Late-onset Noninfectious Pulmonary Complications Research Articles

Late-Onset Noninfectious Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience.

We aimed to reveal the incidence of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome and risk factors involved in development. In this cross-sectional study, we retrospectively investigated 745 patients who underwent allogeneic hematopoietic stem cell transplantation in our hospital between January 2000 and December 2020. We evaluated demographic characteristics, comorbidities, and hematopoietic stem cell transplantation characteristics to determine possible risk factors affecting development of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome. Of 745 patients, 8.9% (n = 66) had late-onset noninfectious pulmonary complications. Complications included 38 patients with bronchiolitis obliterans syndrome, 13 with venous thromboembolism, 8 with cryptogenic organizing pneumonia, 5 with pneumothorax, 4 with interstitial lung disease-restrictive graft-versus-host disease, 5 with bronchiectasis, 2 with pneumomediastinum, and 1 with pleural effusion. Patients with and without complications were not significantly differentin terms of smoking history, hematopoietic stem cell transplantation characteristics, and conditioning regimens. Patients with complications had higher busulfan and lower antithymocyte globulin use than those without complications (both P<.05). Patients with complications more commonly had hematopoietic stem cell transplantation from related donors and chronic graft-versus-host disease (P < .05). Patients with bronchiolitis obliterans syndrome had more frequent use of busulfan (P <.05) but less frequent use of total body irradiation (P <.05) and antithymocyte globulin (P <.05) than those without this syndrome. Rate of hematopoietic stem cell transplantation from a related donor (P < .05) and frequency of chronic graftversus-host disease (P < .001) were significantly higher in patients with bronchiolitis obliterans syndrome, presented with bronchiectasis (78.6%), air trapping (67.9%), bronchial wallthickening (53.6%), and mosaic attenuation (39.3%) in thorax computed tomography. Pretransplant spirometry did not predict bronchiolitis obliterans syndrome development. Determining risk factors for late-onset noninfectious pulmonary complications is needed to aid in prevention and follow-up.

Late-onset pulmonary complications following allogeneic hematopoietic cell transplantation in pediatric patients: a prospective multicenter study.

The primary objective of our multicenter prospective study was to describe the incidence of late-onset non-infectious pulmonary complications (LONIPCs) in children undergoing hematopoietic cell transplantation (HCT) using sensitive criteria for pulmonary function test (PFT) abnormalities including the non-specific pattern of airflow obstruction. Secondary objectives were to assess the factors associated with LONIPC occurrence and the sensitivity of the 2014 NIH-Consensus Criteria of bronchiolitis obliterans syndrome (BOS). PFT and clinical assessment were performed prior to HCT and at 6, 12, 24, and 36 months post-HCT. LONIPC diagnosis was validated by an Adjudication Committee. The study comprised 292 children from 12 centers. Thirty-two individuals (11%, 95% CI: 8-15%) experienced 35 LONIPCs: 25 BOS, 4 interstitial lung diseases, 4 organizing pneumonia and 2 pulmonary veno-occlusive diseases. PFT abnormalities were obstructive defects (FEV1/FVC z-score < -1.645; n = 12), restrictive defects (TLC < 80% predicted, FEV1 and FVC z-scores < -1.645; n = 7) and non-specific pattern (FEV1 and FVC z-score< -1.645, FEV1/FVC z-score > -1.645, and TLC > 80% predicted; n = 8). HCT for malignant disease was the only factor associated with LONIPC (P = 0.04). The 2014 NIH-Consensus Criteria would only diagnose 8/25 participants (32%) as having BOS. In conclusion, 11% of children experienced a LONIPC in a prospective design. Clinical Trials.gov identifier (NCT number): NCT02032381.

Hematopoietic Stem Cells Transplant (HSCT)-Related Chronic Pulmonary Diseases: An Overview.

