Pediatric interventional bronchoscopy: from early limitations to achievable opportunities.

PURPOSE OF REVIEW: The rapid evolution of bronchoscopy equipment and technologies, from the introduction of the 1.1 mm flexible cryoprobe to the use of navigational and robotic bronchoscopy, has afforded unprecedented opportunities for pediatric advanced diagnostic and interventional bronchoscopy. While there is growing interest among pediatric pulmonologists to incorporate these new techniques into their practice, the current pediatric landscape is characterized by few practicing interventional bronchoscopists, scant published literature, and no formal training programs. RECENT FINDINGS: While the majority of the published literature consists of case reports and small case series, the increased application of new techniques is starting to yield larger and more structured studies that will be able to provide more objective commentary on the proposed indications, safety, and efficacy of such techniques in the pediatric population. SUMMARY: For many decades, progress in pediatric advanced diagnostic and interventional bronchoscopy was slow and deliberate, limited by the lack of appropriately sized equipment and experienced interventional bronchoscopists. The current opportunities afforded require equal, or perhaps even more, vigilance as pediatric pulmonologists employ new equipment and technologies and define new practices and standards of care. Importantly, this review is meant to serve as a general conspectus of pediatric advanced diagnostic and interventional bronchoscopy and not a consensus guideline for the performance of advanced or even routine bronchoscopy in the pediatric population. For technical standards of pediatric bronchoscopy, refer to existing guidelines [1,2] .

Methylxanthine inhibit fungal chitinases and exhibit antifungal activity.

Chitinases are necessary for fungal cell wall remodeling and cell replication. Methylxanthines have been shown to competitively inhibit family 18 chitinases in vitro. We sought to determine the effects of methylxanthines on fungal chitinases. Fungi demonstrated variable chitinase activity and incubation with methylxanthines (0.5-10 mM) resulted in a dose-dependent decrease in this activity. All fungi tested, except for Candida spp., demonstrated growth inhibition in the presence of methylxanthines at a concentration of 10 mM. India ink staining demonstrated impaired budding and decreased cell size for methylxanthine-treated Cryptococcus neoformans. C. neoformans and Aspergillus fumigatus treated with pentoxifylline also exhibited abnormal cell morphology. In addition, pentoxifylline-treated C. neoformans exhibited increased susceptibility to calcofluor and a leaky melanin phenotype consistent with defective cell wall function. Our data suggest that a variety of fungi express chitinases and that methylxanthines have antifungal properties related to their inhibition of fungal chitinases. Our results highlight the potential utility of targeting chitinases in the development of novel antifungal therapies.

Foreign body aspiration in a child with unilateral lung aplasia.

OBJECTIVE: To present a case of foreign body aspiration in a child with unilateral lung aplasia and successful removal of the foreign body by bedside flexible bronchoscopy. DATA SOURCE: Case details were obtained from medical records. STUDY SELECTION: Eighteen-month-old girl with unilateral lung aplasia. DATA EXTRACTION AND SYNTHESIS: Demographic details (age) and clinical and biochemical data (blood gas) were obtained from medical records. An 18-mo-old girl with the diagnosis of right lung aplasia, who underwent aortopexy in the newborn period for severe respiratory distress, presented with acute-onset respiratory distress. The patient was treated with bronchodilators and steroids without success and rapidly progressed to respiratory failure. Flexible bronchoscopy done at the bedside showed a foreign body completely obstructing the left main bronchus. The rigid bronchoscopy was unsuccessful in extracting the foreign body because of the complex airway anatomy. The foreign body was successfully extracted by basket forceps via a flexible bronchoscope, and the patient recovered remarkably within few hours of the procedure. CONCLUSIONS: Because foreign body aspiration in a child with a unilateral lung can result in abrupt respiratory compromise and death, a high index of suspicion is necessary when these children present with acute respiratory symptoms. Although rigid bronchoscopy is the procedure of choice for the removal of foreign bodies, flexible bronchoscopy may be necessary for patients with abnormal airway anatomy.

Susceptibility to bronchiolitis in infants.

