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1.
Association between Polyunsaturated Fatty Acid Profile and Bronchial Inflammation in Bronchiolitis Obliterans
Jerkic, S. P., Bächle, L., Duecker, R. P., Gronau, L., Chiocchetti, A. G., Zielen, S., Schubert, R.
Mediators of inflammation. 2023;2023:3406399
Abstract
INTRODUCTION Bronchiolitis obliterans (BO) is a chronic lung disease, which occurs after an insult to the lower airways, in particular after airway infections or after stem cell transplantation, and which results in persistent inflammation. N-3 and n-6 polyunsaturated fatty acids (PUFA) have been shown to influence the inflammatory processes in chronic inflammatory conditions. Since BO is maintained by persistent pulmonary inflammation, a disbalanced n-6/n-3 fatty acid profile could support the inflammatory process in patients with BO and therefore, could become an approach to new therapeutic options. METHODS Twenty-five patients with BO (age: 13; 7-39) and 26 healthy controls (age: 19; 7-31) participated in the study. Lung function (forced viral capacity (FVC), forced expiratory volume 1 (FEV1), residual volume (RV)), and lung clearance index (LCI) were measured. Induced sputum was analyzed for cytology and cytokine levels (IL-1ß, IL-6, IL-8, TNF-α) using cytometric bead array (CBA). The PUFA profile was determined in the serum and induced sputum by gas chromatography. RESULTS Patients presented with significantly lower FVC and FEV1 as well as higher RV and LCI measurements compared to the control group. Apart from a massive airway inflammation indicated by elevated numbers of total cells and neutrophils, the CBA analysis showed significantly increased levels of IL-1β, IL-6, and IL-8. The analysis of PUFA in sputum and serum revealed a significant difference in the ratio between the n-6 PUFA arachidonic acid (AA) and the n-3 PUFA docosahexaenoic acid (DHA) (AA : DHA). Furthermore, the AA : DHA ratio significantly correlated with the inflammatory cytokines in induced sputum. CONCLUSION Lung function in BO is significantly impaired and associated with uncontrolled neutrophil-dominated airway inflammation. Furthermore, the imbalance in the AA/DHA ratio in favor of n-6 PUFA demonstrates a pro-inflammatory microenvironment in the cell membrane, which correlates with the inflammatory cytokines in induced sputum and might be an option for an anti-inflammatory therapy in BO.
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2.
Prognostic implication of pre-transplant FEV(1) on long-term outcomes following allogeneic hematopoietic stem cell transplantation
Novitzky-Basso, I., Lam, W., Chiarello, C., Pasic, I., Law, A. D., Michelis, F. V., Gerbitz, A., Viswabandya, A., Lipton, J. H., Kumar, R., et al
European journal of haematology. 2023
Abstract
BACKGROUND Pre-transplant pulmonary function testing (PFT) is essential before allogeneic hematopoietic stem cell transplant (HCT), yet the optimal cutoff value for affecting transplant outcomes remains poorly defined. STUDY DESIGN Retrospective analysis of pre-HCT PFT data from 605 consecutive patients at the Princess Margaret Cancer Centre between January 1, 2004 and December 31, 2013 used binary recursive partitioning to identify cutoff values for overall survival (OS) as an endpoint of transplant outcomes. These values were compared to HCT comorbidity index (HCT-CI) FEV(1) cutoffs for OS, cumulative incidence of relapse and non-relapse mortality. RESULTS FEV(1) ≥ 81% was the identified cutoff point. The OS rate at 3 years showed 49.8% (FEV(1) ≥ 81%) vs. 36.6% (<81%, p < .001). For HCT-CI cutoffs, the OS rate at 3 years for FEV(1) ≥ 80%, 66%-80% and ≤65% were 49.0%, 38.1% and 37.6% (p = .011), respectively. Multivariate analysis confirmed that FEV(1) ≥ 81% predicted reduced mortality (HR 0.682, p = .001). Subgroup analysis showed both FEV(1) ≥ 81% and FEV(1) by HCT-CI cutoffs may stratify patients according to OS and NRM risk in subgroups receiving myeloablative, but not reduced intensity conditioning. CONCLUSION FEV(1) ≥ 81% can predict OS and NRM in our cohort and is potentially simpler when risk stratifying patients undergoing allogeneic HCT, particularly those receiving myeloablative conditioning.