Recipients of HSCT have a high risk of infective and non-infective pulmonary diseases. Most patients with pulmonary involvement present multiple pathogenetic mechanisms simultaneously with complex interactions. Therefore, it can be difficult to distinguish the contributions of each one and to perform studies on this subject. In this opinion article, we discuss only chronic pulmonary manifestations, focusing on LONIPCs (late-onset non-infectious pulmonary complications). This term embraces drug-related toxicity, allergies, and chronic pulmonary graft versus host disease (GvHD) in all its recently identified clinical variants. Among LONIPCs, GvHD represents the most critical in terms of morbidity and mortality, despite the rapid development of new treatment options. A recently emerging perspective suggests that pulmonary lung rejection in transplant patients shares striking similarities with the pathogenesis of GvHD. In a pulmonary transplant, the donor organ is damaged by the host immune system, whereas in GvHD, the donor immune system damages the host organs. It constitutes the most significant breakthrough in recent years and is highly promising for both hematologists and thoracic transplant surgeons. The number of patients with LONIPCs is scarce, with heterogenous clinical characteristics often involving several pathogenetic mechanisms, making it challenging to conduct randomized controlled trials. Therefore, the body of evidence in this field is scarce and generally of low quality, leading to jeopardized choices in terms of immunosuppressive treatment. Moreover, it risks being outdated by common practice due to the quick evolution of knowledge about the diagnosis and treatment of LONIPCs. The literature is even more pitiful for children with pulmonary involvement related to HSCT.

Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation in children: a propensity score-matched analysis.

To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. This single-center, retrospective, case-control study included 738 consecutive patients who underwent chest CT more than 3 months after HSCT. We identified patients who fulfilled the diagnostic criteria for PPFE and assessed their clinical characteristics and radiologic findings. Propensity score-matched analysis was performed using four covariates (age, sex, HSCT type, and primary disease). The risk factors and clinical outcomes of PPFE were analyzed using the Fine and Gray regression model and stratified log-rank test in the matched groups. PPFE was identified in 4% (31/738, 8.3 ± 3.1 years, 15 males) of the pediatric HSCT recipients with a median time of 2.7 years after HSCT, and it occurred following allogeneic (5%, 15/317), autologous (4%, 15/379), or both (2%, 1/42). Matching yielded 30 and 130 cases in the PPFE and control groups, respectively. The PPFE group showed more frequent late-onset noninfectious pulmonary complications (LONIPCs) and pneumonia more than 3 months after HSCT (p < 0.05). Multivariable analysis showed a significantly higher risk of PPFE in HSCT recipients who had pneumonia more than 3 months after HSCT (hazard ratio = 10.78 [95% confidence interval: 4.29, 27.13], p < 0.001). The PPFE group showed higher mortality (73%, 22/30) and poorer median overall survival (6.8 years [95% confidence interval: 4.1, 9.5]) than the control group (p < 0.001). PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE. • The incidence of pleuroparenchymal fibroelastosis is not negligible (4%), and it can occur after either allogeneic or autologous hematopoietic stem cell transplantation. • Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation showed poor outcome with a high mortality rate of 73% and median overall survival of 6.8 years. • After hematopoietic stem cell transplantation, pneumonia may increase the risk of pleuroparenchymal fibroelastosis development in children. • Lung biopsy should not be indicated in patients with pleuroparenchymal fibroelastosis findings on chest CT as it can cause refractory pneumothorax without helping the diagnosis.

Sleep-related breathing disorder in non-infectious pulmonary complications after pediatric allogeneic stem cell transplantation

