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Detection of bronchiolitis obliterans syndrome using nitrogen multiple breath washout in children post-haemopoietic stem cell transplant
Westrupp, N., Berry, C. D., Cole, T., Shanthikumar, S., Welsh, L.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a severe complication following haemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI(2.5)) derived from the nitrogen multiple breath washout (N(2)MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. OBJECTIVE We aimed to examine the feasibility of performing surveillance N(2)MBW in children post-HSCT, and in an exploratory analysis, determine if LCI(2.5) led to earlier detection of BOS when compared to spirometric indices. STUDY DESIGN Participants aged 5 - 17 years were recruited prior to receiving HSCT into a prospective, single-centre, feasibility study at the Royal Children's Hospital, Melbourne. N(2)MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9 and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. RESULTS Twenty-one (12 male) children with a mean age of 13.4 (range 9.2-17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI(2.5), while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV(1)). Ninety-nine percent of N(2)MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while two participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI(2.5) ranging from 3 to 5 units and mean reductions in FEV(1) % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI(2.5) values were significantly worse when compared with the no BOS group (p<0.001). Relative changes in LCI(2.5) and FEV(1) were both predictive of BOS at 6 months post HSCT. CONCLUSION This study demonstrates that N(2)MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI(2.5) did not lead to earlier detection of BOS, when compared to spirometry.
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Lung Injury Prediction Model in Bone Marrow Transplantation: A Multicenter Cohort Study
Herasevich, S., Schulte, P. J., Hogan, W. J., Alkhateeb, H., Zhang, Z., White, B. A., Khera, N., Roy, V., Gajic, O., Yadav, H.
American journal of respiratory and critical care medicine. 2023
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Abstract
RATIONALE Pulmonary complications contribute significantly to non-relapse mortality following hematopoietic stem cell transplantation (HCT). Identifying high-risk patients can help enroll such patients into clinical studies to better understand, prevent and treat post-transplant respiratory failure syndromes. OBJECTIVE Develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. METHODS Patients underwent HCT between January 1, 2019, and December 31, 2021. Those in Rochester, Minnesota formed the derivation cohort and those from Scottsdale, Arizona or Jacksonville, Florida formed the validation cohort. The primary outcome was development of acute respiratory distress syndrome (ARDS), with secondary outcomes including need for invasive/noninvasive ventilation. Predictors were based on prior case-control studies. MEASUREMENTS AND MAIN RESULTS Of 2450 patients undergoing stem cell transplantation, there were 1718 hospitalizations (888 patients) in the training cohort and 1005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from pre-hospital predictors and 11 points from post-transplant or early (<24h) in-hospital predictors. The model performed well for predicting ARDS (C-statistic = 0.905, 95%CI: 0.870-0.941) and need for invasive/noninvasive ventilation (C-statistic = 0.863, 95%CI: 0.828-0.898). The test cohort differed markedly in demographic, medical and hematologic characteristics. The model performed well in this setting as well for predicting ARDS (C-statistic = 0.841 (95%CI: 0.782-0.900) and need for invasive/noninvasive ventilation (C-statistic = 0.872, 95%CI: 0.831-0.914). CONCLUSION A novel prediction model incorporating data elements from the pre-transplant, post-transplant and early in-hospital domains can reliably predict development of post-HCT acute respiratory failure.
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Pulmonary function and long-term survival in patients with PERDS after autologous hematopoietic stem cell transplantation
Zhang, Z., Wieruszewski, P. M., Hefazi Torghabeh, M., Hogan, W. J., Yadav, H.