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3.
The ISHLT Chronic Lung Allograft Dysfunction Consensus Criteria is Applicable to Pulmonary Chronic Graft-versus-Host Disease
Pang, Y., Charya, A. V., Keller, M. B., Sirajuddin, A., Fu, Y. P., Holtzman, N. G., Pavletic, S. Z., Agbor-Enoh, S.
Blood advances. 2022
Abstract
Pulmonary chronic graft-versus-host disease (PcGvHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 NIH chronic GvHD (cGvHD) Consensus Criteria (NIH Criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 Criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGvHD and compared the performance of this criteria with the NIH Criteria to identify high-risk PcGvHD patients. We reviewed consecutive patients in a cGvHD natural history protocol (NCT00092235) and adapted the 2019 CLAD Criteria (the Adapted Criteria) to define PcGvHD as post-HCT FEV1 <80% predicted value, with four phenotypes: obstructive, restrictive, mixed obstructive/restrictive and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the Adapted Criteria, including obstructive (n = 12, 3.4%), restrictive (n=67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%) and undefined (n = 40, 11.4%). In these patients, less than half (n= 78) met the NIH criteria for BOS (NIH+), the rest (n=88) did not (NIH-). The NIH- subjects showed increased risk of death compared to those without PcGvHD (HR = 1.88, 95%CI = 1.20-2.95, p = 0.006) that was similar to NIH+ subjects (p = 0.678). Our study demonstrated the potential of the Adapted Criteria in identifying high risk PcGvHD patients that have been missed by the NIH Criteria. The Adapted Criteria could become a valuable tool to better phenotype and study lung disease in cGvHD.
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4.
Significance of alveolar nitric oxide concentration in the airway of patients with organizing pneumonia after allogeneic hematopoietic stem cell transplantation
Kajimura, Y., Nakamura, Y., Hirano, T., Tanaka, Y., Yamamoto, K., Tokunaga, Y., Sasaki, T., Oishi, K., Yujiri, T., Matsunaga, K., et al
Annals of hematology. 2022
Abstract
Organizing pneumonia (OP) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a manifestation of peripheral airway/alveolar inflammation. Recently, alveolar nitric oxide concentration (Calv) has been revealed as a noninvasive marker of peripheral airway inflammation; however, whether Calv levels are associated with OP and peripheral airway in patients after allo-HSCT remains unclear. Herein, we evaluated whether Calv levels could reflect the presence of OP and structural airway changes in patients after allo-HSCT. We measured the eNO levels of 38 patients (6 with OP and 32 without OP) who underwent allo-HSCT. Three-dimensional computed tomography (CT) analysis of the airway was performed in 19 patients. We found that in patients with OP, Calv levels were significantly higher than in those without OP (10.6 vs. 5.5 ppb, p < 0.01). Receiver-operating characteristic analyses revealed a Calv cut-off value for OP detection of 10.2 ppb. No significant differences in the patient characteristics, except for the presence of OP (p < 0.01), were noted between the two groups stratified by the Calv cut-off value. Three-dimensional CT images of the airway revealed gradually increasing positive correlations between Calv levels and airway wall area of the third-, fourth-, and fifth-generation bronchi (r = 0.20, 0.31, 0.38; p = 0.42, 0.19, 0.038, respectively), indicating that Calv levels are strongly correlated with the wall thickness of the distal bronchi. Our results suggest that the Calv level may be a useful noninvasive detectable marker for OP after an allo-HSCT.
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5.
Association between early corticosteroid administration and long-term survival in non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation
Kambara, Y., Fujii, N., Usui, Y., Yamamoto, A., Higo, H., Fujiwara, H., Asada, N., Ennishi, D., Nishimori, H., Fujii, K., et al
International journal of hematology. 2022
Abstract
Non-infectious pulmonary complications (NIPCs) after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with poor outcomes. It is important to maximize the effectiveness of primary treatment because secondary treatment has not been established. We analyzed data from 393 patients who underwent allogeneic HSCT during a 10-year period. Thirty-seven were diagnosed with NIPCs, which consisted of idiopathic pneumonia syndrome, bronchiolitis obliterans, and interstitial lung disease including cryptogenic organizing pneumonia. Among these, 18 died (Dead group) while 19 remained alive (Alive group) during the study period. The median time between NIPC diagnosis and first administration of ≥ 1 mg/kg/day corticosteroids (prednisolone dose equivalent) was significantly longer in the Dead group than the Alive group, at 9 days versus 4 days (p = 0.01). We further divided these cases into those who received prednisolone within seven days and after 8 days. We found that the ≤ 7 days group were more likely to survive after their NIPC diagnosis compared to the ≥ 8 days group (p = 0.06). Our analysis showed that early initiation of corticosteroid therapy is associated with long-term survival in NIPCs.
