While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplantation (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of, cGVHD is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, and development of new treatments and specifies aims of future research endeavors.

Ganciclovir and foscarnet are two representative anti-cytomegalovirus (CMV) agents. A previous regional study revealed a lower risk of chronic graft-versus-host disease (GVHD) in patients who received pre-emptive foscarnet. We conducted a retrospective nationwide study to confirm the results. A total of 8890 patients aged 16 or older with hematological malignancies who received foscarnet (n = 1555) or ganciclovir (n = 7335) during their first hematopoietic stem cell transplantation (HSCT) were included. The risks of chronic GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.13-1.40; P < 0.001) and extensive chronic GVHD (HR, 1.16; 95% CI, 1.01-1.33; P = 0.033) were higher with ganciclovir. Among male patients with a female donor, the incidence of extensive chronic GVHD 3 years after HSCT was clearly lower with foscarnet (13%; 95% CI, 9-16%) than with ganciclovir (27%; 95% CI, 25-29%; P < 0.001). In male patients who received HSCT from female donors, foscarnet recipients showed significantly lower incidence of extensive chronic GVHD than ganciclovir recipients, regardless of donor source or previous acute GVHD. While caution is necessary, these results indicate that foscarnet affects alloimmunization and might reduce the incidence of chronic GVHD.

Haematopoietic stem cell transplantation (HCT) is an established treatment for a wide variety of haematological diseases, both malignant and non-malignant. Infectious and non-infectious post-HCT pulmonary complications are a major cause of morbidity and mortality, with non-infectious complications becoming more prominent in recent decades as prophylaxis has led to a decrease in infectious complications. Globally, these complications can be divided into three phases (neutropenic, early and late phase) depending on their time of onset in relation to the graft. There is a growing awareness that the assessment of the patient undergoing HCT should start before the transplantation itself. It is known that total body irradiation dose, the source of HCT, myeloablative regimens or lower baseline lung function are key risk factors in the development of pulmonary complications. In general, the treatment of these entities consists of administration of corticosteroids with variable response, which highlights the need to better understand the underlying biology in order to have new drugs with more directed targets to improve the prognosis of post-HCT non-infectious pulmonary complications. In view of the limited therapeutic response mentioned above, preventive measures for patients undergoing HCT, such as conditioning of less ablative regimens or pre-selection of high-risk cases, are of paramount importance in order to mitigate the severity of these devastating pulmonary complications.

Haematologic malignancies are considered among the more common adolescent and young adult (AYA) cancers. Many female AYA patients with haematopoietic malignancies face impaired fertility. Haematologic malignancies patients tend to be treated with more aggressive systemic chemotherapy than that of solid tumours. In adult women, treatment-related contraception causes age-related fertility loss. Graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation is associated with decreased fertility. Ovarian cryopreservation is often indicated for haematopoietic malignancies; however, follicle loss associated with ovarian cryopreservation and ovarian minimal residual disease, which result in the withdrawal of the transplantation, are important issues. These problems may not be fully addressed by conventional methods of fertility preservation, such as oocyte, embryo, and ovarian cryopreservation, leaving room for research into new treatment approaches, such as fertility preservation drugs. In recent years, preclinical studies have shown that mTOR inhibitors may preserve chemotherapy-induced follicular loss, may have follicle-preserving effects on follicle loss associated with cryopreservation and transplantation of ovarian tissue, may have fertility-preserving effects on aging-related infertility. Clinical studies have shown that mTOR inhibitors may have the potential for indirect fertility preservation by controlling GVHD, have a limited anti-tumor effect against haematopoietic malignancies. The purpose of this article is to outline the various issues faced by female survivors of haematopoietic malignancies and discuss the potential of mTOR inhibitors as a safe treatment option. Based on current research, mTOR inhibitors seem promising and innovative fertility preservation agents regarding preclinical conditions, and further study, including clinical trials, should be expected.

