Predischarge death or lung transplantation in tracheostomy and ventilator dependent grade 3 bronchopulmonary dysplasia.

BACKGROUND: Premature infants surviving beyond a postmenstrual age (PMA) of 36 weeks with severe or grade 3 bronchopulmonary dysplasia (sBPD) have significant predischarge mortality. The in-hospital mortality for BPD supported by invasive mechanical ventilation beyond 36 weeks PMA is not well described. The role of lung transplantation in treating severe BPD is uncertain. We studied our experience over 20 years to better define the predischarge mortality of infants with progressive grade 3 BPD and whether lung transplant is a feasible intervention. METHODS: Data were obtained from a retrospective review of medical records from Children's Minnesota over a 20-year period (1997-2016). Inclusion criteria included prematurity <32 weeks PMA, BPD, tracheostomy for chronic respiratory failure, and survival beyond 36 weeks PMA. Collected data included perinatal demographics, in-hospital medications and interventions, level of respiratory support, and outcomes. RESULTS: In all, 2374 infants were identified who survived beyond 36 weeks PMA with a diagnosis of <32 weeks gestation prematurity and BPD. Of these, 143/2374 (6.0%) survived beyond 36 weeks PMA and required invasive mechanical ventilation with subsequent tracheostomy for management. Among these patients, discharge to home with tracheostomy occurred in 127/143 (88.8%), and predischarge death or lung transplantation occurred in 16/143 (11.2%). Deteriorating cardiopulmonary status was associated with pulmonary hypertension, prolonged hypoxemic episodes and the need for deep sedation or neuromuscular relaxation. Three of four patients referred for lung transplantation had >5-year survival, chronic allograft rejection, and mild to moderate developmental delays. CONCLUSIONS: Chronic respiratory failure requiring invasive mechanical ventilation for grade 3 BPD is associated with significant morbidity and mortality. For selected patients and their families, timely referral for lung transplantation is a viable option for end-stage grade 3 BPD. As in other infants receiving solid organ transplants, long-term issues with co-morbidities and special needs persist into childhood.

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.

Cystic fibrosis lung transplant recipients 10 years of age or younger: Predisposing factors for end-stage disease.

BACKGROUND: The largest age group among children and adolescents referred for lung transplantation for cystic fibrosis (CF) have been those in the pubertal or postpubertal age range. However, over 100 younger patients with CF have undergone lung transplantation over the last three decades in the United States. METHODS: We performed a retrospective review of our experience with 18 children with CF who underwent lung transplantation in our center before the age of 11 years and compared them to our older CF lung transplant recipients and our larger CF Center population. RESULTS: The transplant population was demographically distinct from our CF center in terms of ethnicity, country of origin, and insurance status. Other notable findings were a high prevalence of methicillin-resistant Staphylococcus aureus, a high prevalence of CF-related diabetes mellitus, and a high prevalence of consolidated lobar or whole lung disease. Posttransplant outcomes were comparable to those older than 10 years of age in our center until 5 years after transplant after which the younger cohort showed a superior enduring survival. CONCLUSIONS: In an era of increasingly effective medications modifying the natural history of CF, identification of risk factors for early severe lung disease in CF remains relevant to permit interventions to prevent or postpone the time of future lung transplantation.

Application of lung volume reduction surgery for a child with filamin A (FLNA) mutations.

Diffuse lung disease in early childhood due to mutations in the filamin A gene has been recently reported. Clinical outcomes vary among individuals indicating variability in phenotype but a substantial proportion of reported cases in early life have ended up in death or lung transplantation. We recently encountered a school-aged child in whom the diagnosis of a filamin A mutation was delayed and the natural history of emphysematous lung disease was altered by serial lung volume reduction surgeries. She eventually underwent a bilateral lung transplant and we report the natural history of her disease and treatments applied herein.

Diagnosis and treatment of cryptococcal osteomyelitis in a pediatric lung transplant patient.

BACKGROUND: Asymptomatic pulmonary nodules may appear at any point after lung transplantation. The differential diagnosis is broad and includes serious life-threatening disease entities. METHODS: A retrospective case report of a single patient who developed a pulmonary nodule after lung transplantation. RESULTS: At 2 years post-transplant, an 11-year-old with cystic fibrosis was asymptomatic and had normal lung function. A single nodule was noted on surveillance chest CT scan. Initial evaluation was negative, but subsequently, he was diagnosed with cryptococcal osteomyelitis in a thoracic rib. He responded well to an extended course of antifungal therapy without loss of allograft function or infectious complications. CONCLUSION: Pulmonary nodules after lung transplantation may be a harbinger of serious complications. A systematic approach to evaluation and follow-up is recommended.

