Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

Use of Berlin EXCOR cannulas in both venovenous and venoarterial central extracorporeal membrane oxygenation configurations overcomes the problem of cannula instability while bridging infants and young children to lung transplant.

Objectives: Infants and young children awaiting lung transplantation present challenges that often preclude successful extracorporeal membrane oxygenation support as a bridge to transplantation. Instability of neck cannulas often results in the need for intubation, mechanical ventilation, and muscle relaxation creating a worse transplant candidate. With the use of Berlin Heart EXCOR cannulas (Berlin Heart, Inc) in both venoarterial and venovenous central cannulation configurations, 5 pediatric patients were successfully bridged to lung transplant. Methods: We performed a single-center retrospective case review of central extracorporeal membrane oxygenation cannulation used as a bridge to lung transplantation cases performed at Texas Children's Hospital between 2019 and 2021. Results: Six patients, 2 with pulmonary veno-occlusive disease (15-month-old male and 8-month-old male), 1 with ABCA3 mutation (2-month-old female), 1 with surfactant protein B deficiency (2-month-old female), 1 with pulmonary arterial hypertension in the setting of D-transposition of the great arteries after repair as a neonate (13-year-old male), and 1 with cystic fibrosis and end-stage lung disease, were supported for a median of 56.3 days on extracorporeal membrane oxygenation while awaiting transplantation. All patients were extubated after initiation of extracorporeal membrane oxygenation, participating in rehabilitation until transplant. No complications due to central cannulation and use of the Berlin Heart EXCOR cannulas were observed. One patient with cystic fibrosis developed fungal mediastinitis and osteomyelitis resulting in discontinuation of mechanical support and death. Conclusions: Novel use of Berlin Heart EXCOR cannulas for central cannulation eliminates the problem of cannula instability allowing extubation, rehabilitation, and bridge to lung transplant for infants and young children.

Application of organ dysfunction assessment scores following pediatric lung transplantation.

OBJECTIVE: Organ dysfunction (OD) after lung transplantation can reflect preoperative organ failure, intraoperative acute organ damage and post-operative complications. We assessed two OD scoring systems, both the PEdiatric Logistic Organ Dysfunction (PELOD) and the pediatric Sequential Organ Failure Assessment (pSOFA) scores, in recognizing risk factors for morbidity as well as recipients with prolonged post-transplant morbidity. DESIGN: Medical records of recipients from January 2009 to March 2016 were reviewed. PELOD and pSOFA scores were calculated on post-transplant days 1-3. Risk factors assessed included cystic fibrosis (CF), prolonged surgical time and worst primary graft dysfunction (PGD) score amongst others. Patients were classified into three groups based on their initial scores (group A) and subsequent trends either uptrending (group B) or downtrending (group C). Morbidity outcomes were compared between these groups. RESULTS: Total 98 patients were enrolled aged 0-20 years. Risk factors for higher pSOFA scores ≥ 5 on day 1 included non-CF diagnosis and worst PGD scores (p = .0006 and p = .03, respectively). Kruskal Wallis analysis comparing pSOFA group A versus B versus C scores showed significantly prolonged ventilatory days (median 1 vs. 4 vs. 2, p = .0028) and ICU days (median 4 vs. 10 vs. 6, p = .007). Similarly, PELOD group A versus B versus C scores showed significantly prolonged ventilatory days (1 vs. 5 vs. 2, p = < .0001). CONCLUSION: Implementing pSOFA scores bedside is a more effective tool compared to PELOD in identifying risk factors for worsened OD post-lung transplant and can be valuable in providing direction on morbidity outcomes in the ICU.