Bone marrow transplantation. 2023
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The Role of Pre-bone Marrow Transplantation Pulmonary Function Test in Predicting Post-transplant Noninfectious Pulmonary Complications
Ahmed, A. S., Gassas, R. S., Ahmed, M. E., Osman, G., Alsaeed, A. S., Absi, A. N., Alamoudi, S. M., Alahmadi, M. D., Khalil, M. M., ElDadah, S. K., et al
Saudi journal of medicine & medical sciences. 2023;11(4):339-344
Abstract
BACKGROUND Pulmonary function test (PFT) is used as a tool for pre-transplant risk assessment and as a predictor of post-transplant outcomes. As there are currently few studies that discuss the role of PFT in bone marrow transplantation (BMT) patients in Saudi settings, and as the number of transplant patients with benign and malignant conditions continues to increase, this study was conducted with the aim of assessing the local practice. METHODS This retrospective cohort study included all adult patients who underwent BMT at Princess Noorah Oncology Center, King Abdulaziz Medical City, Jeddah, between 2014 and 2020. The association between established patient-related risk factors and the incidence of pulmonary complications among autologous and allogeneic groups was assessed. RESULTS A total of 186 patients were included (autologous = 143; allogenic = 43), of which 115 (61.8%) were male. At the pre-BMT phase, about 30% of the patients had comorbidities and 51% had received two rounds of salvage chemotherapy, while 16.1% had received radiation therapy. In the autologous group, the only PFT parameter that was a significant predictor of post-BMT pulmonary complications was forced vital capacity <80% (P = 0.012), while in the allogenic group, no parameter was significantly associated with pulmonary complications. The patient-related factors that were associated with respiratory distress in the autologous group were lung involvement (P = 0.03) and pre-transplant radiation (P = 0.044). CONCLUSION The findings of this study indicated that forced vital capacity <80% was a significant factor in predicting non-infectious complications in the autologous group. Furthermore, lung involvement and pre-transplant radiation were the patient-related factors associated with pulmonary complications.
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Metagenomic Next-Generation Sequencing for Pathogens in Bronchoalveolar Lavage Fluid Improves the Survival of Patients with Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation
Shen, Z., Wang, Y., Bao, A., Yang, J., Sun, X., Cai, Y., Wan, L., Huang, C., Xu, X., Niu, J., et al
Infectious diseases and therapy. 2023
Abstract
INTRODUCTION Unbiased metagenomic next-generation sequencing (mNGS) has been used for infection diagnosis. In this study, we explored the clinical diagnosis value of mNGS for pulmonary complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS From August 2019 to June 2021, a prospective study was performed to comparatively analyze the pathogenic results of mNGS and conventional tests for bronchoalveolar lavage fluid (BALF) from 134 cases involving 101 patients with pulmonary complications after allo-HSCT. RESULTS More pathogens were identified by mNGS than with conventional tests (226 vs 120). For bacteria, the diagnostic sensitivity (P = 0.144) and specificity (P = 0.687) were similar between the two methods. For fungus except Pneumocystis jirovecii (PJ), conventional tests had a significantly higher sensitivity (P = 0.013) with a similarly high specificity (P = 0.109). The sensitivities for bacteria and fungi could be increased with the combination of the two methods. As for PJ, both the sensitivity (100%) and specificity (99.12%) of mNGS were very high. For viruses, the sensitivity of mNGS was significantly higher (P = 0.021) and the negative predictive value (NPV) was 95.74% (84.27-99.26%). Pulmonary infection complications accounted for 90.30% and bacterium was the most common pathogen whether in single infection (63.43%) or mixed infection (81.08%). The 6-month overall survival (OS) of 88.89% in the early group (mNGS ≤ 7 days) was significantly higher than that of 65.52% (HR 0.287, 95% CI 0.101-0.819, P = 0.006) in the late group (mNGS > 7 days). CONCLUSIONS mNGS for BALF could facilitate accurate and fast diagnosis for pulmonary complications. Early mNGS could improve the prognosis of patients with pulmonary complications after allo-HSCT. TRIAL REGISTRATION ClinicalTrials.gov identifier, NCT04051372.
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Prognostic Significance of Early Declines in Pulmonary Function after Allogeneic Hematopoietic Stem Cell Transplantation
Yadav, H., Torghabeh, M. H., Hogan, W. J., Limper, A. H.
