI 25.0-37.0] vs 27.0 [95%CI 26.0-32.0] vs 53.0 [95%CI 46.0-58.0] days). Moreover, mortality-adjusted rates of severe IVH, NEC, or intestinal perforation and multiple sepsis tended to decrease.   Conclusion: In spite of significant clinical advancements and adherence to novel treatment guidelines in our neonatal intensive care unit, the incidence of BPD increased over time. What is Known: • Rates of BPD are stable or increase in population-based studies. • Extremely preterm infants are particularly susceptible to developing BPD. What is New: • Despite increased use of evidence-based corticosteroid administration and early initiation of caffeine, the incidence of BPD has not decreased over the past decade.  • Increased usage of non-invasive ventilation is associated with an increase of BPD incidence.

Combination of µCT and light microscopy for generation-specific stereological analysis of pulmonary arterial branches: a proof-of-concept study.

Various lung diseases, including pulmonary hypertension, chronic obstructive pulmonary disease or bronchopulmonary dysplasia, are associated with structural and architectural alterations of the pulmonary vasculature. The light microscopic (LM) analysis of the blood vessels is limited by the fact that it is impossible to identify which generation of the arterial tree an arterial profile within a LM microscopic section belongs to. Therefore, we established a workflow that allows for the generation-specific quantitative (stereological) analysis of pulmonary blood vessels. A whole left rabbit lung was fixed by vascular perfusion, embedded in glycol methacrylate and imaged by micro-computed tomography (µCT). The lung was then exhaustively sectioned and 20 consecutive sections were collected every 100 µm to obtain a systematic uniform random sample of the whole lung. The digital processing involved segmentation of the arterial tree, generation analysis, registration of LM sections with the µCT data as well as registration of the segmentation and the LM images. The present study demonstrates that it is feasible to identify arterial profiles according to their generation based on a generation-specific color code. Stereological analysis for the first three arterial generations of the monopodial branching of the vasculature included volume fraction, total volume, lumen-to-wall ratio and wall thickness for each arterial generation. In conclusion, the correlative image analysis of µCT and LM-based datasets is an innovative method to assess the pulmonary vasculature quantitatively.

A Systematic Review of the Influence of Continuous Positive Airway Pressure on Fetal and Newborn Animal Models: Suggestions to Improve Neonatal Respiratory Care.

INTRODUCTION: Prematurely born infants regularly develop respiratory distress syndrome and require assisted ventilation. Ventilation may injure the premature lung and increase the risk of bronchopulmonary dysplasia. Continuous positive airway pressure (CPAP), a form of noninvasive ventilation, is commonly used in modern neonatology. Limited clinical data are available on the acute and long-term effect of neonatal exposure to CPAP on the lung. Given the restricted clinical data, newborn animal models have been used to study the influence of CPAP on lung structure and function. The findings of animal studies can guide neonatal care and improve the use of CPAP. METHODS: A systematic review of electronic databases (Medline, Embase, and Cinahl) was performed using the medical subject heading terms, "CPAP" or "continuous positive airway pressure" and "animals" and "newborn." Abstracts were screened for inclusion using predetermined eligibility criteria. RESULTS: In total, 235 abstracts were identified and screened for inclusion. Of these, 21 papers were included. Large (N = 18) and small (N = 3) animal models investigated the effects of CPAP. Pulmonary outcomes included gas exchange, lung structure and function, surfactant metabolism, lung inflammation and injury, and the effect of intrapulmonary therapy. Compared to mechanical ventilation, CPAP improves lung function, evokes less lung injury, and does not disrupt alveolar development. Surfactant administration combined with CPAP further improves respiratory outcomes. Of concern are findings that CPAP may increase airway reactivity. DISCUSSION/CONCLUSION: CPAP offers numerous advantages over mechanical ventilation for the immature lung. The combination of CPAP and exogenous surfactant administration offers further pulmonary benefit.

A semi-automated method for unbiased alveolar morphometry: Validation in a bronchopulmonary dysplasia model.

Reproducible and unbiased methods to quantify alveolar structure are important for research on many lung diseases. However, manually estimating alveolar structure through stereology is time consuming and inter-observer variability is high. The objective of this work was to develop and validate a fast, reproducible and accurate (semi-)automatic alternative. A FIJI-macro was designed that automatically segments lung images to binary masks, and counts the number of test points falling on tissue and the number of intersections of the air-tissue interface with a set of test lines. Manual selection remains necessary for the recognition of non-parenchymal tissue and alveolar exudates. Volume density of alveolar septa ([Formula: see text]) and mean linear intercept of the airspaces (Lm) as measured by the macro were compared to theoretical values for 11 artificial test images and to manually counted values for 17 lungs slides using linear regression and Bland-Altman plots. Inter-observer agreement between 3 observers, measuring 8 lungs both manually and automatically, was assessed using intraclass correlation coefficients (ICC). [Formula: see text] and Lm measured by the macro closely approached theoretical values for artificial test images (R2 of 0.9750 and 0.9573 and bias of 0.34% and 8.7%). The macro data in lungs were slightly higher for [Formula: see text] and slightly lower for Lm in comparison to manually counted values (R2 of 0.8262 and 0.8288 and bias of -6.0% and 12.1%). Visually, semi-automatic segmentation was accurate. Most importantly, manually counted [Formula: see text] and Lm had only moderate to good inter-observer agreement (ICC 0.859 and 0.643), but agreements were excellent for semi-automatically counted values (ICC 0.956 and 0.900). This semi-automatic method provides accurate and highly reproducible alveolar morphometry results. Future efforts should focus on refining methods for automatic detection of non-parenchymal tissue or exudates, and for assessment of lung structure on 3D reconstructions of lungs scanned with microCT.

