Diagnostic yield of bronchoscopy in children with leukemia or post hematopoietic stem cell transplant.

BACKGROUND: The utility of bronchoscopy with bronchoalveolar lavage (BAL) in immunocompromised children is not well understood. We aim to describe the bronchoscopy diagnostic yield and complications and to investigate factors associated with diagnostic yield. METHODS: This is a single-center, retrospective cohort study of 60 children with leukemia or post-hematopoietic stem cell transplant who had a bronchoscopy with BAL between 2017 and 2021. Comparisons were done with regression analysis. RESULTS: Of the 60 bronchoscopies performed, 46 (77%) revealed diagnostic information: 39 (65%) identified a pathogen, 14 (23.3%) found secretions/mucus plugging, and 6 (10%) found pulmonary hemorrhage. BAL results changed antimicrobial therapy in 27 (45%) cases. Bronchoscopies were performed in the intensive care unit (27/60) or operating room (33/60), with the former having a higher diagnostic yield (96% vs. 60%, p = 0.001). Half (50%) of bronchoscopies found a new infectious diagnosis. Respiratory symptoms (n = 58, 97%), supplemental oxygen use (n = 39, 65%), and antibiotic use (n = 56, 93%) before bronchoscopy were all common. The median volume of fluid instilled during bronchoscopy was 1.3 mL/kg (interquatile range [IQR]: 0.7, 2.6). None of these factors were associated with the diagnostic yield. Complications were rare and minor with only one child having self-resolved bleeding and four children, previously in room air requiring a nasal cannula. For the 27 (45%) children on mechanical ventilation when the bronchoscopy was performed, there was no difference in ventilator settings pre- and post-bronchoscopy. CONCLUSION: Bronchoscopies with BAL are useful, safe, and important in the diagnostic management of pulmonary complications in this cohort of children.

Adjusting ventilator settings to avoid air trapping in extremely premature infants reduces the need for tracheostomy and length of stay.

Despite the improving understanding of how lung mechanics and tidal volume requirements evolve during the evolution of bronchopulmonary dysplasia (BPD), clinical management continues to be heterogeneous and inconsistent at many institutions. Recent reports have examined the use of high tidal-volume low respiratory rate strategies in these patients once disease has been well established to help facilitate their eventual extubation and improve their long-term neurodevelopmental outcomes. In this retrospective observational research study, we describe how intentional adjustment of ventilator settings based on patient lung mechanics by an interdisciplinary BPD team improved the care of the at-risk population of infants, reduced the need for tracheostomies, as well as length of stay over a period of over 3 years. The team aimed to establish consistency in the management of these children using a high tidal volume, low-rate approach, and titrating PEEP to address the autoPEEP and bronchomalacia that is frequently observed in this patient population.

Wheezing in preterm infants and children.

Wheezing is a common outcome of preterm birth. This article will review the mechanisms, epidemiology, and treatment of wheezing in preterm children with and without a history of bronchopulmonary dysplasia.

Lung biopsy in children's interstitial and diffuse lung disease: Does it alter management?

INTRODUCTION: Pediatric patients with acute life-threatening consequences of interstitial and diffuse lung disease are often treated with empiric systemic corticosteroids, immune modulators, and/or broad antibiotic therapy. Histological evaluation of lung tissue represents the final necessary step in diagnosis-however, a definitive diagnosis may still remain elusive and medical therapies may not be changed following biopsy. We hypothesized that lung biopsy from pediatric patients with children's interstitial and diffuse lung disease (chILD) without a defined lesion on computed tomography (CT) imaging would guide diagnosis, but not substantially alter clinical management. METHODS: After IRB approval, patients who underwent a lung biopsy at a single large children's hospital between 2013 and 2018 were retrospectively reviewed. Patients without a defined lesion were included. Demographics, length of stay, oxygen-requirements, steroid, unique number of immune modulators, and antibiotics prebiopsy and postbiopsy were reviewed. Nonparametric data were compared by the Mann Whitney U and Kruskal Wallace tests and expressed as median with interquartile range. Decision tree alterations were analyzed by t test. P < .05 was significant. RESULTS: Sixty-four patients underwent lung biopsy during the period. Nineteen (30%) did not have a defined lesion on CT scan, and were included. A significant difference was seen between prebiopsy, 2 weeks, and 2 months postbiopsy prednisone dosing (P = .03), while the number of unique immune modulators, antibiotics, type of oxygen support and FiO2 were not significantly different before or after obtaining biopsy results. Pathology results provided additional information in 12 of 19 (63%) patients which resulted in management changes. CONCLUSIONS: Lung biopsy in chILD may guide clinical management, especially influencing the management of steroid dosing. Although on aggregate the number of antibiotics, immune modulators, mode of oxygen support and FiO2 did not differ significantly before and after biopsy, the pathologic evaluation provided diagnostic information that led to a variety of changes in therapeutic management in greater than half of the population.