BackgroundChronic lung problems are a rare but serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). We studied clinical phenotypes and polysomnography appearance of breathing abnormality in late onset non-infectious pulmonary complications (NIPS).MethodsWe reviewed Finnish national reference database between the years 1999 and 2016. We identified 12 children with most severely decreased pulmonary function and performed polysomnography and 24 aged-matched controls out of 325 performed pediatric allogeneic HSCTs.ResultsAll patients with NIPS had severely decreased pulmonary function already at 6 months post HSCT with median FEV1 value 42% (interquartile range (IQR) 30–52%) of predicted normal values. Seven children had obstructive and five children more restrictive lung function. Children with obstructive lung function showed laborious breathing (7/7), decreased oxygenation and ventilation-to-perfusion mismatch (6/7), or REM-sleep-related hypoventilation (4/7) on polysomnography. Children with restrictive lung function (5/12) did not show sleep-related breathing disorder.ConclusionsChildren going through allogeneic HSCT who develop severe chronic obstructive lung function are more likely to present with sleep-related hypoxia and hypoventilation than children with restrictive lung function.ImpactChildren with severe obstructive lung function and chronic lung graft-versus-host disease following hematopoietic stem cell transplantation are more likely to present with sleep-related mild hypoxia and hypoventilation than children with restrictive lung disease.To our knowledge there are no reports on sleep-related breathing disorders and ventilatory function measured by polysomnography in children with pulmonary complications after allogeneic HSCT.Polysomnography may add to the differential diagnostics between patients with BOS and other non-infectious pulmonary complications.

Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation

Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.

Late-Onset, Noninfectious Pulmonary Complications following Allogeneic Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study of Long-Term Survivors

Background: Survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are at risk for pulmonary adverse events. Data on late-onset noninfectious pulmonary complications in long-term adult survivors of allo-HSCT are limited and incomplete. Objectives: This study aimed (1) to determine occurrence and degree of pulmonary sequelae in adult survivors of allo-HSCT and (2) to identify associations between pulmonary function, high-resolution CT (HRCT), and clinical characteristics. Method: In a nationwide, single-center cross-sectional study, 103 survivors (aged median [range] 35 [17–58] years, 53% females) were examined 17 (6–32) years after allo-HSCT and compared with healthy controls (n = 105). Methods included pulmonary function tests and HRCT. Results: Chronic graft-versus-host disease was diagnosed in 33% of survivors, including 12% with bronchiolitis obliterans syndrome (BOS). Mean lung volumes (TLC, FVC, and FEV₁) and gas diffusing capacity were >80% of predicted for the survivors as a group, but significantly lower than in healthy controls. Pathological HRCT findings were detected in 48% of the survivors (71% airways disease, 35% interstitial lung disease, and 24% apical subpleural interstitial thickening). Air trapping (%) on HRCT correlated with % predicted FEV₁, p < 0.001. In a multiple logistic regression model, both BOS and pathological findings on HRCT were associated with chemotherapy prior to allo-HSCT, p < 0.05. Conclusions: Long-term allo-HSCT survivors had significantly lower pulmonary function than age- and gender-matched healthy controls and nearly half had pathological findings on HRCT. Longitudinal data will determine if pulmonary sequelae will remain stable or progress. We recommend lifelong monitoring of pulmonary function in allo-HSCT survivors. HRCT provides additional information, but is not suited for surveillance.

Changes in the health-related quality of life and social reintegration status after lung transplantation following hematopoietic stem cell transplantation

Late-onset non-infectious pulmonary complications (LONIPCs) after allogeneic hematopoietic stem cell transplantation are fatal; however, lung transplantation might achieve good survival. Nevertheless, improving the health-related quality of life (HRQoL) is still a major concern. This study aimed to investigate, in detail, the recovery in HRQoL and social reintegration status after lung transplantation in patients with LONIPC after allo-HSCT. This prospective cohort study involving 18 patients examined changes in the health and social reintegration status after lung transplantation following LONIPC. Physical function and HRQoL were lowest before lung transplantation. Two years after lung transplantation, the dyspnea scores and performance status improved. Most patients had made a successful return to society, and patients who achieved social reintegration were significantly younger and had a good performance status. However, their Physical Functioning score and Physical Component Summary did not show significant improvement after lung transplantation. Moreover, recipients who were unemployed before lung transplantation were likely to remain unemployed and continued to show poor HRQoL. These results showed poor recovery of HRQoL, especially in terms of physical function, and the likelihood of failure to reintegrate into society within 2years after lung transplantation. It is necessary to consider long-term follow-up and physical training to improve social reintegration and HRQoL.