Type-1 Laryngeal Cleft and Pathogenic Bacterial Growth in the Lower Airway in Children.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to evaluate the association between type-1 laryngeal clefts and pathogenic bacterial growth in the lower airway in children. STUDY DESIGN: Retrospective chart review. METHODS: A retrospective chart review was conducted for all children who underwent direct laryngoscopy, flexible bronchoscopy with bronchoalveolar lavage (BAL), and esophagogastroduodenoscopy, under a single anesthetic event from 2015 until 2018 at an academic tertiary referral center. Type-1 laryngeal clefts were diagnosed as an interarytenoid depth at or below the level of the vocal folds, on direct laryngoscopy, via palpation by a fellowship-trained pediatric otolaryngologist. Pathogenic bacterial growth in the lower airway was defined as presence of BAL culture growth of nonrespiratory flora. RESULTS: A total of 217 patients were identified. Type-1 laryngeal cleft was significantly associated with chronic cough (P = .0016) and cough with feeds (P < .0001). However, an abnormal video fluoroscopic swallow study was not found to be significantly associated with type-1 laryngeal cleft (P = .92) or pathogenic bacterial growth in the lower airway (P = 0.19). Overall, 122 (56%) patients were diagnosed with type-1 laryngeal cleft, 75 (35%) had pathogenic bacterial growth in the lower airway and 50 (23%) had both type-1 laryngeal cleft and pathogenic bacterial growth in the lower airway. Type-1 laryngeal cleft was significantly associated with pathogenic bacterial growth in the lower airway on both univariate analysis (P = .0307) and multivariate analysis (P = .0298, odds ratio 1.922, 95% confidence interval 1.066-3.467). CONCLUSION: Children with type-1 laryngeal clefts are at higher risk of having pathogenic bacterial growth in the lower airway. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1825-1828, 2022.

Palliative Care in Pediatric Pulmonology.

Children with End Stage Lung Disease (ESLD) are part of the growing population of individuals with life-limiting conditions of childhood. These patients present with a diverse set of pulmonary, cardiovascular, neuromuscular, and developmental conditions. This paper first examines five cases of children with cystic fibrosis, bronchopulmonary dysplasia, neuromuscular disease, pulmonary hypertension, and lung transplantation from Texas Children's Hospital. We discuss the expected clinical course of each condition, then review the integration of primary and specialized palliative care into the management of each diagnosis. This paper then reviews the management of two children with end staged lung disease at Hospital Civil de Guadalajara, providing an additional perspective for approaching palliative care in low-income countries.

Infections Within the First Month After Pediatric Lung Transplantation: Epidemiology and Impact on Outcomes.

BACKGROUND: Despite successes in lung transplantation, with infection as the leading cause of death in the first year following lung transplantation, there remains a lag in survival compared with other solid organ transplants. Infections that occur early after transplantation may impact short- and long-term outcomes in pediatric lung transplant recipients (LTRs). METHODS: We performed a retrospective review of pediatric LTRs at a large quaternary-care hospital from January 2009 to March 2016 to evaluate both epidemiologic features of infection in the first 30 days post-transplantation and mortality outcomes. The 30 days were divided into early (0-7 days) and late (8-30 days) periods. RESULTS: Among the 98 LTRs, there were 51 episodes of infections. Cystic fibrosis (CF) was associated with early bacterial infections (P = .004) while non-CF was associated with late viral (P = .02) infections. Infection after transplantation was associated with worse survival by Kaplan-Meier analysis (P value log rank test = .007). Viral infection in the late period was significantly associated with 3-year mortality after multivariable analysis (P = .02). CONCLUSIONS: Infections in pediatric LTRs were frequent in the first 30 days after transplant, despite perioperative antimicrobial coverage. The association of 3-year mortality with late viral infections suggests a possible important role in post-transplant lung physiology and graft function. Understanding the epidemiology of early post-lung transplant infections can help guide post-operative management and interventions to reduce their incidence and the early- and long-term impact in this population.