Association of Antibiotics, Airway Microbiome, and Inflammation in Infants with Cystic Fibrosis.

RATIONALE: The underlying defect in the cystic fibrosis (CF) airway leads to defective mucociliary clearance and impaired bacterial killing, resulting in endobronchial infection and inflammation that contributes to progressive lung disease. Little is known about the respiratory microbiota in the early CF airway and its relationship to inflammation. OBJECTIVES: To examine the bacterial microbiota and inflammatory profiles in bronchoalveolar lavage fluid and oropharyngeal secretions in infants with CF. METHODS: Infants with CF from U.S. and Australian centers were enrolled in a prospective, observational study examining the bacterial microbiota and inflammatory profiles of the respiratory tract. Bacterial diversity and density (load) were measured. Lavage samples were analyzed for inflammatory markers (interleukin 8, unbound neutrophil elastase, and absolute neutrophil count) in the epithelial lining fluid. RESULTS: Thirty-two infants (mean age, 4.7 months) underwent bronchoalveolar lavage and oropharyngeal sampling. Shannon diversity strongly correlated between upper and lower airway samples from a given subject, although community compositions differed. Microbial diversity was lower in younger subjects and in those receiving daily antistaphylococcal antibiotic prophylaxis. In lavage samples, reduced diversity correlated with lower interleukin 8 concentration and absolute neutrophil count. CONCLUSIONS: In infants with CF, reduced bacterial diversity in the upper and lower airways was strongly associated with the use of prophylactic antibiotics and younger age at the time of sampling; less diversity in the lower airway correlated with lower inflammation on bronchoalveolar lavage. Our findings suggest modification of the respiratory microbiome in infants with CF may influence airway inflammation.

Effect of treatment of cystic fibrosis pulmonary exacerbations on systemic inflammation.

RATIONALE: In cystic fibrosis (CF), pulmonary exacerbations present an opportunity to define the effect of antibiotic therapy on systemic measures of inflammation. OBJECTIVES: Investigate whether plasma inflammatory proteins demonstrate and predict a clinical response to antibiotic therapy and determine which proteins are associated with measures of clinical improvement. METHODS: In this multicenter study, a panel of 15 plasma proteins was measured at the onset and end of treatment for pulmonary exacerbation and at a clinically stable visit in patients with CF who were 10 years of age or older. MEASUREMENTS AND MAIN RESULTS: Significant reductions in 10 plasma proteins were observed in 103 patients who had paired blood collections during antibiotic treatment for pulmonary exacerbations. Plasma C-reactive protein, serum amyloid A, calprotectin, and neutrophil elastase antiprotease complexes correlated most strongly with clinical measures at exacerbation onset. Reductions in C-reactive protein, serum amyloid A, IL-1ra, and haptoglobin were most associated with improvements in lung function with antibiotic therapy. Having higher IL-6, IL-8, and α1-antitrypsin (α1AT) levels at exacerbation onset were associated with an increased risk of being a nonresponder (i.e., failing to recover to baseline FEV1). Baseline IL-8, neutrophil elastase antiprotease complexes, and α1AT along with changes in several plasma proteins with antibiotic treatment, in combination with FEV1 at exacerbation onset, were predictive of being a treatment responder. CONCLUSIONS: Circulating inflammatory proteins demonstrate and predict a response to treatment of CF pulmonary exacerbations. A systemic biomarker panel could speed up drug discovery, leading to a quicker, more efficient drug development process for the CF community.

Why exercise capacity does not improve after pulmonary valve replacement.

Optimal timing of pulmonary valve replacement (PVR) for pulmonary regurgitation is a debated topic. It is logical that maximal aerobic capacity (VO2peak) would decline when a PVR is needed, but a diminished VO2peak is not always present before PVR, and previous studies show no improvement in VO2peak after PVR. This study aimed to evaluate changes in resting spirometry from pre- to post-PVR sternotomy, to determine the limiting factors of VO2peak before and after PVR, and to determine whether changes in resting lung function after PVR may explain the lack of improvement in VO2peak after surgery. For 26 patients (age, 19.7 ± 7.8 years) with a history of right ventricular outflow tract revision, the study prospectively evaluated echocardiograms, resting spirometry, and maximal exercise tests before PVR and then an average of 15 months after PVR. Flow volume loops were reviewed by a pulmonologist and categorized as obstructive, restrictive, both obstructive and restrictive, or normal. Exercise tests were interpreted using Eschenbacher's algorithm to determine the primary factors limiting exercise. No change in VO2peak or spirometry after PVR was observed. Before PVR, many patients had abnormal resting lung functions (85 % abnormal), which was unchanged after PVR (86 5 % abnormal). The majority of the patients had a ventilatory limitation to VO2peak before PVR (66.7 %), whereas 28.5 % had a cardiovascular limitation, and 4.8 % had no clear limitation. After PVR, 65.2 % of the patients had a ventilatory limitation, whereas 30.4 % had a cardiovascular limitation, and 4.4 % had no clear limitation to VO2peak. Pulmonary function did not change up to 15 months after surgical PVR. The frequency of pulmonary limitation to VO2peak after PVR did not increase. The effect of pulmonary function on exercise-related symptoms must be considered in this patient population. Improved cardiac hemodynamics are unlikely to improve VO2peak in a primarily pulmonary-limited patient.