Intratracheal budesonide/surfactant attenuates hyperoxia-induced lung injury in preterm rabbits.

Recent clinical trials have shown improvements in neonatal outcomes after intratracheal administration of a combination of budesonide/surfactant (ITBS) in infants at risk of bronchopulmonary dysplasia. However, the effect of ITBS on lung function and alveolar structure is not known. We aimed to determine the effect of ITBS on lung function, parenchymal structure, and inflammatory cytokine expression in a relevant preterm animal model for bronchopulmonary dysplasia. Premature neonatal rabbits were administered a single dose of ITBS on the day of delivery and exposed to 95% oxygen. Following 7 days of hyperoxia, in vivo forced oscillation and pressure-volume maneuvers were performed to examine pulmonary function. Histological and molecular analysis was performed to assess alveolar and extracellular matrix (ECM) morphology, along with gene expression of connective tissue growth factor (CTGF), IL-8, and CCL-2. ITBS attenuated the functional effect of hyperoxia-induced lung injury and limited the change to respiratory system impedance, measured using the forced oscillation technique. Treatment effects were most obvious in the small airways, with significant effects on small airway resistance and small airway reactance. In addition, ITBS mitigated the decrease in inspiratory capacity and static compliance. ITBS restricted alveolar septal thickening without altering the mean linear intercept and mitigated hyperoxia-induced remodeling of the ECM. These structural changes were associated with improved inspiratory capacity and lung compliance. Gene expression of CTGF, IL-8, and CCL-2 was significantly downregulated in the lung. Treatment with ITBS shortly after delivery attenuated the functional and structural consequences of hyperoxia-induced lung injury to day 7 of life in the preterm rabbit.

Intermittent CPAP limits hyperoxia-induced lung damage in a rabbit model of bronchopulmonary dysplasia.

A significant proportion of preterm infants develop bronchopulmonary dysplasia (BPD) leading to poor lifelong respiratory health. Limited treatment options exist with continuous positive airway pressure (CPAP) ventilation being one of the few associated with diminished BPD. However, little is known about the effect of the distending pressure of CPAP on the developing lung exposed to hyperoxia. We aimed to identify the functional and structural effects of CPAP in a preterm hyperoxia rabbit model of BPD. Premature rabbit pups were randomized to normoxia, hyperoxia (≥95% O2), or hyperoxia plus 4 h daily CPAP [fraction of inspired oxygen (FiO2) 0.95, 5 cmH2O]. On day 7 postdelivery we performed invasive pressure-volume- and forced oscillation-based pulmonary function tests, before lung harvest for histological evaluation. Alveolar and vascular morphology, airway smooth muscle content, respiratory epithelium height, extracellular matrix components, and inflammatory cytokine expression were quantified. Hyperoxia-reared pups had restrictive lungs: alveolar walls were thickened, with the lung parenchymal tissue, collagen content, and airway smooth muscle content increased. In addition, peripheral pulmonary artery wall thickness was increased. CPAP increased alveolar recruitment and limited the structural effect of hyperoxia on the respiratory epithelium and pulmonary arteries. Additionally, CPAP improved lung function, mitigating hyperoxia-associated changes to respiratory system resistance, tissue damping, and tissue elastance. Hyperoxia disrupted functional and structural lung development. Daily intermittent CPAP limited hyperoxia-associated decreased lung function and attenuated structural changes to pulmonary arteries and respiratory epithelium while having no structural alveolar consequences. The mechanism by which CPAP has these beneficial effects needs further investigation.

Preterm birth impairs postnatal lung development in the neonatal rabbit model.