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.

Lung transplant referrals for individuals with cystic fibrosis: A pediatric perspective on the cystic fibrosis foundation consensus guidelines.

Lung transplant referral guidelines for individuals with cystic fibrosis (CF) were published recently. Most of the recommendations focus on the specific indications and barriers to transplantation in adults with CF. Although the number of children with CF and end-stage lung disease continues to decrease, the specific issues related to pediatric patients merit further elucidation. We address each recommendation from the recent publication with a pediatric perspective. Furthermore, we note some significant differences between the practice and policy related to lung transplantation between Canada and the United States.

Influence of early extubation on post-operative outcomes after pediatric lung transplantation.

Lung transplantation has become an accepted therapeutic option for a select group of children with end-stage lung disease. We evaluated the impact of early extubation in a pediatric lung transplant population and its post-operative outcomes. Single-center retrospective study. PICU within a tertiary academic pediatric hospital. Patients <22 years after pulmonary transplant between January 2011 and December 2016. A total of 74 patients underwent lung transplantation. The primary pretransplantation diagnoses included cystic fibrosis (58%), pulmonary fibrosis (9%), and surfactant dysfunction disorders (10%). Of 60 patients, 36 (60%) were extubated within 24 hours and 24 patients after 24 hours (40%). A total of seven patients (11.6%) required reintubation within 24 hours. Median length of stay for the early extubation group was shorter at 3 days ([(IQR) 2.2-4.7]) compared to 5 days (IQR, 3-7) (P = .02) in the late extubation group. Median costs were lower for the early extubation group with 13,833 US dollars (IQR, 9980-22,822) vs 23 671 US dollars (IQR, 16 673-39 267) (P = .043). Fourteen patients were in the PICU prior to their transplantation; this did not affect their early extubation success. Neither did the fact of requiring invasive or non-invasive mechanical ventilation before transplantation. Early extubation appears to be safe in a pediatric population after lung transplantation and is associated with a shorter LOS and decreased hospital costs. It may prevent known complications associated with mechanical ventilation.

Pulmonary growth abnormalities as etiologies for pediatric pulmonary hypertension.

Pulmonary growth abnormality (PGA) is a common type of diffuse lung disease in infants. Although the histologic and radiographic features of PGA have been described in the literature in varying detail, the clinical spectrum of disease has not. The array of case series and case reports has led to a clinical picture that could be confusing to clinicians. We describe three subsets of PGA, including its association with the histologic marker of pulmonary interstitial glycogenosis, and its common association with pulmonary hypertension. We propose a new approach to what we consider an increasingly broad array of different disease entities.

Management of severe pulmonary Langerhans cell histiocytosis in children.

Patients with pulmonary Langerhans cell histiocytosis (LCH) typically have a benign course but may have extensive cystic lung disease with rare life-threatening complications including multiple and recurrent pneumothoraces and respiratory failure. We report seven severely affected pediatric patients treated with chemotherapy, aggressive chest tube management, and pleurodesis of whom five survived. Patients with extraordinary amounts of pulmonary cystic disease and multiple pneumothoraces due to LCH can have remarkable, curative outcomes with early recognition, optimal LCH-directed therapy, and supportive care.

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.

Predictive value of oxygenation index for outcomes in left-sided congenital diaphragmatic hernia.