PURPOSE OF REVIEW: Bronchiolitis is a complex disease that exhibits tremendous heterogeneity with respect to cause, clinical presentation, outcome and susceptibility of afflicted patients. Although respiratory syncytial virus (RSV) is widely considered to be the most important cause of bronchiolitis in children, little is known about the mechanisms of susceptibility to severe infection. RECENT FINDINGS: Over the last several years, there have been important advances in our understanding of RSV bronchiolitis, ranging from large-scale epidemiologic observations to novel in-vitro discoveries, including those related to environmental and host risk factors. In addition, new investigative techniques have been developed, which may enhance our understanding about the interaction between RSV and the pediatric airway. SUMMARY: RSV remains the most frequently encountered cause of bronchiolitis and contributes to significant morbidity and mortality worldwide. The investigations highlighted in this review may serve as foundations for future mechanistic studies, the implementation of new preventive strategies and the discovery of novel treatments.

Bronchoscopy in severe childhood asthma: Irresponsible or irreplaceable?

For children with severe asthma, guideline-based management focuses on the escalation of anti-inflammatory and bronchodilatory medications while addressing comorbid conditions. Bronchoscopy, in this context, has been relegated to ruling out asthma mimickers. More recently, however, there have been questions surrounding the clinical utility of bronchoscopy in severe childhood asthma. In this solicited lecture summary, we discuss the past, present, and potential future applications of bronchoscopy in severe childhood asthma.

Pulmonary cryptococcosis induces chitinase in the rat.

BACKGROUND: We previously demonstrated that chronic pulmonary infection with Cryptococcus neoformans results in enhanced allergic inflammation and airway hyperreactivity in a rat model. Because the cell wall of C. neoformans consists of chitin, and since acidic mammalian chitinase (AMCase) has recently been implicated as a novel mediator of asthma, we sought to determine whether such infection induces chitinase activity and expression of AMCase in the rat. METHODS: We utilized a previously-established model of chronic C. neoformans pulmonary infection in the rat to analyze the activity, expression and localization of AMCase. RESULTS: Our studies indicate that intratracheal inoculation of C. neoformans induces chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats. Chitinase activity is also elicited by pulmonary infection with other fungi (e.g. C. albicans), but not by the inoculation of dead organisms. Enhanced chitinase activity reflects increased AMCase expression by airway epithelial cells and alveolar macrophages. Systemic cryptococcosis is not associated with increased pulmonary chitinase activity or AMCase expression. CONCLUSION: Our findings indicate a possible link between respiratory fungal infections, including C. neoformans, and asthma through the induction of AMCase.

Flexible bronchoscopy and interdisciplinary collaboration in pediatric large airway disease.

OBJECTIVE: Demonstrate the benefits of a multidisciplinary pediatric airway team prepared to evaluate and treat otolaryngology patients with flexible bronchoscopy. DESIGN: Case series. SETTING: Tertiary, academic children's hospital. PATIENTS: 10 children (5 male, 5 female age range 2 months-16 years) presenting with complex symptoms potentially referable to large airways. INTERVENTION: Flexible bronchoscopy for diagnostic (bronchoalveolar lavage, ciliary biopsy, assess ongoing surgical intervention, and rule in or rule out foreign body; N=6) or therapeutic (evacuate bronchial mucus plug, laser subglottis when patient has fused cervical spine, and distal instillation [fibrin glue for bronchopleural fistula and dornase alpha for plastic bronchitis]; N=4). MAIN OUTCOME MEASURE: Retrospectively ask if flexible bronchoscopy and interdisciplinary management improved patient care in these select otolaryngology cases. RESULTS: 10/10 patients benefited from interdisciplinary management including flexible bronchoscopy. CONCLUSION: Our experience illustrates many uses for flexible bronchoscopy in otolaryngology patients, and suggests that an airway team prepared to use flexible bronchoscopy will create opportunities for improved patient care.

Cryotherapy to treat and prevent airway stenosis in a patient with granulomatosis with polyangiitis.

We report our use of cryotherapy delivered via flexible bronchoscopy in a 15-year old girl with granulomatosis with polyangiitis to both treat established airway stenosis and prevent multi-level progression of disease.