Effective treatment of late-onset noninfectious pulmonary complication with ruxolitinib in an 8-year-old boy.

Ruxolitinib could be considered as an option in the treatment of LONIPCs in children when other treatments are ineffective. Spirometry is a valuable tool for both diagnosis and follow-up of LONIPCs in children. https://bit.ly/3BmOYfb

Lung transplantation for late-onset non-infectious chronic pulmonary complications of allogenic hematopoietic stem cell transplant

BackgroundLate onset non-infectious pulmonary complications (LONIPCs) following allogenic hematopoietic stem cell transplantation (allo-HSCT) confer a significant mortality risk. Lung transplantation (LTx) has the potential to provide survival benefit but the impact of prior allo-HSCT on post-LTx outcomes is not well studied.MethodsThis retrospective, single-centre cohort study assessed the post-LTx outcomes of adults with LONIPCs of allo-HSCT. Outcomes of LTx for LONIPCs were compared to propensity-score matched LTx controls (n = 38, non-HSCT) and recipients of re-LTx (n = 70) for chronic lung allograft dysfunction (CLAD).ResultsNineteen patients underwent DLTx for LONIPCs of allo-HSCT between 2003 and 2019. Post-LTx survival was 50% at 5-years. Survival to 1-year post-LTx was similar to matched controls (p = 0.473). Survival, conditional on 1-year survival, was lower in the allo-HSCT cohort (p = 0.034). An increased risk of death due to infection was identified in the allo-HSCT cohort compared to matched controls (p = 0.003). Compared to re-LTx recipients, the allo-HSCT cohort had superior survival to 1-year post-LTx (p = 0.034) but conditional 1-year survival was similar (p = 0.145).ConclusionThis study identifies an increased risk of post-LTx mortality in recipients with previous allo-HSCT, associated with infection. It supports the hypothesis that allo-HSCT LTx recipients are relatively more immunosuppressed than patients undergoing LTx for other indications. Optimisation of post-LTx immunosuppressive and antimicrobial strategies to account for this finding should be considered.

Physical function after lung transplantation for late-onset noninfectious pulmonary complications after allogeneic hematopoietic stem cell transplantation.

Late-onset noninfectious pulmonary complications (LONIPCs) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are fatal, and lung transplantation is the only curative treatment. Although lung transplantation for LONIPCs may confer good survival rates, it is unclear whether or how impaired physical functioning is restored. Thus, this study aimed to investigate the long-term course and associated changes in physical functions after lung transplantation in patients with LONIPCs after allo-HSCT. This prospective cohort study enrolled 15 patients who received lung transplantation for LONIPCs after allo-HSCT between 2012 and 2018. Dyspnea scores, performance status, physical function, and exercise tolerance were assessed before lung transplantation and up to 2 years after transplantation. Two years after lung transplantation, the dyspnea scores and performance status improved, but did not recover completely. Physical function was assessed using the knee extensor strength (KES) and 6-min walk test (6MWT); the results were poor until 3 months after transplantation but improved over 2 years. The 6MWT distance showed improvement to a nearly healthy level (562.7 m). Recovery of exercise tolerance was associated with recovery in % vital capacity (%VC; r=0.5) and KES (r=0.4) from 3 months to 2 years after lung transplantation. Furthermore, a flat thorax, which is a characteristic of patients with LONIPCs, affected the %VC at 2 years after transplantation (r=0.8). Lung transplantation for LONIPCs may restore impaired physical function. A multifaceted rehabilitation program should be considered, especially to improve muscle weakness and pulmonary function.

The thoracic air-leak syndrome (TALS): the frequency of occurrence and radiological signs in the structure of late non-infectious lung lesions in children after the allogeneic HSСT

The thoracic air-leak syndrome (TALS) can be a presentation of late-onset noninfectious pulmonary complications in children with a chronic pulmonary graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation. We determined the frequency of occurrence of TALS in patients of the Center after HSСT in the period from January 2012 to December 2017. We have described the main X-ray signs of the Thoracic air-leak syndrome and manifestations of late onset noninfectious pulmonary complications in children. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Parents patients agreed to use personal data in research and publications.