BACKGROUND & OBJECTIVES: Congenital Diaphragmatic Hernia (CDH) is associated with significant morbidity and mortality. This study compares the efficacy of the highest oxygenation index in the first 48 h (HiOI) versus current prenatal indices to predict survival and morbidity. METHODS: Medical records of 50 prenatally diagnosed, isolated, left-sided CDH patients treated from January 2011 to April 2016 were reviewed. Data abstracted included HiOI, lung to head ratio (LHR), observed to expected total fetal lung volume (O/E TFLV), percent liver herniation (%LH), 6 month survival, respiratory support at discharge, ventilator days and length of stay. Data were analyzed using parametric and nonparametric tests and regression analyses as appropriate. RESULTS: HiOI was associated with significantly increased LOS (p<0.001), respiratory support at discharge (p<0.001), greater ventilator days (p=0.001) and higher odds of death (p=0.004) with risk of death increasing by 5% for every one-unit increase in OI. HiOI was statistically a better predictor of LOS than O/E TFLV (p=0.007) and %LH (p=0.02). CONCLUSIONS: In isolated, left-sided CDH patients, HiOI is associated with higher mortality, greater length of stay, more ventilator days and increased respiratory support at discharge. HiOI is a better predictor of length of stay than O/E TFLV and %LH. TYPE OF STUDY: Retrospective Study LEVEL OF EVIDENCE: II.

Waiting list outcomes in pediatric lung transplantation: Poor results for children listed in adult transplant programs.

BACKGROUND: Low case volume has been associated with lower survival after pediatric lung transplantation. Our aim was to analyze waitlist outcomes among pediatric lung transplant centers in the USA. METHODS: We studied a cohort of 1,139 pediatric candidates listed in the Organ Procurement and Transplantation Network for lung transplantation between 2002 and 2014. Of these candidates, 720 (63.2%) received a transplant. Candidates were divided into groups according to the clinical activity of the center of listing: high-volume pediatric (≥4 transplants per year); low-volume pediatric (<4 transplants per year); and adult (transplant volume predominantly in adults). We used multivariate Cox regression analysis to identify independent risk factors for waitlist mortality. We also determined the transplant rate-or likelihood of transplant after listing-over the study period. RESULTS: Fifty-eight percent of the children and adolescents were listed in adult centers where the resultant transplant rate was low-only 42% received a transplant compared with 93% in pediatric programs. Listing in an adult program was also the most significant risk factor for death on the waiting list (hazard ratio 15.6, 95% confidence interval 5.8 to 42.1). CONCLUSIONS: Most children (58%) are listed for lung transplantation in adult centers and have a reduced rate of transplantation and a greater chance of waitlist mortality.

Transplant center volume and outcomes in lung transplantation for cystic fibrosis.

Transplant volume represents lung transplant (LTx) expertise and predicts outcomes, so we sought to determine outcomes related to center volumes in cystic fibrosis (CF). United Network for Organ Sharing data were queried for patients with CF in the United States (US) receiving bilateral LTx from 2005 to 2015. Multivariable Cox regression was used to model survival to 1 year and long-term (>1 year) survival, conditional on surviving at least 1 year. A total of 2025 patients and 67 centers were included in the analysis. The median annual LTx volumes were three in CF [interquartile range (IQR): 2, 6] and 17 in non-CF (IQR: 8, 33). Multivariable Cox regression in cases with complete data and surviving at least 1 year (n = 1510) demonstrated that greater annual CF LTx volume (HR per 10 LTx = 0.66; 95% CI: 0.49, 0.89; P = 0.006) but not greater non-CF LTx volume (HR = 1.00; 95% CI: 0.96, 1.05; P = 0.844) was associated with improved long-term survival in LTx recipients with CF. A Wald interaction test confirmed that CF LTx volume was more strongly associated with long-term outcomes than non-CF LTx volume (P = 0.012). In a US cohort, center volume was not associated with 1-year survival. CF-specific expertise predicted improved long-term outcomes of LTx for CF, whereas general LTx expertise was unassociated with CF patients' survival.

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.

Changes in body composition after lung transplantation in children.

BACKGROUND: The evaluation of nutritional status, including body composition measurements, in pediatric patients before and after lung transplant (LTx) can aid in adapting nutrition support and physical rehabilitation programs to meet individual patient needs. The purpose of this retrospective study was to determine the changes in weight, lean body mass (LBM), and body fat (BF) before and after LTx and their association with lung function in pediatric patients. METHODS: Included were 41 LTx patients, aged 3 months to 20.7 years, who had at least 2 body composition measurements determined by dual-energy X-ray absorptiometry (GE Lunar Prodigy, Waukesha, WI) in the first 2 years after LTx were measured pre-LTX and at 12 or 24 months post-LTX, for weight, LBM, and BF. RESULTS: Pre-LTx, 29% of patients had moderate and 12% had severe chronic malnutrition (growth stunting). This compares with 21% of patients being moderately LBM-depleted and 23% being BF-depleted. The weight change at 12 and 24 months was +9.3% (interquartile range, 5.6%-23%) and +4.7% (0.9%-11.6%), respectively; whereas the LBM change at 12 and 24 months was +15.2% (6.8%-17.1%) and +4.2% (-0.6% to 7.7%), respectively. LBM percentiles correlated with pulmonary function tests ( % predicted forced vital capacity [ρ = 0.36, p = 0.001] and forced expiratory volume in 1 second [ρ = 0.265, p = 0.015). CONCLUSIONS: Maximum weight and LBM gain occur at 12 months after LTx, with smaller gains noted at 24 months. Clinicians must look beyond height and weight and evaluate LBM and fat mass in pediatric patients after LTx.