BACKGROUND: Bronchopulmonary dysplasia continues to cause important respiratory morbidity throughout life, and new therapies are needed. The common denominator of all BPD cases is preterm birth, however most preclinical research in this area focusses on the effect of hyperoxia or mechanical ventilation. In this study we investigated if and how prematurity affects lung structure and function in neonatal rabbits. METHODS: Pups were delivered on either day 28 or day 31. For each gestational age a group of pups was harvested immediately after birth for lung morphometry and surfactant protein B and C quantification. All other pups were hand raised and harvested on day 4 for the term pups and day 7 for the preterm pups (same corrected age) for lung morphometry, lung function testing and qPCR. A subset of pups underwent microCT and dark field imaging on day 0, 2 and 4 for terms and on day 0, 3, 5 and 7 for preterms. RESULTS: Preterm pups assessed at birth depicted a more rudimentary lung structure (larger alveoli and thicker septations) and a lower expression of surfactant proteins in comparison to term pups. MicroCT and dark field imaging revealed delayed lung aeration in preterm pups, in comparison to term pups. Preterm birth led to smaller pups, with smaller lungs with a lower alveolar surface area on day 7/day 4. Furthermore, preterm birth affected lung function with increased tissue damping, tissue elastance and resistance and decreased dynamic compliance. Expression of vascular endothelial growth factor (VEGFA) was significantly decreased in preterm pups, however in the absence of structural vascular differences. CONCLUSIONS: Preterm birth affects lung structure and function at birth, but also has persistent effects on the developing lung. This supports the use of a preterm animal model, such as the preterm rabbit, for preclinical research on BPD. Future research that focuses on the identification of pathways that are involved in in-utero lung development and disrupted by pre-term birth, could lead to novel therapeutic strategies for BPD.

Simvastatin attenuates lung functional and vascular effects of hyperoxia in preterm rabbits.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a frequent complication following preterm birth, affecting respiratory health throughout life. Transcriptome analysis in a preterm rabbit model for BPD revealed dysregulation of key genes for inflammation, vascular growth and lung development in animals exposed to hyperoxia, which could be prevented by simvastatin. METHODS: Preterm rabbits were randomized to either normoxia (21% O2) or hyperoxia (95% O2) and within each condition to treatment with 5 mg/kg simvastatin daily or control. Lung function, structure and mRNA-expression was assessed on day 7. RESULTS: Simvastatin partially prevented the effect of hyperoxia on lung function, without altering alveolar structure or inflammation. A trend towards a less fibrotic phenotype was noted in simvastatin-treated pups, and airways were less muscularized. Most importantly, simvastatin completely prevented hyperoxia-induced arterial remodeling, in association with partial restoration of VEGFA and VEGF receptor 2 (VEGFR2) expression. Simvastatin however decreased survival in pups exposed to normoxia, but not to hyperoxia. CONCLUSION: Repurposing of simvastatin could be an advantageous therapeutic strategy for bronchopulmonary dysplasia and other developmental lung diseases with pulmonary vascular disease. The increased mortality in the treated normoxia group however limits the translational value at this dose and administration route.

Local pulmonary drug delivery in the preterm rabbit: feasibility and efficacy of daily intratracheal injections.

Recent clinical trials in newborns have successfully used surfactant as a drug carrier for an active compound, to minimize systemic exposure. To investigate the translational potential of surfactant-compound mixtures and other local therapeutics, a relevant animal model is required in which intratracheal administration for maximal local deposition is technically possible and well tolerated. Preterm rabbit pups (born at 28 days of gestation) were exposed to either hyperoxia or normoxia and randomized to receive daily intratracheal surfactant, daily intratracheal saline, or no injections for 7 days. At day 7, the overall lung function and morphology were assessed. Efficacy in terms of distribution was assessed by micro-PET-CT on both day 0 and day 7. Lung function as well as parenchymal and vascular structure were altered by hyperoxia, thereby reproducing a phenotype reminiscent of bronchopulmonary dysplasia (BPD). Neither intratracheal surfactant nor saline affected the survival or the hyperoxia-induced BPD phenotype of the pups. Using PET-CT, we demonstrate that 82.5% of the injected radioactive tracer goes and remains in the lungs, with a decrease of only 4% after 150 min. Surfactant and saline can safely and effectively be administered in spontaneously breathing preterm rabbits. The described model and method enable researchers to evaluate intratracheal pharmacological interventions for the treatment of BPD.

Modelling Bronchopulmonary Dysplasia in Animals: Arguments for the Preterm Rabbit Model.

Bronchopulmonary dysplasia (BPD) remains a frequent and disabling consequence of preterm birth, despite the recent advances in neonatal intensive care. There is a need to further improve outcomes and many novel therapeutic or preventive strategies are therefore investigated in animal models. We discuss in this review the aspects of human BPD pathophysiology and phenotype, which ideally should be mimicked by an animal model for this disease. Prematurity remains the common denominator in the heterogeneous spectrum of human BPD, and preterm animal models thus have a clear translational advantage. Additional factors, like excessive oxygen, mechanical ventilation and infection, which frequently have been studied in animal models, can contribute to preterm lung injury however are not indispensable to develop BPD. The phenotype of human BPD is characterized by alveolar developmental arrest with extracellular matrix remodeling, signs of obstructive airway disease and pulmonary vascular disease. Many animal models mimic this phenotype and have their place in BPD research, but results should be interpreted bearing in mind the specific advantages and disadvantages of the model. Term mice and rats are well suited for basic explorative research on specific disease mechanisms, essential for the generation of new hypotheses, while the larger ventilated preterm baboons and lambs provide a good platform for the ultimate translation of these strategies towards clinical application. The preterm rabbit model seems a promising model as it the smallest model that includes a factor of prematurity and has a unique position between the small and large animal models.