Cause of pleuroparenchymal fibroelastosis following allogeneic hematopoietic stem cell transplantation.

Late-onset noninfectious pulmonary complications (LONIPCs) are life-threatening complications after hematopoietic stem cell transplantation (HSCT). Pleuroparenchymal fibroelastosis (PPFE) is a LONIPC, but its etiology remains elusive. Chronic graft-versus-host disease (cGVHD) and alkylating agents used for conditioning have been considered possible causes of PPFE. Therefore, to investigate the primary cause of PPFE in allogeneic HSCT, we compared three secondary PPFE groups, namely, the post-lung-transplantation, post-autologous-HSCT or chemotherapy-alone, and post-allogeneic-HSCT groups, and focused on the coexistence of bronchiolitis obliterans (BO), a typical phenotype of cGVHD. We found a trend towards higher rates of PPFE with BO in the post-allogeneic-HSCT and post-lung-transplantation groups (71% and 90%, respectively) than in the post-autologous-HSCT or chemotherapy-alone group (25%). The incidence of BO following allogeneic HSCT is reportedly <10%. If PPFE in the post-allogeneic-HSCT group has no association with BO and is induced by alkylating agents rather than cGVHD, the incidence of BO in PPFE in this group is estimated to be <10%, which is inconsistent with our data (71%). Thus, this study suggests that PPFE following allogeneic HSCT could be mainly induced by cGVHD because the majority of cases are associated with BO, a typical phenotype of cGVHD.

Reconsidering Indication of Lung Transplantation for Late-Onset Noninfectious Pulmonary Complications after Hematopoietic Stem Cell Transplantation

Purpose Late-onset noninfectious pulmonary complications (LONIPCs) after hematopoietic stem cell transplantation (HSCT) may occur within 2 years after HSCT. Its prognosis is still poor with a survival rate of less than 20 % at 5 years after its diagnosis, and early lung transplantation (LT) may be required in some cases. However, according to the current international guideline, the time interval between HSCT and LT must be more than 5 years for patients with a history of hematologic malignancy. It should be also noted that blood type may be changed at the time of HSCT, however, ABO-incompatible lung transplantation is contraindicated in general. Therefore, we devised the following two policies.First, when the relapse risk of the original hematologic malignancy is judged to be less than 30 % by expert hematologists, patients are accepted as LT candidates.Second, when a recipient has no anti-A and / or B antibodies after HSCT, donors with incompatible ABO blood type have been accepted in living-donor lobar lung transplantation (LDLLT). The aim of this study was to assess LT outcomes in such patients. Methods Retrospective chart review was performed to identify patients who underwent LT for LONIPCs after HSCT at our institution between 2008 and 2017. Results Forty patients (32 LDLLTs) were identified. The median time interval between HSCT and LT was 64.5 months (range, 14-188 months). Thirty-one patients underwent HSCT for hematologic malignancy, and no patient developed relapse of the original hematologic malignancy after LT. The 5-year survival rate was 78.4 %. There was no significant difference in survival between patients with the time interval of more than 5 years (n=27) and less than 5 years (n=13). There were 4 cases of ABO incompatible LDLLTs. None of them developed complications related to ABO incompatibility. Conclusion Contrary to the current international guideline, our results suggest that carefully selected patients with LONIPCs may be accepted as lung transplant candidates even when the time interval between HSCT and LT is less than 5 years. ABO incompatible LDLLTs may be indicated when the recipient has no antibody to the respective living-donors after HSCT.

Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study

BackgroundRadiological pleuroparenchymal fibroelastosis (PPFE) lesion is characterized by pleural thickening with associated signs of subpleural fibrosis on high-resolution computed tomography (HRCT). This study evaluated the clinical significance of radiological PPFE as an isolated finding or associated with other interstitial lung diseases (ILDs) in patients having fibrotic ILDs and registered for cadaveric lung transplantation (LT).MethodsThis retrospective study included 118 fibrotic ILD patients registered for LT. Radiological PPFE on HRCT was assessed. The impact of radiological PPFE on clinical features and transplantation-censored survival were evaluated.ResultsRadiological PPFE was observed in 30/118 cases (25%): definite PPFE (PPFE concentrated in the upper lobes, with involvement of lower lobes being less marked) in 12 (10%) and consistent PPFE (PPFE not concentrated in the upper lobes, or PPFE with features of coexistent disease present elsewhere) in 18 (15%). Of these, 12 had late-onset non-infectious pulmonary complications after hematopoietic stem-cell transplantation and/or chemotherapy (LONIPCs), 9 idiopathic PPFE, and 9 other fibrotic ILDs (idiopathic pulmonary fibrosis, IPF; other idiopathic interstitial pneumonias, other IIPs; connective tissue disease-associated ILD, CTD-ILD, and hypersensitivity pneumonia, HP). Radiological PPFE was associated with previous history of pneumothorax, lower body mass index, lower percentage of predicted forced vital capacity (%FVC), higher percentage of predicted diffusion capacity of carbon monoxide, less desaturation on six-minute walk test, and hypercapnia. The median survival time of all study cases was 449 days. Thirty-seven (28%) received LTs: cadaveric in 31 and living-donor lobar in six. Of 93 patients who did not receive LT, 66 (71%) died. Radiological PPFE was marginally associated with better survival after adjustment for age, sex, %FVC, and six-minute walk distance < 250 m (hazard ratio 0.51 [0.25–1.05], p = 0.07). After adjustment for covariates, idiopathic PPFE and LONIPC with radiological PPFE was associated with better survival than fibrotic ILDs without radiological PPFE (hazard ratio 0.38 [0.16–0.90], p = 0.03), and marginally better survival than other fibrotic ILDs with radiological PPFE (hazard ratio, 0.20 [0.04–1.11], p = 0.07).Conclusionsidiopathic PPFE and LONIPC with radiological PPFE has better survival on the wait list for LT than fibrotic ILDs without radiological PPFE, after adjustment for age, sex, %FVC, and six-minute walk distance.

Whole-Body Lung Function Test–Derived Outcome Predictors in Allogenic Stem Cell Transplantation

Despite clinical advances, late onset pulmonary complications in adult recipients of allogenic stem cell transplantation are a major cause of morbidity and mortality. Reported incidence and risk factors in the literature vary broadly and are partly contradictory. Identification of pretransplant factors associated with major complications would be helpful to define individual treatment strategies and early initiation of preventive measures.To evaluate incidence and risk factors of late onset noninfectious pulmonary complications, with special regard to small airways disease (SAD) and bronchiolitis obliterans syndrome (BOS), indicating graft-versus-host disease, following myeloablative versus nonmyeloablative allogenic stem cell transplantation.We reviewed the clinical records and assessed the course of lung function and pulmonary complications in adults who underwent allogenic stem cell transplantation for hematological malignancies between 1999 and 2015 using nonmyeloablative (n = 179) or myeloablative (n = 130) conditioning at the Division of Hematology of the Medical University of Graz. All patients underwent body plethysmography pulmonary function test (PFT), diffusion capacity for carbon monoxide, and arterial blood gas analysis before and repeatedly after transplant. SAD was defined as maximal expiratory flow at 50% and 25% of forced vital capacity <70% predicted.Ventilatory disorders and gas transfer abnormalities were common before and after allogenic stem cell transplantation, independent of conditioning regimen. SAD was common in the nonmyeloablative (34%) and myeloablative (29%) groups. The 100-day post-transplant mortality was significantly associated with reduced pretransplant total lung capacity <80%. Mortality 100 days post-transplant was significantly associated with pretransplant SAD and a pretransplant smoking history. In this subset, a smoking history was independently associated with increased mortality, with a 5-year mortality of 45% compared with 26% in never-smokers. Pretransplant SAD was not predictive for the later development of BOS.Smoking history, pretransplant restrictive PFT, and pre-existing SAD are important risk factors for death following allogenic stem cell transplantation. However, pretransplant SAD is not a predictor of long-term complications, including BOS.