Clinico-radiologic features of pleuroparenchymal fibroelastosis in children.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) may be underdiagnosed clinically and radiographically in children with a remote history of cancer, leading to a delay in care and unnecessary lung biopsies. OBJECTIVE: To describe the characteristic clinical and radiologic findings of PPFE in a cohort of children to facilitate recognition and noninvasive diagnosis. MATERIALS AND METHODS: Clinical presentation, history of chemotherapy or radiation therapy, lung or bone marrow transplantation, and lung function testing and outcome were retrospectively extracted from the electronic medical records of eight children treated at our institution's pulmonary medicine clinic with histopathology confirmation of PPFE from 2008 to 2018. Two pediatric radiologists evaluated the chest imaging studies for the presence or absence of published radiologic findings of PPFE in adults, including platythorax, pneumothorax, upper lobe predominant pleural and septal thickening, and bronchiectasis. Platythorax indices were calculated from the normal chest CT exams of eight age- and gender-matched individuals obtained via the radiology search engine. RESULTS: The mean presentation age was 12.9 years (range: 7-16 years). Seven of the eight had a history of chemotherapy and radiation therapy for cancer. Three of the eight had undergone bone marrow transplantation and none had undergone lung transplantation. The mean time between chemotherapy, radiation therapy, and/or bone marrow transplantation and the presentation of PPFE was 8.4 years (range: 5.6-12.1 years). Most of the patients presented with dyspnea (63%), cough (50%) and/or pneumothorax (38%). The mean percentage of predicted FEV1 (forced expiratory volume in one second) was 14.1 (range: 7.7-27.5). All eight patients demonstrated platythorax, bronchiectasis, pleural and septal thickening (upper lobes in four, upper and lower lobes in four) and six had pneumothorax. Five underwent lung biopsies, four of whom developed pneumothoraces. CONCLUSION: Clinical and radiologic findings of pediatric PPFE are similar to those in adults, although a majority of the former have a history of treated cancer. Clinical presentation of restrictive lung disease, dyspnea, cough or spontaneous pneumothorax years after treatment for childhood cancer combined with platythorax, upper lobe pleural and septal thickening and traction bronchiectasis on chest CT establishes a presumptive diagnosis of PPFE.

Risk factors for infection after pediatric lung transplantation.

Although infection is the leading cause of death in the first year following pediatric lung transplantation, there are limited data on risk factors for early infection. Sepsis remains under-recognized and under-reported in the early post-operative period for lung transplant recipients (LTR). We evaluated the incidence of infection and sepsis, and identified risk factors for infection in the early post-operative period in pediatric LTRs. A retrospective review of medical records of LTRs at a large quaternary-care hospital from January 2009 to March 2016 was conducted. Microbiology results on days 0-7 after transplant were obtained. Sepsis was defined using the 2005 International Pediatric Consensus Conferencecriteria. Risk factors included history of recipient and donor infection, history of multi-drug resistant (MDR) infection, nutritional status, and surgical times. Among the 98 LTRs, there were 22 (22%) with post-operative infection. Prolonged donor ischemic time ≥7 hours, cardiopulmonary bypass(CPB) time ≥340 minutes, history of MDR infection and diagnosis of cystic fibrosis were significantly associated with infection. With multivariable regression analysis, only prolonged donor ischemic time remained significant (OR 4.4, 95% CI: 1.34-14.48). Further research is needed to determine whether processes to reduce donor ischemic time could result in decreased post-transplant morbidity.

Lung Transplantation for FLNA-Associated Progressive Lung Disease.