An infant with pulmonary interstitial glycogenosis: clinical improvement is associated with improvement in the pulmonary diffusion capacity.

Pulmonary interstitial glycogenosis (PIG) is an idiopathic interstitial lung disease of infants. The underlying pulmonary pathophysiology of PIG has not been well characterized. Herein we report a term-gestation infant who presented with persistent tachypnea and hypoxia. A chest CT scan demonstrated a diffuse ground glass appearance and lung biopsy demonstrated increased alveolar septae cellularity with glycogen-containing cells, consistent with a diagnosis of PIG. At 3 months of age, pulmonary function testing included: pre- and post-bronchodilator forced expiratory flows using the raised-volume technique and the ratio of pulmonary diffusing capacity for carbon monoxide to alveolar volume (DLCO /VA ). He was prescribed 5 days of oral prednisolone (2mg/kg/day) and pulmonary function testing (PFT) was repeated at 5, 13, and 20 months of age. Initial PFTs demonstrated reduced forced vital capacity (FVC: Z-score = -2.36) and an increased ratio of forced expiratory volume in 0.5 sec to FVC (FEV0.5/FVC: Z-score = 1.15) with no significant change following an inhaled bronchodilator. There was also a marked reduction in DLCO /VA (Z-score = -4.74) compared to age-matched controls. Follow-up demonstrated progressive clinical improvement as well as an increase in Z-FVC and normalization of DLCO /VA . Our in vivo physiological findings are consistent with previous reports that symptom resolution correlated with histological thinning of the alveolar septae upon repeat lung biopsy. The restrictive lung disease we observed is consistent with expected reduced compliance of an alveolar interstitial lung process like PIG, whereas the absence of a reduction in FEV0.5/FVC confirms the absence of obstructive airway disease.

Propranolol in the treatment of upper airway hemangiomas.

Airway hemangiomas (AHs), which are common in infant airways, often cause significant upper airway obstruction. The various therapies used for AH have limitations and complications. Propranolol may have a potential role in its treatment, since it leads to regression or stabilization of cutaneous infantile hemangiomas. To date, only 4 previous case reports (7 patients) in which propranolol was used for AH have been published. Based on encouraging preliminary data on propranolol use for AH treatment, our goal was to further investigate propranolol as an effective initial treatment of upper AHs that cause significant obstruction symptoms. In this retrospective case series, we reviewed the medical records of 5 consecutive pediatric patients with AH (glottic and subglottic) treated with propranolol at a tertiary care children's hospital. All 5 patients were 2 months of age at the time of hemangioma diagnosis and had stridor and physical signs of severe upper airway obstruction. Hemangioma was diagnosed by flexible laryngoscopy or flexible bronchoscopy. All patients received propranolol 2 mg/kg/day and showed significant relief of obstruction symptoms within 24 hours of treatment initiation. All patients tolerated propranolol without significant cardiovascular complications. Outcomes from this case series, in conjunction with available case reports in the literature, suggest that propranolol is a safe initial treatment for symptomatic upper AH.

Randomized controlled trial of fish oil and montelukast and their combination on airway inflammation and hyperpnea-induced bronchoconstriction.

BACKGROUND: Both fish oil and montelukast have been shown to reduce the severity of exercise-induced bronchoconstriction (EIB). The purpose of this study was to compare the effects of fish oil and montelukast, alone and in combination, on airway inflammation and bronchoconstriction induced by eucapnic voluntary hyperpnea (EVH) in asthmatics. METHODS: In this model of EIB, twenty asthmatic subjects with documented hyperpnea-induced bronchoconstriction (HIB) entered a randomized double-blind trial. All subjects entered on their usual diet (pre-treatment, n = 20) and then were randomly assigned to receive either one active 10 mg montelukast tablet and 10 placebo fish oil capsules (n = 10) or one placebo montelukast tablet and 10 active fish oil capsules totaling 3.2 g EPA and 2.0 g DHA (n = 10) taken daily for 3-wk. Thereafter, all subjects (combination treatment; n = 20) underwent another 3-wk treatment period consisting of a 10 mg active montelukast tablet or 10 active fish oil capsules taken daily. RESULTS: While HIB was significantly inhibited (p<0.05) by montelukast, fish oil and combination treatment compared to pre-treatment, there was no significant difference (p>0.017) between treatment groups; percent fall in forced expiratory volume in 1-sec was -18.4 ± 2.1%, -9.3±2.8%, -11.6 ± 2.8% and -10.8 ± 1.7% on usual diet (pre-treatment), fish oil, montelukast and combination treatment respectively. All three treatments were associated with a significant reduction (p<0.05) in F(E)NO, exhaled breathe condensate pH and cysteinyl-leukotrienes, while the fish oil and combination treatment significantly reduced (p<0.05) urinary 9α, 11ß-prostaglandin F(2) after EVH compared to the usual diet; however, there was no significant difference (p>0.017) in these biomarkers between treatments. CONCLUSION: While fish oil and montelukast are both effective in attenuating airway inflammation and HIB, combining fish oil with montelukast did not confer a greater protective effect than either intervention alone. Fish oil supplementation should be considered as an alternative treatment for EIB. TRIAL REGISTRATION: ClinicalTrials.gov NCT00676468.