Airway Autoimmune Inflammatory Response (AAIR) Syndrome: An Asthma-Autoimmune Overlap Disorder?

Asthma encompasses numerous phenotypes that may require alternate approaches to diagnosis and therapy, particularly for patients whose symptoms remain poorly controlled despite escalating treatment. We describe 3 patients with apparent asthma who demonstrated unusual findings on cryobiopsy by flexible bronchoscopy and responded to therapy directed against autoimmune disease.

Effect of carbon dioxide on neonatal mouse lung: a genomic approach.

Despite the deleterious effects associated with elevated carbon dioxide (CO(2)) or hypercapnia, it has been hypothesized that CO(2) can protect the lung from injury. However, the effects of chronic hypercapnia on the neonatal lung are unknown. Hence, we investigated the effect of chronic hypercapnia on neonatal mouse lung to identify genes that could potentially contribute to hypercapnia-mediated lung protection. Newborn mouse litters were exposed to 8% CO(2), 12% CO(2), or room air for 2 wk. Lungs were excised and analyzed for morphometric alterations. The alveolar walls of CO(2)-exposed mice appeared thinner than those of controls. Analyses of gene expression differences by microarrays revealed that genes from a variety of functional categories were differentially expressed following hypercapnia treatment, including those encoding growth factors, chemokines, cytokines, and endopeptidases. In particular and of major interest, the expression level of genes encoding surfactant proteins A and D, as well as chloride channel calcium-activated 3, were significantly increased, but the expression of WNT1-inducible signaling pathway protein 2 was significantly decreased. The significant changes in gene expression occurred mostly at 8% CO(2), but only a few at 12% CO(2). Our results lead us to conclude that 1) there are a number of gene families that may contribute to hypercapnia-mediated lung protection; 2) the upregulation of surfactant proteins A and D may play a role as anti-inflammatory or antioxidant agents; and 3) the effects of CO(2) seem to depend on the level to which the lung is exposed.

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development.

Lung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increased TIMP-3 expression. MMP-14, MMP-20, TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2. These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

Heterogeneity of lower airway inflammation in children with severe-persistent asthma.

RATIONALE: The treatment of children with severe-persistent asthma remains problematic. Recent studies suggest that stratification of this cohort by inflammatory type may be useful in designing effective treatment strategies. In this study, we examined the inflammatory profile in bronchoalveolar lavage fluid from children with severe-persistent asthma and compared this profile with serum IgE levels. METHODS: The inflammatory profile in the bronchoalveolar fluid from 32 children who met criteria for severe-persistent asthma as defined by the Severe Asthma Research Program (SARP) were analyzed retrospectively. Inflammatory patterns were classified as neutrophilic, eosinophilic, mixed, or pauci-granulocytic. Serum total IgE was measured prior to bronchoscopy and determined by ELISA at each hospital's lab by standard procedures. RESULTS: The most common pattern of inflammation in this cohort was neutrophilic (37.5%) followed by eosinophilic (28.1%), mixed (21.9%), and pauci-granulocytic (11.1%). The odds ratio of an eosinophilic BAL pattern for patients with an elevated serum IgE was 4.67 (CI 0.78-28, P = 0.12). A correlation between serum IgE levels and BAL eosinophil percentages was present (P = 0.04). CONCLUSIONS: To our knowledge, ours is one of few studies to systematically investigate the pattern of lower airway inflammation in children with severe-persistent asthma. Our results differ from a recent investigation in children, showing more heterogeneity and a greater proportion of neutrophilic inflammation. Further investigation is required to determine whether specific inflammatory patterns are associated with specific etiologies, and whether individualized therapy is warranted.

Regulation of TGF-beta ligand and receptor expression in neonatal rat lungs exposed to chronic hypoxia.