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6.
Multiple breath washout testing to identify pulmonary chronic graft versus host disease in children after haematopoietic stem cell transplantation
Rayment, J. H., Sandoval, R. A., Roden, J. P., Schultz, K. R.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Pulmonary chronic graft versus host disease (p-cGvHD) is a highly morbid, late complication of haematopoietic stem cell transplantation (HSCT). The 2014 NIH cGvHD consensus criteria require a tissue biopsy or a drop in spirometry (with other features) to establish the diagnosis of p-cGvHD. Unfortunately, children are often incapable of performing spirometry, which can delay the diagnosis of this condition. Multiple breath washout testing (MBW) can detect abnormal pulmonary physiology in older children and adults after HSCT, but its feasibility and utility have not been assessed in younger children and in those who cannot perform spirometry. OBJECTIVE In this study, we assess the feasibility and sensitivity of MBW to detect p-cGvHD in children as young as 3 years of age following HSCT STUDY DESIGN : We performed a cross sectional analysis of children age 3 to 18 years, between 100 days and 5 years after allogenic HSCT. Participants were recruited from the HSCT population at BC Children's Hospital (Vancouver, Canada). All participants attempted nitrogen MBW and children age 6 years and over attempted spirometry. Non-parametric statistical techniques were employed; descriptive statistics used median (interquartile range [IQR]) and group medians were compared using Wilcoxon rank-sum test RESULTS : Twenty-six children, median age 11.0 (range 3.6-18.5) years, were recruited a median of 26.4 (IQR 15.7, 51.8) months after HSCT. Six of the 26 children (23%) had a clinical diagnosis of p-cGvHD. MBW was successful in all (26/26, 100%) participants. The lung clearance index (LCI; the primary outcome of MBW) was higher in those with a history of p-cGvHD (median 11.8 [IQR 9.6, 18.7]) than in those with no history of cGvHD (median 7.7 [IQR 7.1, 8.0]; p=0.001) or a history of extra-pulmonary cGvHD (median 7.5 [IQR 6.9, 7.6], p=0.007). A threshold LCI=9 resulted in a sensitivity of 100% and specificity of 90% for the correct identification of clinically diagnosed p-cGvHD using MBW (area under the receiver operator characteristic curve is 0.97 [95%CI 0.80, 0.99]) Spirometry was successful in most (17/26, 65%) participants. Similar to LCI, FEV1/FVC could distinguish between p-cGvHD and no cGvHD (p=0.02) and extrapulmonary cGvHD (p=0.01). FEV1 alone could not distinguish between either of these groups (p=0.87, p=0.24 respectively). CONCLUSIONS MBW is feasible in young children after HSCT and in those who cannot perform spirometry. LCI has high discriminative power for correctly identifying p-cGvHD but these preliminary results require confirmation in a larger validation cohort.
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7.