OBJECTIVE: To describe a series of patients with pathogenic variants in FLNA and progressive lung disease necessitating lung transplantation. STUDY DESIGN: We conducted a retrospective chart review of 6 female infants with heterozygous presumed loss-of-function pathogenic variants in FLNA whose initial presentation was early and progressive respiratory failure. RESULTS: Each patient received lung transplantation at an average age of 11 months (range, 5-15 months). All patients had pulmonary arterial hypertension and chronic respiratory failure requiring tracheostomy and escalating levels of ventilator support before transplantation. All 6 patients survived initial lung transplantation; however, 1 patient died after a subsequent heart-lung transplant. The remaining 5 patients are living unrestricted lives on chronic immunosuppression at most recent follow-up (range, 19 months to 11.3 years post-transplantation). However, in all patients, severe ascending aortic dilation has been observed with aortic regurgitation. CONCLUSIONS: Respiratory failure secondary to progressive obstructive lung disease during infancy may be the presenting phenotype of FLNA-associated periventricular nodular heterotopia. We describe a cohort of patients with progressive respiratory failure related to a pathogenic variant in FLNA and present lung transplantation as a viable therapeutic option for this group of patients.

Bronchial artery revascularization and en bloc lung transplant in children.

BACKGROUND: Long-term success in pediatric lung transplantation is limited by infection and bronchiolitis obliterans syndrome (BOS). The bilateral sequential lung transplantation (BSLT) technique may result in airway ischemia leading to bronchial stenosis, dehiscence, or loss of small airways. En bloc lung transplant (EBLT) with bronchial artery revascularization (BAR) minimizes airway ischemia, thus promoting superior airway healing. BAR also allows for safe tracheal anastomosis, circumventing the need for bilateral bronchial anastomoses in small children. METHODS: This was a retrospective review of bilateral transplantations from 2005 to 2014. Both techniques were used in parallel. Redo and multiorgan transplants were excluded. RESULTS: There were 119 recipients comprising 88 BSLTs and 31 EBLTs. Follow-up time was 3 years (interquartile range, 1-5 years). Donor ischemic and cardiopulmonary bypass times were not different between techniques (p = 0.48 and p = 0.18, respectively). Degree of graft dysfunction and cellular rejection scores were not different (p = 0.83 and p = 0.93, respectively). There were 3 hospital deaths after BSLT and 2 after EBLT (p = 0.60). Overall survival was 61% for the BSLT group and 77% for the EBLT group (p = 0.54). Freedom from BOS was 71% in the BSLT group and 94% in the EBLT group (p = 0.08). On routine bronchoscopy, 57% BSLT and 16% EBLT patients had 1 or more airway ischemic findings (p < 0.0001). Multivariate analysis showed BSLT was associated with higher ischemic injury (relative risk, 2.86; 95 confidence interval, 1.3-6.5; p = 0.01) and non-airway complications (relative risk, 4.62; 95% confidence interval, 1.1-20.2; p = 0.04) but not airway reinterventions (p = 0.07). Airway dehiscence occurred in 3 BSLT patients. CONCLUSIONS: Pediatric EBLT with BAR can be safely performed without increasing operative or graft ischemic times. Airway ischemia and non-airway complications were significantly reduced when BAR was combined with tracheal anastomosis, potentially diminishing morbidity caused by anastomotic healing complications.

Interstitial lung disease in children.

PURPOSE OF REVIEW: In this review, we discuss the recent advances in our understanding of the cause, pathogenesis, presentation, diagnosis, treatment, and prognosis of interstitial lung disease (ILD) in children. RECENT FINDINGS: The classification of ILD syndromes in children greater than 2 years of age is based largely on adult classification schemes. In children less than 2 years of age, classification has been developed and evaluated pathologically. Entities can be categorized into developmental disorders, growth abnormalities, and surfactant dysfunction disorders based on pathologic findings. Two distinctive entities, neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis, present early in life with characteristic findings. These two disorders appear to have a favorable prognosis. Diagnosis of ILD syndromes is based on the summation of history and physical findings and both noninvasive and invasive studies. Newer approaches are being evaluated to decrease the need for lung biopsy. SUMMARY: Children's interstitial lung diseases are rare diffuse lung diseases resulting from a variety of pathogenic processes that include genetic factors, association with systemic disease processes, and inflammatory or fibrotic responses to stimuli. There are unique causes and presentations seen in infancy. Diagnosis in these disorders is made by the summation of clinical, radiologic, and pathologic findings.