Noninfectious lung complications after allogeneic haematopoietic stem cell transplantation.

Epidemiological data on late-onset noninfectious pulmonary complications (LONIPCs) following allogeneic haematopoietic stem cell transplantation (HSCT) are derived exclusively from retrospective studies and are conflicting. We aimed to evaluate prospectively the incidence, risk factors and outcomes for LONIPCs.All consecutive patients scheduled to receive allogeneic HSCT between 2006 and 2008 at a university teaching hospital in France were screened for inclusion in the study. Eligible patients were those surviving at day 100. Among 243 screened patients, 198 patients were included in the analysis. The median (interquartile range) follow-up was 72.3 (15.2-88.5) months. 55 LONIPCs were diagnosed in 43 patients. Bronchiolitis obliterans syndrome (n=22) and interstitial lung disease (n=12) were the most common LONIPCs. At 36 months after inclusion, the estimated cumulative incidence of LONIPCs was 19.8% (95% CI 14.2-25.3%). The estimated median survival after the diagnosis of LONIPCs was 78.5 months (95% CI 20.0-not reached). Based on a multivariate Cox model, a history of chest irradiation anytime prior to HSCT, a history of pneumonia within 100 days post-HSCT and a low mean forced expiratory flow at 25-75% of forced vital capacity at day 100 were associated with the development of LONIPCs.Our data provide clues to identify patients at high risk of developing LONIPCs. These patients should be targeted for close monitoring to provide earlier LONIPC treatment or prophylactic treatment.

Lung transplantation after allogeneic stem cell transplantation: a pan-European experience.

Late-onset noninfectious pulmonary complications (LONIPCs) affect 6% of allogeneic stem cell transplantation (SCT) recipients within 5 years, conferring subsequent 5-year survival of 50%. Lung transplantation is rarely performed in this setting due to concomitant extrapulmonary morbidity, excessive immunosuppression and concerns about recurring malignancy being considered contraindications. This study assesses survival in highly selected patients undergoing lung transplantation for LONIPCs after SCT.SCT patients undergoing lung transplantation at 20 European centres between 1996 and 2014 were included. Clinical data pre- and post-lung transplantation were reviewed. Propensity score-matched controls were generated from the Eurotransplant and Scandiatransplant registries. Kaplan-Meier survival analysis and Cox proportional hazard regression models evaluating predictors of graft loss were performed.Graft survival at 1, 3 and 5 years of 84%, 72% and 67%, respectively, among the 105 SCT patients proved comparable to controls (p=0.75). Sepsis accounted for 15 out of 37 deaths (41%), with prior mechanical ventilation (HR 6.9, 95% CI 1.0-46.7; p<0.001) the leading risk factor. No SCT-specific risk factors were identified. Recurring malignancy occurred in four patients (4%). Lung transplantation <2 years post-SCT increased all-cause 1-year mortality (HR 7.5, 95% CI 2.3-23.8; p=0.001).Lung transplantation outcomes following SCT were comparable to other end-stage diseases. Lung transplantation should be considered feasible in selected candidates. No SCT-specific factors influencing outcome were identified within this carefully selected patient cohort.

Effect of reduced-intensity conditioning and the risk of late-onset non-infectious pulmonary complications in pediatric patients.