The predictive value of pulmonary function test before transplantation for chronic pulmonary graft-versus-host-disease after allogeneic hematopoietic stem cell transplantation
Yang, L., Cheng, J., Li, F., Qian, R., Zhang, X., Jin, S., He, X., Xu, T., Hu, X., Ma, X., et al
BMC pulmonary medicine. 2022;22(1):473
Abstract
BACKGROUND Pulmonary chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a devastating complication and often diagnosed at a late stage when lung dysfunction is irreversible. Identifying patients before transplant who are at risk may offer improved strategies to decrease the mortality. Bronchiolitis obliterans syndrome (BOS) is the typical manifestation of pulmonary cGVHD, which is clinically diagnosed by pulmonary function test (PFT). This study aimed to evaluate the predictive value of PFT pre-HSCT for BOS. METHODS A single center cohort of 923 allo-HSCT recipients was analyzed, including 15 patients who developed pulmonary cGVHD. Kaplan-Meier method was used to analyze the 3 year progression free survival and 3 year overall survival (OS). A Cox regression model was applied for univariate and multivariate models. RESULTS The 3 year cumulative incidence of pulmonary cGVHD was 2.04% (95% CI 1.00-3.08%). According to the cut-off values determined by receiver operator characteristic curve, higher ratio of forced expiratory volume during one second to forced vital capacity (FEV1/FVC) pre-HSCT was correlated to a lower incidence of pulmonary cGVHD [0.91% (95% CI 0.01-1.81%) vs. 3.61% (95% CI 1.30-5.92%), P < 0.01], and so as peak expiratory flow to predictive value (PEF/pred) [0.72% (95% CI 0-1.54%) vs. 3.74% (95% CI 1.47-6.01%), P < 0.01]. Multivariate analysis showed that FEV1/FVC (HR = 3.383, P = 0.047) and PEF/pred (HR = 4.426, P = 0.027) were independent risk factors for onset of BOS. Higher FEV1/FVC and PEF/pred level were related to a significantly decreased 3 year non-relapse mortality. The 3 year OS was superior in patients with higher PEF/pred [78.17% (95% CI 74.50-81.84%) vs. 71.14% (95% CI 66.08-76.20%), P = 0.01], while FEV1/FVC did not show significance difference. CONCLUSION Our results suggested that PFT parameters such as PEF/pred and FEV1/FVC could be predictors for pulmonary cGVHD and even transplant outcomes before HSCT.
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8.
Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation
Kishida, Y., Shingai, N., Hara, K., Yomota, M., Kato, C., Sakai, S., Kambara, Y., Atsuta, Y., Konuma, R., Wada, A., et al
Scientific reports. 2022;12(1):14155
Abstract
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 (%FEV(1)), and FEV(1)/forced VC ratio (FEV(1)%), 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.
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9.
Pulmonary Function is a Strong Predictor of 2-year Overall Survival and Non-relapse Mortality after Allogenic Hematopoietic Cell Transplantation
Schierbeck, F., Mortensen, J., Andersen, N. S., Friis, L. S., Kornblit, B., Petersen, S. L., Schjødt, I., Sengeløv, H.
European journal of haematology. 2022
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Abstract
OBJECTIVES The purpose of the study was to assess the validity of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and of pulmonary comorbidity prior to hematopoietic cell transplantation (HCT) in terms of predicting non-relapse mortality (NRM) and overall survival (OS). METHODS In this retrospective single-center study of 663 consecutive adult recipients of HCT, we stratified patients into groups by pulmonary comorbidity: low-risk, intermediate-risk and high-risk. The predictive value of this pulmonary comorbidity score (PCS) was compared to HCT-CI. RESULTS In univariate analysis, the HCT-CI and the PCS were associated with OS after transplantation when comparing patients in high-risk groups with patients in low-risk groups. Using the PCS, the hazard ratios (HRs) of the 2-year OS in the entire population and in the myeloablative conditioning (MAC) group were 1.98 (P<0.001) and 3.27 (P<0.001), respectively, whereas the HRs using the HCT-CI were 1.83 (P<0.001) and 2.57 (P=0.002). The 2-year NRM incidence in the three risk-groups in the entire population was significant using both indexes. In the MAC group, the 2-year NRM was significant using the PCS (P=0.003), but not using the HCT-CI (P=0.23). CONCLUSIONS Our study suggest that pulmonary function alone is a strong predictor of 2-year OS and NRM after HCT.
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10.
Pleuroparenchymal fibroelastosis after hematopoietic stem cell transplantation in children: a propensity score-matched analysis
Oh, S. L., Lee, J. W., Yoo, S. Y., Kim, J. H., Kim, Y. J., Han, J., Kim, K., Kim, J., Jeon, T. Y.
European radiology. 2022
Abstract
OBJECTIVES To investigate the incidence, risk factors, and clinical outcomes of pleuroparenchymal fibroelastosis (PPFE) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. METHODS 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. RESULTS 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). CONCLUSIONS PPFE represents a severe type of LONIPC after HSCT. HSCT recipients with pneumonia after HSCT may have an increased risk of PPFE. KEY POINTS • 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.