Respiratory care. 2023
Abstract
BACKGROUND Pulmonary function test (PFT) impairments are common after allogeneic hematopoietic stem cell transplantation. The prognostic significance of these declines on outcomes is not well understood. The objectives were to determine the frequency of declines in pulmonary function (FVC, FEV(1), and diffusing capacity for carbon monoxide [D(LCO)]) in the early post-transplantation period; and to determine the prognostic significance of these declines on mortality or development of bronchiolitis obliterans syndrome. METHODS This was a retrospective cohort study conducted at Mayo Clinic, Rochester, Minnesota. PFTs were obtained at baseline and at day +100. Competing risk survival models were developed, which accounted for pre-transplantation pulmonary function and relapse status. RESULTS Between January 1, 2005, and December 31, 2020, 1,145 subjects underwent allogeneic hematopoietic stem cell transplantation and had a pre-transplantation PFT performed. Of these, 900 (78.6%) survived to day 100 and had post-transplantation PFTs performed (median [interquartile range] 97 [94-103] d). A decline of ≥10% in FEV(1,) FVC, or D(LCO) was seen in 401 of 900 subjects (44.5%). Declines of ≥20% in FEV(1) (hazard ratio 1.65, 95% CI 1.07-2.56; P = .02), FVC (hazard ratio 1.72, 95% CI [1.11-2.67]; P = .02), and D(LCO) (hazard ratio 1.46, 95% CI 1.04-2.07; P = .028) were all associated with reduced survival when compared with those with < 10% decline in PFT measures. These findings were independent of pre-transplantation pulmonary function or relapse status. Bronchiolitis obliterans syndrome was diagnosed in 118 subjects (10.3%), and there was no relationship between early PFT decline and a subsequent diagnosis of bronchiolitis obliterans syndrome. The subjects who received myeloablative conditioning with cyclophosphamide plus total body irradiation or cyclophosphamide plus fludarabine plus total body irradiation were more likely to have lower spirometry values after hematopoietic stem cell transplantation. The subjects who received reduced intensity conditioning or nonmyeloablative conditioning with fludarabine plus total body irradiation were more likely to have higher post-hematopoietic stem cell transplantation FEV(1), FVC, and D(LCO). CONCLUSIONS An absolute decline of ≥20% in FEV(1), FVC, or D(LCO) were associated with reduced survival independent of pre-transplantation pulmonary function or relapse status. In contrast to previous work, early declines in PFT measures were not associated with future development of bronchiolitis obliterans syndrome.
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Diffuse alveolar hemorrhage after hematopoietic cell transplantation- response to treatments and risk factors for mortality
Schoettler, M. L., Dandoy, C. E., Harris, A., Chan, M., Tarquinio, K. M., Jodele, S., Qayed, M., Watkins, B., Kamat, P., Petrillo, T., et al
Frontiers in oncology. 2023;13:1232621
Abstract
Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of hematopoietic cellular therapy (HCT). This study aimed to evaluate the effect of DAH treatments on outcomes using data from consecutive HCT patients clinically diagnosed with DAH from 3 institutions between January 2018-August 2022. Endpoints included sustained complete response (sCR) defined as bleeding cessation without recurrent bleeding, and non-relapse mortality (NRM). Forty children developed DAH at a median of 56.5 days post-HCT (range 1-760). Thirty-five (88%) had at least one concurrent endothelial disorder, including transplant-associated thrombotic microangiopathy (n=30), sinusoidal obstructive syndrome (n=19), or acute graft versus host disease (n=10). Fifty percent had a concurrent pulmonary infection at the time of DAH. Common treatments included steroids (n=17, 25% sCR), inhaled tranexamic acid (INH TXA,n=26, 48% sCR), and inhaled recombinant activated factor VII (INH fVIIa, n=10, 73% sCR). NRM was 56% 100 days after first pulmonary bleed and 70% at 1 year. Steroid treatment was associated with increased risk of NRM (HR 2.25 95% CI 1.07-4.71, p=0.03), while treatment with INH TXA (HR 0.43, 95% CI 0.19- 0.96, p=0.04) and INH fVIIa (HR 0.22, 95% CI 0.07-0.62, p=0.005) were associated with decreased risk of NRM. Prospective studies are warranted to validate these findings.
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Post-Transplant and In-Hospital Risk Factors for ARDS After Hematopoietic Stem Cell Transplantation
Herasevich, S., Frank, R. D., Hogan, W. J., Alkhateeb, H., Limper, A. H., Gajic, O., Yadav, H.
