Noninfectious Pulmonary Complication Research Articles

Clinical risk factors and prognostic model for patients with bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, predictive tools for BOS are not available. We aimed to identify the clinical risk factors and establish a prognostic model for BOS in patients who undergo allo-HSCT. We retrospectively identified a cohort comprising 195 BOS patients from 6100 consecutive patients who were allografted between 2008 and 2022. The entire cohort was divided into a derivation cohort and a validation cohort based on the time of transplantation. Via multivariable Cox regression methods, declining forced expiratory volume at 1 s (FEV1) to <40%, pneumonia, cGVHD except lung, and respiratory failure were found to be independent risk factors for the 3-year mortality of BOS. A risk score called FACT was constructed based on the regression coefficients. The FACT model had an AUC of 0.863 (95% CI: 0.797-0.928) in internal validation and 0.749 (95% CI: 0.621-0.876) in external validation. The calibration curves showed good agreement between the FACT-predicted probabilities and actual observations. The FACT risk score will help to identify patients at high risk and facilitate future research on developing novel, effective interventions to personalize treatment.

A Systematic Review on Pulmonary Complications Secondary to Hematopoietic Stem Cell Transplantation.

The main purpose of this systematic review was to identify and synthesize evidence about pulmonary complications following stem cell transplantation to raise awareness among physicians since it is a lesser-known topic. Studies that included targeted pulmonary complications that occurred after stem cell transplantation; in humans; and were randomized controlled trials, cohort studies, and case studies between January 2011 and 2021. Fifteen intervention features were identified and analyzed in terms of their association with successful or unsuccessful interventions. Fifteen of 15 studies that met inclusion criteria had positive results. Features that appeared to have the most consistent positive effects included relevant information consisting of clinical presentations and management of complications. Hematopoietic stem cell transplantation is a therapeutic method that has been introduced for various hematological diseases. Its main objective is to restore the hematopoietic function that has been eradicated or affected. The stem cell transplantation requires a period of administration of chemotherapeutic agents that may lead to infectious and/or non-infectious pulmonary complications that require follow-up.Noninfectious pulmonary complications include bronchiolitis obliterans, alveolar hemorrhage, fibroelastosis, pulmonary hypertension, and infections. Bronchiolitis obliterans syndrome is an obstructive lung disease that affects the small airways, reducing lung function, and it’s the most frequent late-onset complication. Furthermore, diffuse pulmonary hemorrhage is a fatal adverse effect and the most common noninfectious pulmonary complication of acute leukemia, observed within the first weeks after the procedure. Pulmonary hypertension has multiple etiologies, mainly related to the pulmonary veno-occlusive disease. It carries a poor prognosis, with a 55% mortality rate. The area of hematology is very wide and prone to new development of treatments and procedures that could be available for new emerging diseases and improving survival rates.

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

Primary immunodeficiency-related bronchiectasis in adults: comparison with bronchiectasis of other etiologies in a French reference center

BackgroundBronchiectasis is a heterogeneous disease depending on etiology. It represents the most frequent non-infectious pulmonary complication of primary immunodeficiencies (PID). We investigated whether bronchiectasis associated with PID had a distinct course in comparison to bronchiectasis of other causes.MethodsRetrospective single-center study of adult patients diagnosed with non-cystic fibrosis bronchiectasis with more than 5 years of follow-up and at least 4 pulmonary functional tests available at one year apart. They were divided into three groups: PID- related bronchiectasis, idiopathic/post infectious-related bronchiectasis and other causes of bronchiectasis. Respiratory functional data and clinical outcomes were compared.ResultsOf 329 patients with bronchiectasis diagnosed in Foch Hospital (Suresnes, France), 98 patients fulfilled the selected criteria (20 PID-related cases, 39 idiopathic or post-infectious cases, and 39 cases with other causes). Median time of follow-up was 9.5 years. Groups were similar concerning initial characteristics (female 70.4%, never smokers 59.2%, mild severity bronchiectasis according to the FACED score and median FEV1 at diagnosis 73.5% predicted values [Q1–Q3: 53.75–90.5]), except PID patients who were younger (median age of 51.5 vs 62 years, p = 0.02). Eighty-five percent of PID patients received immunoglobulin substitution (median trough level was measured at 10.5 g/dl [10;10.92]). Global median FEV1 annual decline was 25.03 ml/year [8.16;43.9] and 19.82 ml/year [16.08;48.02] in the PID patients group. Forty-five percent of patients had bacterial colonization, pneumoniae occurred in 56% of patients and median exacerbation annual rate was 0.8 [0.3–1.4]. Hemoptysis occurred in 31.6% of patients. Global mortality rate was 11.2%. We did not record any significant difference for all clinical and functional outcomes between patients with PID and other etiologies. The median decline in FEV1 was similar in the three groups.ConclusionsThe course of PID-related bronchiectasis was similar to bronchiectasis of other causes. Provided that patients receive immunoglobulin replacement, the course of PID-related bronchiectasis seems to be independent of the underlying immune disorder.

GRANULOMATOUS LYMPHOCYTIC INTERSTITIAL LUNG DISEASE: MOST COMMON NONINFECTIOUS PULMONARY COMPLICATION OF COMMON VARIABLE IMMUNODEFICIENCY

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Common Variable Immunodeficiency (CVID) is the most common primary immunodeficiency. Patients with CVID suffer from recurrent sinopulmonary infections. Granulomatous lymphocytic interstitial lung disease (GLILD) is one of the dreaded noninfectious pulmonary complication of CVID. CASE PRESENTATION: A 28-year-old female was seen in Pulmonology clinic for evaluation of an abnormal CT scan of the chest, progressively worsening chest tightness, chronic productive cough and dyspnea on exertion for last 1 year. Patient had history of CVID, Chiari I malformation, and iron deficiency anemia. She worked with construction companies to monitor archeological changes. Vitals and physical exam on presentation were normal. Initial investigations showed thrombocytopenia; Sputum gram stain, fungal and acid-fast smear and aerobic and anaerobic cultures were unremarkable. CT scan of the chest, abdomen and pelvis with contrast showed diffuse reticulonodular pulmonary infiltrates predominantly in the basal lung fields, peri bronchial thickening in the lower lobes and mildly enlarged lymphadenopathy in the axilla, retroperitoneum and mesentery, and splenomegaly (13.5 cm). Differential diagnosis at the time were sarcoidosis, GLILD, fungal/atypical infections, vasculitis and malignancy. Bronchoscopy revealed acutely inflamed mucosa throughout the tracheobronchial tree, petechiae in right lower lobe. Bronchoalveolar lavage (BAL) in right medial segment and transbronchial biopsy (TBBx) in left lower lobe showed 54% lymphocytes, but no vasculitis, fungal/bacterial/viral infection, and malignancy. Working diagnosis was narrowed down to sarcoidosis and GLILD. Video assisted thoracoscopic surgery and open lung biopsy of right middle and lower lobes revealed nodular and diffuse mononuclear cell infiltrates and scattered non-necrotizing granulomas. 2nd opinion from a tertiary care center confirmed follicular bronchiolitis with associated non-necrotizing granulomatous inflammation and foci of fibrinous organizing pneumonia consistent with GLILD seen in CVID. DISCUSSION: GLLID is the most common cause of diffuse parenchymal lung disease in patients with CVID. It occurs in 8-22% of persons with CVID. The etiology of GLILD is unknown. It presents between the ages of 20 and 50. Presence of hypersplenism and polyarthritis increases the risk of GLILD in patients with CVID. Classic histopathologic pattern of GLILD is a cellular interstitial pneumonia with a combination of granulomatous and lymphoproliferative features. Optimal treatment is unknown. Glucocorticoids, IVIGs and immunosuppressive therapies have been tried. CONCLUSIONS: In patients with CVID development of respiratory signs or symptoms should be carefully evaluated for GLILD as presence of GLILD shortens the survival by approximately 50%. Reference #1: Fernández Perez ER. 2012 November. Granulomatous Lymphocytic Interstitial Lung Disease. Immunol Allergy Clin AM. 32(2012):621-32 Reference #2: Bates CA, Ellison MC, Lynch DA, et al. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004;114(2):415–21. Reference #3: Tou w CM, van de Ven AA, de Jong PA, et al. Detection of pulmonary complications in common variable immunodeficiency. Pediatric Allergy Immunol 2010;21(5):793–805. DISCLOSURES: No relevant relationships by Shujaa Faryad, source=Web Response No relevant relationships by Rajamurugan Meenakshisundaram, source=Web Response

Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation

Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication after hematopoietic cell transplantation (HCT) and is difficult to diagnose. In 41 patients with IPS, we evaluated 6 candidate proteins in plasma samples at day 7 post-HCT and at onset of IPS to identify potential diagnostic or prognostic biomarkers for IPS. Samples at similar times from 162 HCT recipients without documented infections and 37 HCT recipients with respiratory viral pneumonia served as controls. In multivariable models, a combination of Stimulation-2 (ST2; odds ratio [OR], 2.8; P < .001) and IL-6 (OR, 1.4; P = .025) was the best panel for distinguishing IPS at diagnosis from unaffected controls, whereas tumor necrosis factor receptor 1 (TNFR1; OR, 2.9; P = .002) was the best marker when comparing patients with IPS and viral pneumonia. The areas under the curve of the receiver operating characteristic (ROC) curves for discriminating between IPS and unaffected controls at day 7 post-HCT were .8 for ST2, .75 for IL-6, and .68 for TNFR1. Using estimated sensitivity and specificity values from cutoffs determined with the ROC analysis (cutoff level: ST2, 21 ng/mL; IL-6, 61 pg/mL; TNFR1, 3421 pg/mL), we calculated positive predictive values (PPV) for a range of estimated population prevalence values of IPS. Among the 3 markers, ST2 showed the highest PPV for IPS occurrence. Based on an assumed prevalence of 8%, a positive ST2 test increased likelihood of IPS to 50%. We conclude that a prospective validation study is warranted to determine whether a plasma biomarker panel can aid the noninvasive diagnosis and prognosis of IPS.

A retrospective study of 10 cases of post-transplant bronchiolitis obliterans

Objective: To analyze the clinical features of bronchiolitis obliterans syndrome (BOS) in patients with allogeneic hematopoietic stem cell transplantation (HSCT). Methods: This retrospective study included patients who underwent allogeneic HSCT from January 1998 to December 2016. The clinical features, radiological manifestations and treatment of clinically proven BOS were reviewed. Results: Of 681 patients who experienced HSCT, 10(1.47%) met the diagnostic criteria. The duration of BOS onset after transplantation was 5-48 months, averaging (18±15) months. Cough and worsening dyspnea were present in most cases, and 9 (90%) of the cases had manifestations of chronic graft versus host disease. Hyperinflation with areas of decreased attenuation and bronchiectasis were present in 7 (70%) cases and air trapping was present during the expiratory phase of imaging. The management of BOS consisted of high dose systemic corticosteroids and immunosuppressive therapy. Patients were treated with bronchodilators if they were symptomatic and during acute exacerbations of respiratory symptoms. In 5 (50%) patients the condition deteriorated and caused death, while in 3 patients the condition was improved. Two patients were lost to follow up. Conclusion: BOS is the most common late noninfectious pulmonary complication following allogeneic HSCT and has a poor prognosis.

Air-leak Syndrome by Pleuroparenchymal Fibroelastosis after Bone Marrow Transplantation.

Objective Air-leak syndrome (ALS) is a life-threatening pulmonary complication following allogeneic bone marrow transplantation (allo-BMT) which is thought to be associated with graft-versus-host disease (GVHD). Recently, it has been reported that pleuroparenchymal fibroelastosis (PPFE) also occurs after allo-BMT and often causes ALS. We sought to extract common features of ALS caused by PPFE after allo-BMT. Methods The clinical data of patients who developed ALS caused by PPFE after undergoing allo-BMT (ALS-PPFE) between April 1996 and December 2007 at our institution were collected and reviewed retrospectively. The clinical findings, radiological and pathological features and treatment outcomes of ALS-PPFE were assessed. Results Five patients who developed ALS had histologically proven PPFE (four men, one woman: median age, 37 years). The age of onset of ALS-PPFE was 13 to 109 months (median, 68.8 months) after BMT. Alkylating agents were used as conditioning chemotherapy for BMT in all patients. Only one patient developed chronic GVHD (limited type). The common radiological findings were subpleural thickening and traction bronchiectasis predominantly in the bilateral upper lung fields. The histological pulmonary specimens showed no findings of bronchiolitis obliterans or GVHD. Immunosuppressive therapy was not effective in any of the cases, and all patients died of respiratory failure with or without lung transplantation. Conclusion ALS-PPFE is an extremely late-onset noninfectious pulmonary complication of allo-BMT. This complication is progressive, resistant to immunosuppressive treatment and has a poor prognosis. No association was found between PPFE and GVHD.

Role of IL-26+CD26+CD4 T Cells in Pulmonary Chronic Graft-Versus-Host Disease and Treatment with Caveolin-1-Ig Fc Conjugate.

Obliterative bronchiolitis is the primary noninfectious pulmonary complication after allogeneic hematopoietic cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In our recent study, we identified a novel effect of IL-26, which is absent in rodents, on transplant related-obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγnull mice transplanted with human umbilical cord blood gradually exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26+CD26+CD4 T cells. Moreover, we showed that IL-26 increased collagen synthesis in fibroblasts in vitro and that collagen contents were increased in a murine GVHD model using IL26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by CD4 T cells following CD26 costimulation, while immunoglobulin Fc domain fused with the N-terminal of caveolin-1, the ligand for CD26, (Cav-Ig) effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. We concluded that cGVHD of the lungs is caused in part by IL-26+CD26+CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

A Pediatric Case of Very Late Onset Non-infectious Pulmonary Complication (LONIPC) after Allogeneic Hematopoietic Stem Cell Transplantation

17-months old infant with Wiskott-Aldrich syndrome was transplanted with genetically two-locus mismatched unrelated cord blood cells under the conditioning regimen of busulfan, cyclophosphamide and anti-thymocyte globulin. GVHD prophylaxis was cyclosporine (CSP) plus short-term methotrexate with prednisolone (1 mg/kg). Acute and chronic GVHD were not observed during the course. About six years later, he suffered from severe cough and dyspnea with no fever, and diagnosed as late onset non-infectious pulmonary complications (LONIPC). We have to be careful for LONIPC after SCT even in the absence of chronic GVHD for younger children because the sign of insidious obstructive pulmonary symptoms is difficult to monitor. To avoid the unexpected LONIPC, introduction of RIC regimen should be considered for younger children, although it has been reported that RIC regimen may increase the risk for GVHD and graft rejection.

Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation: Comparison with Viral Infectious Pneumonia

Background: Idiopathic pneumonia syndrome (IPS) is a non-infectious pulmonary complication with diffuse lung injury that develops in 5-10% of patients who undergo hematopoietic cell transplantation (HCT) and the mortality rate remains high at 50-90%. IPS is difficult to distinguish from occult pneumonia after HCT, because it is hard to exclude all infectious etiologies. There are currently no laboratory tests to aid physicians in the early detection of IPS and other pulmonary infections. The aim of this study was to identify prognostic biomarkers of future occurrence of IPS and compare their profiles to that for subjects with infectious pneumonia.Patients and methods: Among patients transplanted between 1988 and 2014 at FHCRC, we identified 42 patients with IPS based on radiographic findings and exclusion of possible pathogens using frozen bronchoalveolar lavage (BAL) samples of occult viral infections as recently reported (Blood 2015: 24: 3789-97). HCT recipients who did not require bronchoscopic examination and who did not grow any bacterial or fungal blood cultures within 100 days after HCT were considered as controls (n=163) and samples were collected at similar timepoints as IPS cases. We examined cases of viral pneumonia confirmed by positive BAL: human rhinovirus (HRV, n=18) and parainfluenza (PIV, n=21). A set of 1129 plasma samples from pre-HCT, day 7, day 14, day 21 post-HCT and at onset of each event was analyzed. The "onset sample" for controls was the sample closest to day 24 (median day of onset for patients with pulmonary symptoms). We measured six proteins by ELISA: Suppressor of tumorigenicity 2 (ST2), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), lymphocyte vessel endothelial receptor (LYVE)-1, endothelial protein C receptor (EPCR), and herpes virus entry mediator (HVEM). TNFR1, LYVE-1, EPCR and HVEM were discovered through a proteomics approach, and ST2 and IL-6 were also measured due to their associations with endothelial processes and IPS (Blood 2015: 15: 2435-44), respectively.Multivariable logistic regression was used to evaluate the association of each protein with IPS vs. controls and IPS vs. HRV+PIV. Protein concentrations were log10 transformed and values below the lower limit of detection were replaced with that value (this occurred in 28% of the IL-6 measurements only). All analyses were adjusted for age, sex, transplant year, and acute GVHD status (grade 0-1 vs 2-4). Odds ratios indicate an increase in the odds of IPS for a tenfold increase in the protein concentration (Table 1). Receiver Operating Characteristic (ROC) curves were generated for each marker and if the area under the ROC (AUC) was greater than 0.7, then the analyte was considered an informative predictor of IPS.Results: Patients' characteristics are detailed in Table 1. Of the six proteins, TNFR1, ST2, LYVE-1, HVEM, and IL-6 were significantly elevated at the onset of IPS compared to controls at similar time point (adjusted, Table 2). ST2 and IL-6 were also elevated in infectious cases, although to a lesser degree. However, the biomarkers were able to distinguish IPS cases from viral infections (HRV and PIV) occurring approximately at the same time post HCT (Figure 1A). We also evaluated the prognostic value of the proteins by analyzing samples measured at day 7 post-HCT. All six proteins were elevated in IPS cases versus controls as early as day 7 with AUC from 0.85 to 0.75 (data not shown), and distinguished IPS from HRV and PIV infections (Figure 1B).Conclusion: Five proteins, TNFR1, ST2, LYVE-, HVEM, and IL-6 were significantly elevated at the onset of respiratory failure in IPS patients as compared to patients without pulmonary injury. Although the markers were also elevated in viral pulmonary infections, they were able to distinguish IPS from HRV and PIV. Importantly, these markers were elevated as early as day 7 after HCT, prior to the clinical signs of IPS. Additional analyses combining proteins together to form a composite panel are currently ongoing. [Display omitted] [Display omitted] [Display omitted] DisclosuresPaczesny:Viracor laboratories: Patents & Royalties: "Methods of detection of graft-versus-host disease" (US- 13/573,766).

254. Hepatocyte Growth Factor Gene Modification Enhances the Inflammation-Alleviating Effect of Umbilical Cord Derived Mesenchymal Stem Cells in a Bronchiolitis Obliterans Model

BACKGROUNDS: Bronchiolitis obliterans is a serious, steadily, noninfectious, and fatal pulmonary complication. Currently specific and effective therapeutics for prevention or reversal of bronchiolitis obliterans is lacking. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF) gene modified mesenchymal stem cells (MSCs) on bronchiolitis obliterans.METHODS: A mouse model of experimental bronchiolitis obliterans was established by subcutaneously transplanting the tracheas from C57BL/6 mice into Balb/C recipients. These model mice were administered saline, Ad-HGF-modified human umbilical cord-MSCs (MSCs-HGF) or Ad-Null-modified MSCs (MSCs-Null). The distribution of the transplanted cells was detected by using real-time PCR (rt-PCR). The therapeutic effects of MSCs-Null and MSCs-HGF were evaluated by using FACS for lymphocyte immunophenotype of spleen, ELISA and rt-PCR for cytokine expression, and histopathological analysis for the transplanted trachea.RESULTS: The administrated MSCs mainly distributed in the transplanted trachea, blood, liver and lung of the recipients; HGF gene modification could enhance the engraftment of MSCs. The histopathological recovery of allografts tracheas was improved significantly after MSCs-Null and MSCs-HGF treatment and the beneficial effects were particularly observed in MSCs-HGFtreated mice. Furthermore, the allo-transplantation induced immunophenotype disorders of the spleen cells, including Treg, Th1, Th2 and Th17 cells, were attenuated in both cell treated groups. MSCs-HGF treatment reduced expression and secretion of inflammation cytokines interferon-gamma and increased expression of anti-inflammatory cytokine IL-4 and IL-10. It also decreased the expression level of the profibrosis factor transforming growth factor-beta.b.CONCLUSIONS: Treatment of bronchiolitis obliterans with HGF gene modified MSCs results in reduction of local inflammation and promotion in recovery of allografts tracheas histopathology in a mouse model. These findings might provide an effective therapeutic strategy for bronchiolitis obliterans.

Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.

Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγ(null) mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26(+)CD26(+)CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26(+)CD26(+)CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

Studying the association of plasma S100A12 and noninfectious pulmonary complication in infants and young children following cardiopulmonary bypass (HUM1P.305)

Abstract Objective To examine the kinetics of plasma S100A12 and sRAGE in infants and young children with CPB, and to investigate whether they could predict the occurrence of noninfectious pulmonary complication (NPC) after cardiac surgery. Methods 20 patients were in NPC group, which included pleural effusion, chylothorax, partial lung collapse, pulmonary hypertensive crisis, airway disorders, pneumothorax, pneumomediastinum, and phrenic nerve palsy, and 40 patients in no-NPC group. Plasma S100A12 and sRAGE were measured at 6 perioperative time points. Results S100A12 and sRAGE increased immediately after CPB (P&amp;lt;0.001). SRAGE dropped to lower than baseline level (P&amp;lt;0.05), while S100A12 was still at high level 24h after operation (P&amp;lt;0.001). S100A12 and sRAGE immediately after CPB in NPC group were significantly higher than no-NPC group (P&amp;lt;0.05). S100A12 were still higher in NPC group than no-NPC at 24h after operation (P&amp;lt;0.01). S100A12 immediately after CPB was a predictor for postoperative NPC (OR=1.042, 95% CI: 1.010-1.076, P=0.011). S100A12 immediately after CPB were positively associated with MV time (r=0.47, P&amp;lt;0.001), duration of surgical Intensive Care Unit (r=0.407, P=0.002) and hospital stay (r=0.421, P=0.001). Conclusions Plasma S100A12 and sRAGE were significantly increased immediately after CPB; The elevated S100A12 immediately after CPB served as an early reliable biomarker of the occurrence and the prognosis of NPC after CPB in infants and young children.

ACE deletion polymorphism is associated with a high risk of non-infectious pulmonary complications after stem cell transplantation

Non-infectious pulmonary complication (NIPC) is a serious adverse event for allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients. NIPC includes both categories of lung complications: early onset idiopathic pneumonia syndrome (IPS) (onset <120days) and late-onset non-infectious pulmonary complications (LONIPCs). Both categories have high mortality and morbidity rates, and critical treatments are not available. The renin-angiotensin system plays a critical role in pulmonary fibrosis. We, therefore, studied the relationship between angiotensin-converting enzyme gene (ACE) insertion/deletion polymorphisms and NIPC incidence in 149 consecutive allo-HSCT recipients. A total of 12.1% (18/149) of these patients were diagnosed with NIPC (IPS, 3; LONIPCs, 15). Eight NIPC patients died from respiratory failure (mortality rate, 44.4%). Peripheral blood stem cell transplantation was associated with a significantly higher incidence of NIPC than bone marrow transplantation and cord blood transplantation by univariate analysis (HR 3.13, P=0.031). The serum ACE levels differed significantly according to the ACE insertion/deletion polymorphism. Patients with an ACE D/D genotype occurred at a significantly higher frequency among NIPC patients than I/D and I/I patients (HR 9.03, P<0.0001). Multivariate analysis confirmed that NIPC is associated with ACE D/D genotypes (HR 8.8, P<0.001). Our data support a role for the renin-angiotensin system in the pathogenesis of NIPC after allo-HSCT, and may represent a therapeutic target for complications.

Inhaled Cyclosporine For The Treatment Of Bronchiolitis Obliterans Following Hematopoietic Stem Cell Transplantation (HSCT) Or Lung Transplantation

BackgroundBronchiolitis Obliterans Syndrome (BOS) is a late-onset non-infectious pulmonary complication of HSCT, resulting in obstructive lung disease. BOS is thought to be a manifestation of chronic graft versus host disease (cGVHD). BOS can also occur after lung transplantation, where it is believed to represent chronic rejection of the lung allograft. In both conditions, the mainstay of therapy includes augmentation of systemic immunosuppression. However, this approach has limited efficacy and is associated with deleterious consequences including an increased risk of infection and decreased graft versus tumor/leukemia effects. We investigated whether targeted, local delivery of inhaled cyclosporine could improve or stabilize lung function in BOS patients. MethodsHSCT recipients with BOS, ages 10-80, were eligible if they met the following inclusion criteria: FEV1<75% predicted, FEV1 decline >10% compared to pre-transplant FEV1, no evidence of pulmonary infection as a causative etiology, and one of the following: FEV1/FVC ratio <70%, air-trapping seen on CT scan or RV ≥120%, or evidence of cGVHD affecting at least one other organ system. Lung transplant recipients with BOS were also eligible. Subjects were characterized as having progressive or stable disease at study entry based on their FEV1 values in the preceding 3-18 weeks. Progressive disease was defined as a ≥10% decline in FEV1, and stable disease as an increase in FEV <5% or a decrease <10%. Subjects received cyclosporine inhalation solution (CIS) 150 mg via nebulizer 3 times weekly for 6 weeks before dose escalation to 300mg three times weekly. The primary endpoint was change in FEV1 at study completion (average of week 18 and 19 values) compared to study baseline. Pharmacokinetic sampling and lung deposition studies were performed on all subjects. Lung deposition studies were performed using SPECT/CT imaging after inhalation of CIS mixed with technetium- 99m sulfur colloid. Bronchoalveolar lavage fluid and peripheral blood samples were collected at study baseline, week 9 and week 18, and were analyzed for cytokine markers and lymphocyte phenotype. Six minute walk tests (6MWT) and quality of life testing was also performed. ResultsEleven subjects (nine evaluable) have been enrolled (median age: 45 years; range: 14-73). Nine subjects had HSCT-associated BOS, and 2 had lung-transplant-associated BOS. Patients were transplanted for various underlying conditions (MDS, aplastic anemia, DLBCL, MM, ALL, Gata-2 deficiency, alpha-1 anti-trypsin deficiency, and idiopathic pulmonary fibrosis). HSCT recipients received both reduced intensity (n=4) and myeloablative (n=5) conditioning, with allografts from HLA matched relatives (n=5) or unrelated donors (n=4). The median time from BOS diagnosis to study enrollment was 9 months (range: 2-37 mos). The median FEV1 at study entry was 1.11 liters (range: 0.5-2.11), with 4 subjects having progressive disease and 7 stable disease. Adverse events associated with CIS occurred in 9/10 patients and included cough, bronchospasm, and dyspnea. Most adverse events were grade 2 (range:1-3) and occurred only during the inhalation.Three subjects went off-study (patient choice) prior to completion of the 18 weeks due to adverse events and were considered non-responders. Four of the 8 (50%) HSCT- associated BOS subjects had a response, including 3 patients with progressive disease and 1 with stable disease at study entry. Among these responders, the improvements in absolute FEV1 from baseline were 19.5%, 15%, 12.7%, and 3.4% respectively (figure). Among the responding patients, 2 were also able to decrease their systemic steroid administration by 50% and 43%. An improvement in 6MWT was noted in 1/4 responders. Four responders have enrolled onto an extension protocol.The median peak systemic absorption of cyclosporine was 99 mcg/L (Range: 32-263) 20 minutes post-CIS inhalation. Lung deposition studies showed the total deposited dose averaged 12% (range: 4-20 %) of the inhaled dose. [Display omitted] ConclusionsInhaled cyclosporine can be delivered safely and can stabilize or improve lung function in HSCT recipients with severe BOS, allowing systemic immunosuppression to be reduced. Use of local, targeted therapy with CIS resulted in minimal systemic absorption compared to typical oral administration, and achieved high drug levels in the lung tissue as demonstrated by the lung deposition results. Disclosures:No relevant conflicts of interest to declare.

Bilateral lung transplantation for bronchiolitis obliterans after allogeneic bone marrow transplantation: a case report and literature review

To explore the feasibility and efficiency of lung transplantation in the treatment of bronchiolitis obliterans (BO) after allogeneic bone marrow transplantation (allo-BMT). We reported one case of bilateral lung transplantation for BO after allo-BMT and reviewed the related literatures. A 23 year-old man diagnosed as BO after allo-BMT underwent a sequential bilateral lung transplantation through bilateral anterolateral thoracotomy without sternal division. The patient suffered from acute rejection on post-operation day (POD) 2, and cured by mechanical ventilation, large dose of methylprednisolone and gamma globulin. The patient was transferred out of the intensive care unit on POD 14 and discharged from the hospital on POD 43. Chest CT scans and pulmonary function tests showed good performance in 3 and 6 months follow-up period. BO is one of the late common non-infectious pulmonary complication after allo-BMT. For patients who have no response to medication, lung transplantation is the only efficient treatment choice so far, which can prolong survival and improve the quality of life. However, limited by small samples, optimal surgery time and appropriate care of postoperative complications still need accumulation of experience by multicenter and large samples studies.

Bronchiolitis obliterans after allogeneic hematopoietic SCT: further insight—new perspectives?

Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHD-patients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L±0.7, P=0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.±0.9 vs 20 p.p.b.±2.1) or healthy controls (25 p.p.b.±2.4, P<0.001). Hypoxia-inducible factor 1 alpha (HIF-1α) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340±61 vs 127±22 vs 140±32, P=0.02). Calculated 5-year survival was superior in female than in male BO-patients (86 vs 45%, P=0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia.

Airway dilation in bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). There is minimal data published on quantitative radiologic characterization of airway remodeling in these subjects. To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS. All adult patients who underwent allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n=1854) between January 1st 2000 and June 30th 2010 were screened for the development of BOS. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. For each subjects discrete measures of airway wall area were performed and the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated. We identified 88 cases of BOS, and 37 of these patients had available HRCT. On CT scans obtained after BOS diagnosis, the Pi10 decreased (consistent with airway dilation) as compared with pre-BOS values (p<0.001). After HSCT the Pi10 correlated with FEV(1)% predicted (r=0.636, p<0.0001), and RV/TLC% predicted (r=-0.736, p<0.0001), even after adjusting for age, sex and total lung capacity (p<0.0001 for both). On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. This is opposite of what has been previously demonstrated in COPD and asthma that quantitative measure of proximal airway wall thickening directly correlate with pulmonary function. Our data suggests that the pathologic process affecting the central airways is different from the pathology observed in the distal airways. Further work is needed to determine if such change can be used as a sensitive and specific tool for the future diagnosis and staging of BOS.

Airway Dilation in Bronchiolitis Obliterans After Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 3058 Rationale:Bronchiolitis obliterans syndrome (BOS) is a late, non-infectious pulmonary complication following hematopoietic stem cell transplantation (HSCT). The prevalence is estimated to be between 5–10% after allogeneic HSCT with a significant increase in morbidity and mortality. We were interested in assessing quantitative radiologic characterization of airway remodeling in these subjects. Objectives:To examine quantitative measurements of airway morphology and their correlation with lung function in a cohort of patients who underwent HSCT and developed BOS. Methods:All patients who underwent an allogeneic HSCT at the Dana-Farber Cancer Institute/Brigham and Women's Hospital (n=1854) between January 1st 2000 and June 30th2010 were screened for the development of BOS using modified NIH diagnostic criteria. Clinically acquired high resolution CT (HRCT) scans of the chest were collected. Discrete measures of airway wall area were performed in a total of 16 manually selected airways in the right and left upper and lower lobes using Airway Inspector (www.airwayinspector.org). From these measures, the square root of wall area of a 10-mm luminal perimeter (Pi10) was calculated. Spearman correlation was used to assess the relationship between square root of wall area at Pi10 and pulmonary function measures. Paired t-test was used for within group comparisons. Analyses were performed with SAS v. 9.2. Measurements and Main Results:Within our cohort 89 cases of BOS were identified of which 37 patients had HRCT scans available for analysis. 33 patients had pulmonary function tests within 30 days of the HRCT (Table 1). Ten of the 37 BOS patients had a HRCT scan at or prior to transplantation and a HRCT scan available after the diagnosis of BOS. Square root of wall area at Pi10 correlated significantly with FEV1(r = 0.636, p<0.0001), RV/TLC (r = −0.736, p< 0.0001) (Fig. 1), and when adjusted for age, sex and total lung capacity, the correlations remained significant (p<0.0001). There was a significant decline in square root of wall area at Pi10 in BOS cases compared to pre-transplant CT scans (p<0.001) (Fig 2). Conclusions:On HRCT scan BOS is characterized by central airway dilation, the degree of which is correlated to decrements in lung function. Future studies will examine whether chest CT assessment of central airway dilation can be used as a sensitive and specific tool for diagnosis and staging of BOS.Table 1Correlation coefficients (r Values) of the univariate regression analysis for square root of wall area at Pi10 with pulmonary function tests. FVC indicates forced vital capacity; FEV1, 1-second forced expiratory volume; FEF25–75 %, forced expiratory flow between 25–75%; VC, vital capacity; IC, inspiratory capacity; ERV, end residual volume; TLC, total lung capacity; RV, residual volume; DLCO,carbon monoxide diffusion capacityPFTr value<0.0001FVC %0.5460.001FEV1 %0.636<0.0001FEV1/FVC0.343NSFEF25–75 %0.5780.0004VC %0.5950.002IC %0.6020.002ERV %−0.353NSTLC %0.219NSRV %−0.5610.002RV/TLC %−0.736<0.0001DLCO %–0.175NS [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.