Eicosapentaenoic acid is more effective than docosahexaenoic acid in inhibiting proinflammatory mediator production and transcription from LPS-induced human asthmatic alveolar macrophage cells.

BACKGROUND & AIMS: The purpose of the study was to determine which of the active constituents of fish oil, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is most effective in suppressing proinflammatory mediator generation and cytokine expression from LPS-stimulated human asthmatic alveolar macrophages (AMphi). METHODS: The AMphi were obtained from twenty-one asthmatic adults using fiberoptic bronchoscopy. Cells were pretreated with DMEM, pure EPA, an EPA-rich media (45% EPA/10% DHA), pure DHA, a DHA-rich media (10% EPA/50% DHA) or Lipovenos (n-6 PUFA), and then exposed to Dulbecco's Modified Eagle's Medium (DMEM) (-) or LPS (+). Supernatants were analyzed for leukotriene (LT)B(4), prostaglandin (PG)D(2), tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta production. Detection of TNF-alpha and IL-1beta mRNA expression levels was quantified by reverse transcriptase polymerase chain reaction. RESULTS: 120 microM pure EPA and EPA-rich media significantly (p<0.05) suppressed TNF-alpha and IL-1beta mRNA expression and the production of LTB(4), PGD(2) and TNF-alpha and IL-1beta in LPS-stimulated primary AMphi cells obtained from asthmatic patients to a much greater extent than 120 microM pure DHA and DHA-rich media respectively. CONCLUSIONS: This study has shown for the first time that EPA is a more potent inhibitor than DHA of inflammatory responses in human asthmatic AMphi cells.

Effect of fish oil-derived omega-3 polyunsaturated Fatty Acid supplementation on exercise-induced bronchoconstriction and immune function in athletes.

UNLABELLED: Exercise-induced bronchoconstriction (EIB) is a condition in which vigorous physical activity triggers acute airway obstruction in asthmatic and nonasthmatic individuals with hyperresponsive airways. Studies have shown that inflammatory mediators and contraction of airway smooth muscle are central components in the pathogenesis of EIB, and it has long been recognized that leukotrienes and prostaglandins play an important role in the EIB response. Clinical responses to current therapy, such as leukotriene modifiers and corticosteroids are heterogeneous, and even with optimal treatment there is a substantial burden of unaddressed disease. While daily medications such as leukotriene modifiers provide only modest protection against symptoms, prolonged use of several medications can result in reduced effectiveness or tachyphylaxis. Although the treatment of EIB almost exclusively involves pharmacotherapy, there is now convincing evidence that dietary modification has the potential to reduce the severity of this condition. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oils, compete with arachidonic acid as substrates for the formation of proinflammatory mediators, such as leukotrienes, prostaglandins, and cytokines. Studies have shown that 3 weeks of fish oil supplementation, rich in EPA and DHA, reduces exercise-induced airway narrowing, airway inflammation, and bronchodilator use in elite athletes and asthmatic individuals with EIB. Based on the evidence to date, fish oil supplementation may represent a potentially beneficial treatment intervention for athletes and asthmatic individuals with EIB. From this, it follows that physicians should pay more attention to what their asthma/EIB patients eat, and incorporate dietary assessment and nutritional counseling in their everyday practice. KEYWORDS: omega-3; polyunsaturated fatty acid; fish oil; exercise-induced bronchoconstriction.

Effects of sildenafil on pulmonary hypertension and exercise tolerance in severe cystic fibrosis-related lung disease.

Cystic fibrosis (CF) patients with advanced lung disease are at risk for developing pulmonary vascular disease and pulmonary hypertension, characterized by progressive exercise intolerance beyond the exercise-limiting effects of airways disease in CF. We report on a patient with severe CF lung disease who experienced clinically significant improvements in exercise tolerance and pulmonary hypertension without changing lung function during sildenafil therapy.