Lung transplantation for childhood diffuse lung disease.

BACKGROUND: Pediatric diffuse lung diseases comprise a heterogeneous group of rare lung disorders which may lead to end stage lung disease and referral for lung transplantation. Previous studies are limited by small numbers of patients with specific forms of diffuse lung disease. Children with all forms of diffuse lung disease who underwent lung transplantation at two pediatric centers were evaluated in terms of several pre- and post-transplant factors and compared to children with other end stage lung disorders. METHODS: A retrospective chart review was performed on all patients transplanted between October 1, 2002 and June 15, 2007 at Texas Children's Hospital and St. Louis Children's Hospital. Multiple pre-transplant characteristics and post-transplant morbidities and mortality were compared between diffuse lung disease, cystic fibrosis, and pulmonary vascular disease groups. RESULTS: There were 31 diffuse lung disease (DLD), 57 cystic fibrosis (CF), and 16 pulmonary vascular disease (PVD) patients included in our analysis. Patients with DLD had significantly higher pre-transplant morbidity including lower percent predicted of forced expiratory volume in first second (P = 0.013) and more patients with pulmonary hypertension (P = 0.001) and hypercapnia (P = 0.031). Compared to CF patients, more DLD and PVD patients required invasive ventilation (P = 0.001) and care in the pediatric intensive care unit (P = 0.001). After transplant, there was a difference among the three groups with regards to number of acute allograft rejections but statistical limitations preclude knowing between which group the difference lies. A difference in time to bronchiolitis obliterans was found between the PVD and CF groups but not when compared to the DLD patients. The three groups had similar time to post-transplant lymphoproliferative disease, rate of infections, and survival. CONCLUSION: Lung transplantation is as successful for patients with end stage diffuse lung disease as compared to other lung transplant candidates.

Does donor arterial partial pressure of oxygen affect outcomes after lung transplantation? A review of more than 12,000 lung transplants.

INTRODUCTION: In lung transplantation (LTx), the arterial partial pressure of oxygen (PaO(2)) is traditionally regarded as critical information for assessment of donor lung function. Each center sets its own thresholds; by convention, a donor PaO(2) of less than 300 mm Hg has been considered disqualifying. Limited literature exists to support such a practice. We analyzed all LTxs performed in the United States over a 9-year period to assess the effect of donor PaO(2) on graft survival. METHODS: The United Network for Organ Sharing (UNOS) database was queried for LTx (January 2000-November 2009). Of 12,545 LTx performed, 12,045 (96%) had donor PaO(2) data on a fraction of inspired oxygen of 1.0, recorded at the time of procurement. RESULTS: Mean donor PaO(2) was 407 ± 140 mm Hg. The majority of LTxs had a donor PaO(2) greater than 300 mm Hg (9593 (80%]) whereas PaO(2) was 200 mm Hg or less in 1830 (15%) and 201 to 300 in 582 (5%) donors. Use of donors with a PaO(2) of less than 200 increased over time from 5% (45) in 2000 to 21% (295) in 2009 (P = .002). Kaplan-Meier survival analysis showed no difference in graft survival with differing donor PaO(2)s, irrespective of whether patients had a single or double LTx. A Cox multivariable analysis of 21 donor characteristics demonstrated that donor PaO(2) had no association with graft survival. CONCLUSIONS: Donor PaO(2) levels did not affect graft survival. The use of donors with lower PaO(2)s could substantially increase the donor pool. We are not suggesting that donor PaO(2) is not important when assessing potential lung donors but its level of importance in regard to other criteria appears less than previously believed.