Long-term effects of hypoxia are largely due to its modulatory effects on proliferation and differentiation of epithelial and endothelial cells, processes also regulated by the transforming growth factor (TGF)-beta system. We investigated the effects of hypoxia on the TGF-beta system in rat lungs from different developmental stages. Sprague-Dawley rats were exposed to 9.5% oxygen during either the first 2 wk of life or adulthood. Analysis revealed an arrest of alveolarization in hypoxic postnatal day 14 rats. Bioactive TGF-beta levels in bronchoalveolar lavage fluid were increased in these animals, and Western blot analysis revealed upregulation of TGF-beta receptor (TbetaR) I and II. None of these changes was observed in hypoxic adults. Hypoxia did, however, lead to decreased expression of TbetaRIII in both postnatal day 14 and adult rats. Immunohistochemical analysis localized TbetaRI-III predominantly to bronchiolar and alveolar epithelium; these patterns did not change with hypoxia. Thus we observed changes in TGF-beta activity and TbetaR isotype expression in rat lung that parallel the arrest in alveolarization seen with chronic hypoxia in early development. These alterations may partly explain the morphological changes observed in hypoxia.

Intrabronchial valves for treatment of alveolar-pleural fistula in a patient with Pneumocystis jirovecii pneumonia.

Alveolo-pleural fistula is a common complication of severe pulmonary infection. Some patients require long-term placement of chest tubes until spontaneous closure of the fistula takes place, whereas others require surgical intervention. We report a case of a patient with alveolo-pleural fistula secondary to Pneumocystis jirovecii pneumonia who was successfully treated with the use of intrabronchial unidirectional valves inserted using flexible bronchoscopy.

Fungal sensitization in childhood persistent asthma is associated with disease severity.

RATIONALE: Recent observations, especially in adults, suggest that asthma severity may be associated with fungal sensitization. Other studies suggest that some patients with severe asthma and fungal sensitization may benefit from anti-fungal therapy. Currently, the prevalence of fungal sensitization among children with severe asthma is not well characterized. METHODS: We determined prevalence of fungal sensitization among children with moderate to severe persistent asthma and compared clinical characteristics between sensitized and non-sensitized children, including asthma severity, serum immunoglobulin E, and pulmonary function. RESULTS: Of the 64 children enrolled, 25 (39%) had evidence of sensitization to one or more fungi. Nineteen of 25 (76%) children with fungal sensitization were categorized as severe persistent compared to 13 of 39 (33%) children without evidence of fungal sensitization (odds ratio = 6.33, 95% confidence interval 2.04-19.68, P = 0.0014). Of 32 severe persistent asthmatics, 19 (59%) demonstrated evidence of fungal sensitization. Serum immunoglobulin E was significantly higher (P < 0.001), and pulmonary function (including FEV1, FEV1/FVC, and FEF25-75%) significantly lower in the fungal-sensitized patients (P = 0.016, 0.0004, and 0.002, respectively). Bronchial biopsy of sensitized children revealed basement membrane thickening and eosinophil infiltration. CONCLUSIONS: Fungal sensitization in children with persistent asthma is associated with disease severity. Almost 60% of our severe persistent asthma patients had evidence of fungal sensitization and, based on our previous studies, may be potential candidates for anti-fungal therapy.

The chitin connection.

Chitin, a polymer of N-acetylglucosamine, is an essential component of the fungal cell wall. Chitosan, a deacetylated form of chitin, is also important in maintaining cell wall integrity and is essential for Cryptococcus neoformans virulence. In their article, Gilbert et al. [N. M. Gilbert, L. G. Baker, C. A. Specht, and J. K. Lodge, mBio 3(1):e00007-12, 2012] demonstrate that the enzyme responsible for chitosan synthesis, chitin deacetylase (CDA), is differentially attached to the cell membrane and wall. Bioactivity is localized to the cell membrane, where it is covalently linked via a glycosylphosphatidylinositol (GPI) anchor. Findings from this study significantly enhance our understanding of cryptococcal cell wall biology. Besides the role of chitin in supporting structural stability, chitin and host enzymes with chitinase activity have an important role in host defense and modifying the inflammatory response. Thus, chitin appears to provide a link between the fungus and host that involves both innate and adaptive immune responses. Recently, there has been increased attention to the role of chitinases in the pathogenesis of allergic inflammation, especially asthma. We review these findings and explore the possible connection between fungal infections, the induction of chitinases, and asthma.