Respiratory care. 2022
Abstract
BACKGROUND ARDS is a serious complication of hematopoietic stem cell transplant (HSCT). Pre-transplant risk factors for developing ARDS after HSCT have been recently identified. The objective of this study was to better understand post-transplant risk factors for developing ARDS after HSCT. METHODS This was a nested case-control study. ARDS cases were matched to hospitalized non-ARDS controls by age, type of transplantation (allogeneic vs autologous), and time from transplantation. In a conditional logistic regression model, any potential risk factors were adjusted a priori for risk factors known to be associated with ARDS development. RESULTS One hundred and seventy ARDS cases were matched 1:1 to non-ARDS hospitalized controls. Pre-admission, cases were more likely to be on steroids (odds ratio [OR] 1.90 [1.13-3.19], P = .02). At time of admission, cases had lower platelet count (OR 0.95 [0.91-0.99], P = .02), lower bicarbonate (OR 0.94 [0.88-0.99], P = .035), and higher creatinine (OR 1.91 [1.23-2.94], P = .004). During the first 24 h after admission, cases were more likely to have received transfusion (OR 2.41 [1.48-3.94], P < .001), opioids (OR 2.94 [1.67-5.18], P < .001), and have greater fluid administration (OR 1.52 [1.30-1.78], P < .001). During the hospitalization, ARDS cases had higher temperature (OR 1.77 [1.34-2.33], P < .001) and higher breathing frequency (OR 1.52 [1.33-1.74], P < .001). ARDS cases were more likely to have had sepsis (OR 68.0 [15.2-301.7], P < .001), bloodstream infection (OR 4.59 [2.46-8.57], P < .001), and pneumonia (OR 9.76 [5.01-19.00], P < .001). CONCLUSIONS Several post-transplant predictors of ARDS development specific to the HSCT population were identified in the pre-hospital and early in-hospital domains. These findings can provide insights into causal mechanisms of ARDS development and be used to develop HSCT-specific risk prediction models.
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Pulmonary microbiome and gene expression signatures differentiate lung function in pediatric hematopoietic cell transplant candidates
Zinter, M. S., Versluys, A. B., Lindemans, C. A., Mayday, M. Y., Reyes, G., Sunshine, S., Chan, M., Fiorino, E. K., Cancio, M., Prevaes, S., et al
Science translational medicine. 2022;14(635):eabm8646
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Abstract
Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pretransplant lung function has hindered the development of lung-targeted interventions. In this study, we quantified the association between bronchoalveolar lavage (BAL) metatranscriptomes and paired pulmonary function tests performed a median of 1 to 2 weeks before allogeneic HCT in 104 children in The Netherlands. Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung injury-related mortality after HCT. Depletion of commensal supraglottic taxa, such as Haemophilus, and enrichment of nasal and skin taxa, such as Staphylococcus, in the BAL microbiome were associated with worse measures of lung capacity and gas diffusion. In addition, BAL gene expression signatures of alveolar epithelial activation, epithelial-mesenchymal transition, and down-regulated immunity were associated with impaired lung capacity and diffusion, suggesting a postinjury profibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality. These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.
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A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation
Rowan, C. M., Smith, L. S., Sharron, M. P., Loftis, L., Kudchadkar, S., Duncan, C., Pike, F., Carpenter, P. A., Jacobsohn, D. A., Bollard, C. M., et al
Blood advances. 2022
Abstract
Plasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (days 7 and 14 post-HCT) risk biomarkers for RF within the first 100 days post-HCT. Using tandem mass-spectrometry discovery, we compared plasma obtained at day 14 post-HCT from 15 patients with RF versus 15 patients without RF. Six lead candidate proteins, either from this discovery cohort or previously identified in the literature, were then measured by ELISA on days 7 and 14 post-HCT samples in training (n=213) and validation (n=119) cohorts. Cox proportional hazard analysis with biomarkers dichotomized by Youden's index, and landmark analysis for the association of biomarkers and RF were performed. Of the six markers, ST2, WFDC2, IL6, and TNFR1 measured at day 14 post-HCT had the most significant association with increased risk for RF in the training cohort (ST2: Hazard Ratio (HR) 4.5, p=0.004, WFDC2: HR 4.2, p=0.010, IL6: HR 6.9, p< 0.001, and TFNR1: HR 6.1, p<0.001) and the validation cohort (ST2: HR 23.2, p=0.013, WFDC2: HR 18.2, p=0.019, IL6: 12.2, p=0.014, and TFNR1: HR 16.1 p=0.001) after adjusting for conditioning regimen. Using cause-specific landmark analysis including days 7 and 14, high plasma ST2, WFDC2, IL6, and TNFR1 values were associated with increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality with RF. ST2, WFDC2, IL6 and TNFR1 levels measured early post-transplantation improve risk stratification for RF and its related mortality.