Late-onset non-infectious pulmonary complications (LONIPCs) contribute to higher morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we investigated the risk factors of LONIPCs in pediatric patients. Between 2001 and 2011, 74 pediatric patients (range, 7months to 22.7years old; median 6.5years old), including 29 with a primary immunodeficiency, underwent 80 allo-HSCTs at our institution. Sixty-seven patients who survived more than 3months after allo-HSCT were analyzed retrospectively. The median follow-up period was 1 973days (range, 126-5 145days). Nine patients (13.4%) developed LONIPCs between 90 and 3 578days after allo-HSCT. A myeloablative conditioning (MAC) regimen and chronic GVHD were determined as significant risk factors of LONIPCs. None of 18 patients who received the reduced-intensity conditioning (RIC) regimen developed LONIPCs, although there was no difference in overall survival between the MAC and RIC regimen. Notably, two immunodeficient patients who received busulfan-based MAC regimen under 2years old developed LONIPC with no history of chronic GVHD after 5years and 10years from SCT, respectively, suggesting the direct toxicity of busulfan. Our study's findings indicate that the RIC regimen reduces the risk of LONIPCs in pediatric patients.

Incidence, Risk Factors and Outcome of Late Onset Noninfectious Pulmonary Complications after Allogeneic Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study

Introduction: Late onset noninfectious pulmonary complications (LONIPCs) occurring beyond the third month following allogeneic hematopoietic stem cell transplantation (HSCT) are various and are associated with a poor outcome. Bronchiolitis obliterans (BO) is the most frequent LONIPC. Available epidemiological data are conflicting and exclusively come from retrospective studies.Methods: We conducted a prospective observational cohort study where all consecutive patients who were scheduled to receive an allogeneic HSCT between January, 31, 2006 and December, 31, 2008 at the university-teaching Saint Louis Hospital (Paris, France) were prospectively screened for inclusion in the study. Those allogeneic HSCT recipients surviving at day 100 were included in the cohort. They were followed-up for at least three years after HSCT. Clinical outcomes were the 3-year incidence and mortality of LONIPC, and the identification of early risk factors for LONIPC and specifically BO. This study is registered with ClinicalTrials.gov, number NCT 01219972.Results: 198 patients were included after a median of 101 [IQR: 99-106] days following HSCT, from a total of 243 screened patients. The actual median follow up of the 198 included patients was 72.3 months [IQR: 15.2-88.5]. 68 patients died within the first 36 months resulting in a 3-year overall survival after inclusion of 65.4% (95%CI: 59.1-72.4%). Fifty five episodes of LONIPC were diagnosed in 43 patients. These 55 LONIPC were diagnosed as BO (n=22), interstitial lung disease (n=12), and others. Ten patients had more than one LONIPC during the follow-up. At 36 months after inclusion, the estimated cumulative incidence of LONIPC was 19.8% (95%CI: 14.2-25.3%). The 36 months cumulative incidence of BOS was 10.7%, (95%CI: 6.3-15.1%). 18 patients with a LONIPC died during the follow up with an estimated median survival of 78.5 months (95%CI: 20.0-not reached) after the diagnosis of LONIPC. The occurrence of LONIPC was associated with an increased hazard of death (HR=2.18, 95%CI= 1.14; 4.15; p= 0.0181). Based on a multivariable Cox model, a chest irradiation prior to HSCT, a history of pneumonia within the 100 days post HSCT and a low FEF 25-75 at day 100 were associated with the development of LONIPC. The use of PBSC was predictive for BOS based on a multivariable Cox model both after multiple imputation and on the complete cases whereas both a history of post transplantation pneumonia and bronchial abnormalities on CT scan at day 100 were also identified as predictive factors after multiple imputation and a 10% FEV1 decline from baseline to day 100 was a predictive factor for BOS on the complete cases.Conclusion: our data give clues to identify high-risk patients for developing LONIPC/BO. These patients should be targeted for close monitoring, and so offer earlier treatment of LONIPC or prophylactic treatment to improve the outcome.Funding: The study was supported by an institutional grant from the French Ministry of Health (CRC 04118). DisclosuresPeffault De La Tour:PFIZER: Consultancy, Honoraria, Research Funding; ALEXION: Consultancy, Honoraria, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding.