Development Of Obliterative Bronchiolitis Research Articles

Bronchiolitis Obliterans Organizing Pneumonia After Breast Radiation Therapy

Presented here is a case report of a 77-year-old woman affected by rheumatoid arthritis who underwent breast-conserving surgery followed by radiation therapy (RT) for left-breast cancer and developed bronchiolitis obliterans organizing pneumonia (BOOP) after RT and during a COVID-19 vaccination campaign. BOOP incidence is an uncommon morbidity after breast RT (1.2%-2.9%); however, specific predisposing factors can play a role. In this patient, both rheumatoid arthritis and the vaccine may have predisposed her to an increased risk of organizing pneumonia, probably by triggering a proinflammatory cascade. Our report highlights the importance of factors that influence the occurrence of uncommon radiation-induced morbidities, such as BOOP, in specific subsets of patients. Further studies are necessary to evaluate factors increasing radiation sensitivity.

Efficacy of surveillance bronchoscopy versus clinically indicated bronchoscopy for detection of acute lung transplant rejection: a systematic review and meta-analysis.

Acute allograft rejection after lung transplantation significantly increases the risk of developing bronchiolitis obliterans syndrome, a form of chronic lung allograft dysfunction and the leading cause of mortality beyond the initial post-transplantation year. There are two diagnostic approaches available for monitoring lung transplant recipients: clinically indicated bronchoscopy (CIB) and surveillance bronchoscopy (SB). The efficacy of both methods and their relative superiority in detecting acute rejection have not been conclusively determined. We systematically searched the MEDLINE, Embase, Cochrane and Scopus databases from inception until 10 October 2023 for prospective studies comparing the efficacy of SB and CIB. Meta-analysis using a random effects model was performed for three observational cohort studies, totalling 122 patients with 527 bronchoscopies. Overall, neither SB nor CIB had a higher likelihood of detecting acute lung transplant rejection of any grade. Subsequent subgroup analyses showed no advantage for SB in detecting minimal rejection (grade A1), but an inverse association was observed for higher-grade rejection. In conclusion, our study found no significant difference in detecting acute lung transplant rejection between SB and CIB. However, due to the limited number of studies and small sample sizes, larger prospective studies are urgently needed to definitely determine whether there truly exists no difference between SB and CIB in detecting acute rejection, particularly A1 minimal rejection.

IL-27 Levels in Bronchoalveolar Lavage Fluid in Children with Post-infectious Bronchiolitis Obliterans.

Pulmonary neutrophils may play a crucial role in the development of bronchiolitis obliterans (BO) following measles virus infection. IL-27 could potentially have a negative regulatory effect on the release of reactive oxygen species and cytotoxic granules in neutrophils. To investigate the levels of IL-27 in the bronchoalveolar lavage fluid (BALF) of children with post-infectious bronchiolitis obliterans (PIBO) and analyze the relationship between IL-27 levels and neutrophil proportions. A total of 24 children with PIBO were recruited for the experimental group, while 23 children with bronchial foreign bodies were included in the control group. Bronchoscopic alveolar lavage was performed in both groups. The levels of IL-27 in BALF were measured using enzyme-linked immunosorbent assay (ELISA). The proportions of neutrophils in BALF were determined by smear staining. The relationship between the levels of IL-27 in BALF and the neutrophil proportions was analyzed by the Pearson test. The levels of IL-27 in BALF were significantly lower in children with PIBO compared to children with bronchial foreign bodies (p<0.05). Additionally, the proportions of neutrophils in BALF were significantly higher in children with PIBO compared to children with bronchial foreign bodies (p<0.05). The levels of IL-27 were negatively correlated with the neutrophil proportions in BALF in children with PIBO (p<0.05), but not in children with bronchial foreign bodies (p>0.05). The present study suggests that a decrease in IL-27 may be associated with an increase in neutrophils in BALF and may contribute to the pathogenesis of PIBO.

Risk factors for the development of bronchiolitis obliterans in children after suffering from adenovirus pneumonia.

Bronchiolitis obliterans (BO) is an irreversible chronic obstructive lung disease in small airways. The aim of this study was to identify the relevant risk factors for the development of BO in children after suffering from adenovirus (ADV) pneumonia. An observational cohort study that included 112 children suffering from ADV pneumonia in our institution from March 2019 to March 2020 was performed. We divided the children into a BO group and a non-BO group based on whether they did develop BO or not. Univariate analysis and multivariate logistic regression analysis were applied to identify risk factors for the development of BO. The prediction probability model was evaluated by receiver operating characteristic (ROC) curve analysis. Twenty-eight children (25%) did develop BO after suffering from ADV pneumonia, while 84 children did not. Respiratory support (OR 6.772, 95% CI 2.060-22.260, P = 0.002), extended length of wheezing days (OR 1.112, 95% CI 1.040-1.189, P = 0.002) and higher lactic dehydrogenase (LDH) levels (OR 1.002, 95% CI 1.000-1.003, P = 0.012) were independently associated with the development of BO. The predictive value of this prediction probability model was validated by the ROC curve, with an area under the curve of 0.870 (95% CI 0.801-0.939, P < 0.001), a standard error of 0.035, a maximum Youden's index of 0.608, a sensitivity of 0.929, and a specificity of 0.679. After suffering an ADV pneumonia, children who have needed respiratory support, had a longer length of wheezing days or had higher LDH levels are more likely to develop BO.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Extracorporeal Photopheresis Suppresses Transplant Fibrosis by Inducing Decorin Expression in Alveolar Macrophages.

Unmanipulated haploidentical hematopoietic stem cell transplantation for pediatric de novo acute megakaryoblastic leukemia without Down syndrome in China: A single-center study.

AMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Several researchers have regarded pediatric AMKL without DS as high-risk or at least intermediate-risk AML and proposed that upfront allogenic hematopoietic stem cell transplantation (HSCT) in first complete remission might improve long-term survival. We conducted a retrospective study with twenty-five pediatric (< 14 years old) AMKL patients without DS who underwent haploidentical HSCT in the Peking University Institute of Hematology, Peking University People's Hospital from July 2016 to July 2021. The diagnostic criteria of AMKL without DS were adapted from the FAB and WHO: ≥ 20% blasts in the bone marrow, and those blasts expressed at least one or more of the platelet glycoproteins: CD41, CD61, or CD42. AMKL with DS and therapy related AML was excluded. Children without a suitable closely HLA-matched related or unrelated donor (donors with more than nine out of 10 matching HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci), were eligible to receive haploidentical HSCT. Definition was adapted from international cooperation group. All statistical tests were conducted with SPSS v.24 and R v.3.6.3. The 2-year OS was 54.5 ± 10.3%, and the EFS was 50.9 ± 10.2% in pediatric AMKL without DS undergoing haplo-HSCT. Statistically significantly better EFS was observed in patients with trisomy 19 than in patients without trisomy 19 (80 ± 12.6% and 33.3 ± 12.2%, respectively, P = 0.045), and OS was better in patients with trisomy 19 but with no statistical significance (P = 0.114). MRD negative pre-HSCT patients showed a better OS and EFS than those who were positive (P < 0.001 and P = 0.003, respectively). Eleven patients relapsed post HSCT. The median time to relapse post HSCT was 2.1 months (range: 1.0-14.4 months). The 2-year cumulative incidence of relapse (CIR) was 46.1 ± 11.6%. One patient developed bronchiolitis obliterans and respiratory failure and died at d + 98 post HSCT. AMKL without DS is a rare but aggressive hematological malignant disease in children, and it is associated with inferior outcomes. Trisomy 19 and MRD negative pre-HSCT might contribute to a better EFS and OS. Our TRM was low, haplo-HSCT might be an option for high-risk AMKL without DS.

349 - HSCT Recipients That Develop Bronchiolitis Obliterans Syndrome Exhibit Significant Proteomic Changes in Complement Activation, Angiotensin Maturation, and Antiprotease Activity Prior to Clinical Diagnosis

349 - HSCT Recipients That Develop Bronchiolitis Obliterans Syndrome Exhibit Significant Proteomic Changes in Complement Activation, Angiotensin Maturation, and Antiprotease Activity Prior to Clinical Diagnosis

Complex Restrictive Lung Disease Patterns Affecting Survival and Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant: A Single-Institution Retrospective Analysis

Background: Allogeneic stem cell transplant is the only curative therapy for some patients with hematologic malignancies. While pulmonary function impairment related to diffusion capacity and air flow obstruction is part of the predictive Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI), restrictive changes are poorly reflected. A new entity known as complex restrictive lung disease (CRLD) refers to a discrepancy between Forced Vital Capacity percent predicted (FVCpp) and Total Lung Capacity percent predicted (TLCpp). FVCpp being disproportionately lower than TLCpp occurs due to impaired lung emptying from neuromuscular disease, obesity, bronchiectasis, occult obstruction, pulmonary hypertension and chest wall limitations. In simple restrictive lung disease (SRLD) such as pulmonary fibrosis, FVCpp is proportionately decreased compared to TLCpp. Methods: Over three years, 124 patients received myeloablative (MA) or reduced intensity conditioning (RIC) followed by matched unrelated donor (MUD) or matched related donor (MRD) grafts. Patients had complete pulmonary function tests (PFT) within 60 days prior to transplant and 6 months post-transplant. Simple Restriction was defined as TLCpp - FVCpp <10%. Complex Restriction was defined as TLCpp - FVCpp >10%. Our primary outcome in this study was Median Overall Survival (mOS). Median follow up was 14 months. Results: For the 124 enrolled patients, demographics included median age of 55 years (range: 18-70), 60% male, MUD status (73%) with male donor (75%); half received RIC (52%) with fludarabine melphalan (62%) vs fludarabine/busulfan (FLU/BU2) (32%) compared to MA (40%) with FLU/BU4 conditioning (77%). The demographics of diagnosis include Acute Myeloid Leukemia (40%), Lymphoma (17%) and Acute Lymphoblastic Lymphoma (16%) and Myelodysplastic Syndrome (16%). The median HCT-CI/Age score was 4 (0-11). Half (62) developed acute graft-versus-host disease (aGVHD) with 80% as Grade 1-2. One patient was lost to follow up, 65 patients were still alive and 22 had relapse of their initial disease with 17 deaths related to relapse. Out of 58 deaths in this study, 41 deaths (71%) were attributed to non-relapse mortality (NRM) with NRM at 33% and relapse mortality rate at 14%. Out of 124 patients, 10 patients had complex restriction prior to transplant and 9 patients developed complex restriction at 6 months post-transplant. The mOS was 7 months for patients with CRLD prior to transplant (1-14 months) compared to 13 months for patients without CRLD (1- 36 months) (p=0.0026). Eight patients with CRLD before transplant were deceased at follow-up of 14 months, with four (50%) out of those eight deaths related to acute respiratory distress syndrome (25%) and hypoxic respiratory failure (25%). The non-relapse mortality rate for this population was 60% and relapse mortality rate was 10%. For all patients with aGVHD, mOS was greater than 30 months for aGVHD Grades 0-1, 16 months for Grade 2, 6 months for Grade 3 and 5 months for Grade 4 (p=0.0048). Six out of six patients with GVHD and CRLD prior to transplant died from acute respiratory distress syndrome (ARDS) hypoxia, or other cause. Out of the 4 patients with CRLD without GVHD, one patient developed respiratory failure as cause of death. There was no statistical difference in mOS due to BMI (p=0.2895). Nonsmokers and past smokers had a m0S of 22 months, with current smokers at 10 months m0S (p=0.13). We found no statistical difference in survival for the 9 patients who developed CRLD after transplant (p=0.45), the 10 patients with simple restriction prior to transplant (p=0.55), the 21 patients who developed Bronchiolitis Obliterans Syndrome (B0S) after transplant (p=0.25), or the 26 patients with Chronic Obstructive Pulmonary Disease (COPD) prior to transplant compared to normal PFT (p=0.14). The mOS for these groups was 12 months. Conclusion: Patients with complex restrictive lung disease prior to allogeneic stem cell transplant are at high risk for poor outcomes from respiratory and non-respiratory disease when compared to the overall population. As complex restriction is not included in the current HCT-CI, patients with this lung disease should have closer monitoring and scrutiny prior to allogeneic stem cell transplantation. Based on the results of this study, addition of complex restrictive lung disease to the HCT-CI to improve predictability of HCT outcomes warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Nintedanib reduces alloimmune-induced chronic airway changes in murine tracheal allografts

BackgroundThe major obstacle for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans (BO) which is one phenotype of chronic lung allograft dysfunction (CLAD). Nintedanib has beneficial effects treating neoplastic diseases and idiopathic pulmonary fibrosis by blocking tyrosine kinase receptors. These receptors play an important role in alloimmune-mediated proliferative diseases. The aim of this study was to determine the effect of nintedanib on proliferative airway changes after orthotopic trachea transplantation in mice. MethodsC57BL/6 mice (H-2b) donor tracheas were orthotopically transplanted into CBA/J mice (H-2k). After transplantation, recipients were daily treated with nintedanib (60 mg/kg; p.o.). Histological and immunofluorescence analysis were performed after 30 days and intragraft gene expression measurements after 14 days of treatment, respectively. ResultsTracheal allografts from mice treated with nintedanib showed significantly less features of chronic rejection than untreated allografts reflected in a higher epithelium/lamina propria ratio (ELR) [ELR: 0.65 ± 0.13 nintedanib vs. 0.50 ± 0.07 untreated controls; p < 0.05] and a reduced submucosal smooth muscle actin (SMA) content [SMA: 1.26% ± 0.78% nintedanib vs. 2.18% ± 1.01% untreated controls; p < 0.01]. Furthermore, lower T cell, macrophage and dendritic cell infiltration was detected in the nintedanib treated grafts. The protein and intragraft mRNA expression of receptor subtypes was considerably decreased in grafts of nintedanib treated mice. The mRNA expression of relevant immune mediators was affected by nintedanib treatment. ConclusionReceptor blocking by nintedanib reduced alloimmune-induced inflammation and chronic airway changes in mouse trachea allografts and might be a promising approach to diminish the development of BO in lung transplants.

Evolution of pathological findings in surveillance biopsies of lung transplant recipients infected with SARS-CoV-2.

BackgroundPrevious reports of coronavirus disease 2019 (COVID‐19) following lung transplantation generally described a grim prognosis, but these were anecdotal case series of symptomatic patients. A systematic study of the outcomes and pathology of SARS‐CoV‐2 infection in a large cohort of lung transplant patients is lacking.MethodsTo determine the histopathologic evolution of COVID‐19 in lung transplant recipients, we identified all patients who underwent surveillance transbronchial biopsies at our institution, tested positive for SARS‐CoV‐2, and had multiple pathology specimens available for evaluation. Histology was reviewed and immunofluorescence for SARS‐CoV‐2 nucleocapsid protein was performed.ResultsTen patients met inclusion criteria. Half (5/10) had incidental diagnosis on routine respiratory pathogen testing at the time of transbronchial biopsy. Six patients were hospitalized, with three requiring intensive care unit (ICU) admission. One patient died. Two specimens showed new onset International Society for Heart and Lung Transplantation (ISHLT) Grade A2 rejection at or following diagnosis. One patient developed bronchiolitis obliterans 111 days following diagnosis and 1 year post transplant. Two patients had organizing pneumonia at diagnosis and three patients showed evolving lung injury following diagnosis. The SARS‐CoV‐2 nucleocapsid protein was detected in a subset of samples at diagnosis and up to 111 days following diagnosis.ConclusionsOverall, the pathology of SARS‐CoV‐2 infection in lung transplant patients is varied, ranging from no pathologic alterations to organizing pneumonia and lung injury. The pathology findings did not necessarily correlate with clinical acuity, as one patient admitted to the ICU had normal pathology. These findings may be generalizable to non‐transplant patients and require more follow‐up regarding long‐term outcomes.

When should you worry about bronchiolitis obliterans?

In this volume of The Journal, Carpenter et al describe a case series of 68 patients with Stevens Johnson Syndrome (SJS), reporting that 9% develop bronchiolitis obliterans. This is potentially an important observation, as it serves to underscore the need to have sufficient diagnostic suspicion to screen for bronchiolitis obliterans in at-risk patients. At the same time, questions remain. The first question centers on case definition of SJS. The authors include both Mycoplasma-induced SJS and drug-induced SJS. With the retrospective design covering January 2004-December 2016, it is not possible to determine whether many of these cases were actually Mycoplasma-induced rash and mucositis (MIRM), a newly described entity (J Am Acad Dermatol 2015;72:239-45). This is particularly important given the relatively high percentage of Mycoplasma-induced SJS and recurrent SJS in those with bronchiolitis obliterans. No patients with bronchiolitis obliterans had drug-induced SJS. We should also note that these cases are from Children's Hospital Colorado. As the mechanism is not yet clear, one speculation is that bronchiolitis obliterans may be more manifest related to altitude or relative hypoxemia. Despite these caveats the report serves to highlight one important complication of these entities and to propose some guidance around screening. As with any rare complication of an already-rare condition, the aggregate experience of multiple centers will need to be examined to clarify the clinical picture. Article page 307 ▸ Stevens-Johnson Syndrome in Children: Consider Monitoring for Bronchiolitis ObliteransThe Journal of PediatricsVol. 236PreviewWe reviewed patients with Stevens-Johnson syndrome (SJS) evaluated at Children's Hospital Colorado and investigated the occurrence of bronchiolitis obliterans (BO). Approximately 9% of patients with SJS developed BO. Pediatricians should consider monitoring patients with SJS for BO, especially those with recurrent SJS and patients treated with mechanical ventilation. Full-Text PDF

MiRNAs Potentially Involved in Post Lung Transplant-Obliterative Bronchiolitis: The Role of miR-21-5p.

Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate miRNAs, previously indicated as possibly being associated with OB, were analyzed by combining the quantitative real time-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) of lung tissues of OB affected patients. Disease and OB-lesion-specific expression of miR-21-5p was confirmed and by computational analysis we were able to identify the network of genes most probably associated miR-21-5p in the context of OB fibrogenesis. Among all potentially associated genes, STAT3 had a very high probability score. Immunohistochemistry showed that STAT3/miR-21-5p were co-over expressed in OB lesions, thus, suggesting miR-21-5p could regulate STAT3 expression. However, miR-21-5p inhibition in cultures of bronchiolitis obliterans syndrome (BOS) derived myofibroblasts did not significantly affect STAT3 mRNA and protein expression levels. This study demonstrates the specificity of miR-21-5p over-expression in OB lesions and contributes to existing knowledge on the miR-21-5p downstream pathway. Activation of STAT3 is associated with miR-21-5p upregulation, however, STAT-3 network activation is most likely complex and miR-21-5p is not the sole regulator of STAT3.

Risk Factors for Bronchiolitis Obliterans Syndrome in Pediatric Lung Transplant Recipients

<h3>Purpose</h3> The purpose of this study is to describe the survival of pediatric patients who develop bronchiolitis obliterans syndrome (BOS) after lung transplant (LTx) and to identify the risk factors leading to the diagnosis. <h3>Methods</h3> The UNOS Registry was queried to identify pediatric LTx recipients (age <18yo) from 1999 to 2019. Kaplan-Meier analysis was used to identify median time to BOS diagnosis. Cox-regression analysis was used to identify potential risk factors leading to diagnosis. <h3>Results</h3> 900 lung transplant recipients were identified. 48% (n=431) of these patients were diagnosed with BOS in the post-transplant period. These patients developed BOS after a median of 4.6 years (95% CI: 4.3-5.0). Compared to non-BOS patients, those who developed BOS were less often infants (9% vs. 15%, p=0.008), more frequently aged 2-11yrs (28% vs. 22%, p=0.049), less frequently ventilator dependent at time of LTx (14% vs. 22%, p=0.001), and more frequently experienced graft rejection within 1-yr post-LTx (38% vs. 23%, p<0.001). Multivariate analysis revealed ages 12-17yrs (HR 1.3, CI 1.0-1.6), donor-recipient weight ratio <0.8 (HR 1.6, CI 1.2-2.2), OB (non-retransplant) diagnosis (HR 1.9, CI 1.3-2.9), and graft rejection within 1-yr post-LTx (HR 1.9, CI 1.6-2.4) to be significant predictors of developing BOS. Within those who developed BOS, ages 12-17yrs (HR 2.0, CI 1.1-3.6) and graft rejection within 1-yr post-LTx (HR 1.5, CI 1.2-2.0) were found to be significant predictors of mortality. On Kaplan-Meier analysis, early BOS (within 3-yrs post-LTx) had significantly lower graft survival from the diagnosis of BOS compared to those who developed BOS later (after 3yrs). (<b>Figure</b>, p<0.001). <h3>Conclusion</h3> BOS remains a significant cause of mortality in children after LTx. Adolescent age, OB (non-retransplant) diagnosis, and graft rejection within 1-yr post-LTx are significant predictors of developing BOS. Early development of BOS (within 3yrs post-LTx) resulted in significantly worse graft survival than later development.

Microvasculature in murine tracheal allografts after combined therapy with clopidogrel and everolimus.

Survival after lung transplantation is mainly limited by the development of chronic lung allograft dysfunction. Previous studies have suggested T-cell mediated proliferation and microvascular changes in experimental small airways models as potential therapeutic targets. The aim of this study was to assess microvascular changes in murine orthotopic tracheal allografts after treatment with everolimus alone or in combination with clopidogrel. C57Bl/6 (H-2b) donor tracheas were orthotopically transplanted into CBA (H-2k) recipients. Mice received daily injections of everolimus (0.05 mg/kg) alone or combined with clopidogrel (1 mg/kg). Twenty-eight days after transplantation, ratio of the thickness of tracheal epithelium and lamina propria was measured as an indicator for chronic rejection. Additionally, graft oxygenation and graft perfusion were detected on postoperative days 4, 10 and 28. Quantitative reverse transcription polymerase chain reaction analysis was used for gene expression analysis. While syngeneic grafts showed a stable tissue pO2 and undisturbed microvascular perfusion, rejecting allografts had a drastic decline in both parameters as well as a flattened epithelium and an increased thickness of the lamina propria. Treatment with everolimus reduced allogeneic fibroproliferation, but had no protective effects on the microvasculature; polymerase chain reaction analysis indicated hypoxic stress and inflammation. Combining everolimus with clopidogrel improved microvascular integrity in the tracheal grafts, but had no synergistic effect in preventing obliterative bronchiolitis development. These data demonstrate that the ability of everolimus to reduce the development of post-transplant obliterative bronchiolitis is not caused by microvascular protection and has no synergistic effects with clopidogrel in acute airway rejection.

Pediatric lung transplantation: Dynamics of the microbiome and bronchiolitis obliterans in cystic fibrosis

Compositional changes in the microbiome are associated with the development of bronchiolitis obliterans (BO) after lung transplantation (LTx) in adults with cystic fibrosis (CF). The association between the lower airway bacterial community and BO after LTx in children with CF remains largely unexplored and is possibly influenced by frequent antibiotic therapy. The objectives of this study were to examine the relationship between bacterial community dynamics and the development of BO and analyze antibiotic resistance trends in children after LTx for CF. For 3 years from the time of transplant, 12 LTx recipients were followed longitudinally, with 5 subjects developing BO during the study period. A total of 82 longitudinal bronchoalveolar lavage samples were collected during standard of care bronchoscopies. Metagenomic shotgun sequencing was performed on the extracted microbial DNA from bronchoalveolar lavage specimens. Taxonomic profiling was constructed using WEVOTE pipeline. The longitudinal association between development of BO and temporal changes in bacterial diversity and abundance were evaluated with MetaLonDA. The analysis of antibiotic resistance genes was performed with the ARGs-OAP v2.0 pipeline. All recipients demonstrated a Proteobacteria-predominant lower airways community. Temporal reduction in bacterial diversity was significantly associated with the development of BO and associated with neutrophilia and antibiotic therapy. Conversely, an increasing abundance of the phylum Actinobacteria and the orders Neisseriales and Pseudonocardiales in the lower airways was significantly associated with resilience to BO. A more diverse bacterial community was related to a higher expression of multidrug resistance genes and increased proteobacterial abundance. Decreased diversity within bacterial communities may suggest a contribution to pediatric lung allograft rejection in CF.

Differential gene analysis during the development of obliterative bronchiolitis in a murine orthotopic lung transplantation model: A comprehensive transcriptome-based analysis.

BackgroundObliterative bronchiolitis (OB) is a known issue during minor histocompatibility antigen (mHA) disparity during lung transplantation. This study evaluated gene expression in a murine orthotropic lung transplantation model using microarray analysis.MethodsLeft lungs from C57BL/10(H-2b) donor mice were transplanted into mHA-mismatched C57BL/6(H-2b) recipient mice. Three groups (OB, non-OB, and sham controls) were confirmed pathologically and analyzed. Gene expression changes in the lung grafts were determined by microarray and immunohistochemical staining, and genes were verified by quantitative PCR in the lungs and mediastinal lymph nodes (LNs).ResultsA total of 1343 genes were upregulated in the OB lungs compared to the sham group. Significant upregulation was observed for genes related to innate, e.g. Tlr2 and CCL3 and adaptive immunity, e.g. H2-ab1 and Il-21. Positive labeling for MHC class II antigen was observed in the bronchial epithelium of OB accompanied with B cells. We found increased Tlr2, Ccl3, H2-ab1, Il-21, Ighg3, Ifng, and Pdcd1 mRNA expression in the OB lung, and increased Il-21, Ighg3, and Pdcd1 expression in the OB LNs.ConclusionsAdaptive and innate immune reactions were involved in OB after lung transplantation, and genetic examination of related genes could be used for detection of OB.

Accelerated Bronchiolitis Obliterans Development after Lung Transplant Promoted by the ATG16l1 rs2241880 Mutation is Coupled to Mitochondrial Damage and Metabolic Alterations in Monocyte-Derived Alveolar Macrophages

Bronchiolitis obliterans (BOS) remains a major cause of death for lung transplant recipients, and mechanisms that drive BOS remain poorly understood. Genetically encoded deficiencies in mitophagy, a specialized autophagy that targets the removal of damaged mitochondria, have been shown to promote Parkinson's disease, but it is unclear if they play a role in other chronic diseases. Recent work has shown that the rs2241880 mutation in the autophagy regulator ATG16L1 leads to protein instability resulting in deficiency of ATG16L1 in monocyte-derived macrophages. We previously observed that human lung recipients that are carriers of rs2241880 had faster BOS development. Here, we analyzed the effects of ATG16L1 deficiency in monocyte-derived alveolar macrophages (Mo-AM) in a mouse orthotopic lung transplant model of BOS. CD11cCre ATG16L1flox/flox (ATG16L1Δ/Δ) and control CD11cCre recipients received major MHC-mismatched FVB lungs and were immunosuppressed to induce acceptance. Following induced epithelial injury, allografts were assessed for obliterative airway lesions (OB) for up to 28 days. Intragraft Mo-AM were analyzed for bulk RNA sequencing and by flow cytometry (FACS) for mitochondrial mass and ROS production. Mitophagic flux was visualized by confocal microscopy using Mt-kiema mitophagy reporter mice. Mo-AM were characterized metabolically using a Seahorse XF analyzer. When compared to controls, CD11cCre ATG16L1flox/flox recipients showed severe and accelerated OB development. RNAseq analysis of ATG16L1Δ/Δ Mo-AM demonstrated a loss of transcripts that encode several subunits of mitochondria electron complex I, II and V. Confocal and FACS analysis revealed attenuated mitophagic flux, high mitochondrial mass and elevated ROS production in ATG16L1Δ/Δ Mo-AM. In line with these observations were decreased maximal mitochondrial respiratory capacity, lower mitochondrial ATP production and increased utilization of glycolysis- consistent with the metabolic adaptation of an M1 inflammatory phenotype. Collectively, these data reveal a new role for ATG16L1 as a regulator of mitochondrial quality control with implications for lung recipients that carry the ATG16L1 rs2241880 mutation.

Risk factors for the development of bronchiolitis obliterans in children with severe adenovirus pneumonia: A retrospective study with dose-response analysis.

To investigate and analyze the relevant risk factors for bronchiolitis obliterans (BO) in children with severe adenovirus pneumonia, a retrospective study of children with severe adenovirus pneumonia was performed in 34 cases that developing BO and 105 cases not developing BO in Children's hospital of Chongqing Medical University from January 2015 to February 2019. The multivariate logistic regression analysis was used to identify factors which were significantly associated with development of BO after the univariate analysis, and receiver operating characteristic (ROC) curve analysis was performed to find out the cut-off value for the significant relevant factors. A nonlinear dose-response relationship between risk factors and the risk of BO was assessed by restricted cubic spline model. Three factors were independently associated with development of BO, which were length of fever (OR 1.129, 95% CI 1.033-1.234), dyspnea (OR 3.922, 95% CI 1.060-14.514) and invasive mechanical ventilation (OR 6.861, 95% CI 1.854-25.387). The cut-off value of length of fever were 10.5 days. A linear dose-response relationship between length of fever and occurrence of BO was observed (P = .57 for nonlinearity). Children with severe adenovirus pneumonia who have a longer duration of fever (especially more than 10.5 days), have dyspnea or require invasive mechanical ventilation in the acute phase are more likely to develop BO.

Post-Breast Cancer Radiotherapy Bronchiolitis Obliterans Organizing Pneumonia.

Radiotherapy for breast cancer has been implicated in the development of bronchiolitis obliterans organizing pneumonia (BOOP). Patients may be asymptomatic or may have pulmonary and constitutional symptoms that are moderate or severe. Postradiotherapy BOOP usually develops during the 12months after completion of radiotherapy and is characterized by ground-glass opacities in the radiation-exposed lung and frequently in the non-irradiated lung. An updated literature search and review was performed to update the systematic review we conducted in 2014. Ten new publications were identified: 2 Japanese epidemiological studies, 1 Japanese case series study, 6 case reports, and 1 review article. The incidence of postradiotherapy BOOP was 1.4% in both Japanese epidemiological studies. Risk factors included increasing age, cigarette smoking, and increasing central lung distance. The case reports included 7 women who had breast cancer postradiation BOOP and 1 woman who had an ataxia telangiectasia mutated (ATM) gene mutation, which may increase radiation sensitivity. Postradiotherapy BOOP in women with breast cancer occurs at a rate of 1.0-3.0% and may occur in women with immune system dysfunction and genetic mutations.

Oral Ribavirin with or without the Addition of Immune Globulin for the Treatment of Lower Respiratory Tract Infections Due to Respiratory Syncytial Virus or Parainfluenza in Patients after Allogeneic Stem Cell Transplantation

Introduction Lower respiratory tract infections (LRTI) due to parainfluenza (PIF) or respiratory syncytial virus (RSV) represent a major challenge for immunocompromised patients especially those after allogeneic stem cell transplantation (allo-SCT). Evidence-based guidelines for the management of respiratory virus infections in allo-SCT recipients are limited due to the paucity of effective antivirals and the lack of prospective randomized trials. In this study, we report our experience with the use of oral ribavirin with or without the addition of IVIgG in allo-SCT recipients with LTRI due to RSV and PIF. Patients and methods This is a retrospective study performed in 3 BMT centers in Athens, Greece (2 adult and 1 pediatric center). Review of medical records was performed with the aim to identify patients with RTIs who received treatment with oral ribavirin. LRTI was defined according to the European Conference on Infections in Leukaemia (ECIL-4) (Ref 1). Presence of RSV or PIF in specimens from nasopharyngeal wash and/or BAL was documented with the use of a PCR assay. Ribavirin was administered at a dose of 20-30mg/kg divided into 4 daily doses, with appropriate dose adjustment according to creatinine clearance. Treatment with ribavirin was continued until significant symptomatic and radiological improvement. Co-administration of IVIgG was at the discretion of the treating physician and was mostly based on the availability of IVIgG and on the severity of underlying illness. IVIgG was administered at a daily dose of 400mg/kg for a total dose of 2 g/kg. Informed consent was given by patients or their parents. Results Forty-nine episodes of LRTI due to RSV or PIF were reported during a nine-year period in 7 children and 37 adult patients after allo-SCT. Three children and 2 adult patients had a second LRTI due to RSV, 6, 8, 8, 10 and 12 months after the first episode. Patient's characteristics are shown in Table 1. All patients presented with fever and cough. In almost all of the patients auscultation revealed a prolonged expiratory phase, diffuse wheezing, while the presence of crackles was more prominent finding in patients presenting with pneumonia. Arterial blood gas analysis showed moderate to severe hypoxemia. In 32 out of 49 episodes oxygen supplementation was required while 7 patients required mechanical ventilation. All 49 episodes treated with oral ribavirin while in 37 cases ribavirin was administered in combination with IVIgG. High resolution CT-scan was performed in 41 episodes and revealed bilateral abnormalities in all patients examined. Small centrilobular nodules, bronchial wall thickening (32 out of 41 episodes) and ground-glass opacities (21 out of 41 episodes) were common findings, while a pattern of diffuse air-space consolidation was observed in 11 cases. In 43 LRTI episodes a rapid response to treatment in a median of 3 days (range, 2 - 5) was observed. Complete resolution of all symptoms and signs of disease occurred after a median of 9 days (7 - 20) of treatment. One patient with pneumonia due to PIF3 who needed mechanical ventilation had a complete resolution of all symptoms of disease. Six deaths attributable to LRTI were observed among a total of 49 episodes (all 6 patients were in need for mechanical ventilation). Disease relapse confirmed microbiologically occurred in only 1 patient with LRTI due to RSV 10 days after the end of treatment with ribavirin. One children developed bronchiolitis obliterans syndrome (BOS) 9 months after the resolution of RSV infection. Cryptogenic organizing pneumonia (COP) was observed in two patients 1 and 2 months after the complete resolution of LRTI due to PIF. Both patients had an excellent response to treatment with steroids. Conclusions Oral Ribavirin has an excellent efficacy and safety profile. Complete and fast resolution of infection occurred in 88% of cases. From the present study it is not clear if the addition of IVIgG offers any therapeutic benefit. References Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for Diagnosis and Treatment of Human Respiratory Syncytial Virus, Parainfluenza Virus, Metapneumovirus, Rhinovirus, and Coronavirus. Clin Infect Dis 2013;56(2):258-66 Disclosures Tsonis: Gilead: Other: Travel Grant; Astellas: Other: Travel Grants; Innovis: Other: Travel Grant; Pfizer: Other: Travel Grant; Takeda: Other: Travel Grant; Aenorasis: Other: Travel Grant. OffLabel Disclosure: Tabl Ribavirin. Current indication: Treatment of active hepatitis C in combination with interferon-a.