Bronchiolitis obliterans syndrome (BOS), as chronic manifestation of graft-versus-host disease (GVHD), is a debilitating complication leading to lung function deterioration in patients after allogeneic hematopoietic cell transplantation (allo-HCT). In the present study, we evaluated BOS development risk in patients after receiving myeloablative conditioning (MAC) regimens. We performed a retrospective analysis of patients undergoing allo-HCT, who received MAC with busulfan/cyclophosphamid (BuCy, n = 175) busulfan/fludarabin (FluBu4, n = 29) or thiotepa/busulfan/fludarabine (TBF MAC, n = 37). The prevalence of lung disease prior allo-HCT, smoking status, GvHD prophylaxis, HCT-CI score, EBMT risk score and GvHD incidence varied across the groups. The cumulative incidence of BOS using the NIH diagnosis consensus criteria at 2 years after allo-HCT was 8% in FluBu4, 23% in BuCy and 19% in TBF MAC (p = 0.07). In the multivariate analysis, we identified associated factors for time to BOS such as FEV1 Collapse

Bone marrow transplantation, now often known as haematopoietic stem cell transplantation (HSCT), is a complex choreographed procedure used to treat both acquired and inherited disorders of the bone marrow. It has proven invaluable as therapy for haematological and immunological disorders, and more recently in the treatment of metabolic and enzyme disorders. As the number of performed transplants grows annually, and with patients enjoying improved survival, a knowledge of both early and late complications of HSCT is essential for respiratory trainees and physicians in practice. This article highlights the spectrum of respiratory complications, both infectious and non-infectious, the timeline of their likely occurrence, and the approaches used for diagnosis and treatment, keeping in mind that more than one entity may occur simultaneously. As respiratory issues are often a leading cause of short- and long-term morbidity, consideration of a combined haematology/respiratory clinic may prove useful in this patient population.

Chronic graft-versus-host disease (cGVHD) is associated with morbidity, mortality, impaired quality of life, prolonged immunosuppressive therapy, and infection risk after allogeneic hematopoietic cell transplantation (HCT). Major strides have occurred in the understanding of cGVHD biology; National Institutes of Health Consensus meetings have refined rigorous approaches to diagnosis, staging, and response criteria; major interventional trials have established standard benchmarks for treatment outcome; and 3 agents to date have been US Food and Drug Administration approved for treating corticosteroid-refractory cGVHD. Promising results from several recent trials have led some, but not others, to conclude that the risk of developing cGVHD is sufficiently low to be considered a major post-HCT complication of the past. We propose that it is time to critically examine the results of contemporary graft-versus-host disease (GVHD) prophylaxis regimens and discuss the state of the science and associated controversies in the spectrum of conclusions reached as to the risk of cGVHD. With these data, the current cGVHD incidence can be most precisely determined, and the present and future burden of cGVHD-affected patients can be accurately modeled. Through review of existing evidence, we highlight unresolved needs and opportunities to refine best GVHD prophylaxis or preemptive therapy approaches and optimize established cGVHD therapy, and make the argument that support of preclinical and clinical research is critical in improving patient outcomes.

Chronic graft-versus-host disease is a frequent and serious complication of allogeneic hematopoietic cell transplantation and is associated with an increased risk of serious infections. Impaired humoral immunity increases the risk of recurrent or severe sinopulmonary infections, and functional asplenia predisposes to infections from encapsulated organisms. Herpesvirus infections and community-acquired respiratory viral infections are problematic as well. Pneumocystis pneumonia remains a risk, and mold infections occur in some patients. Understanding the epidemiology and pathophysiology of these infections is important for determining optimal monitoring and prophylaxis, and guiding patient counseling.

Over the last decades, significant improvements in reducing the toxicities of allogeneic hematopoietic cell transplantation (allo-HCT) have widened its use as consolidation or salvage therapy for high-risk hematological malignancies. Nevertheless, relapse of the original malignant disease remains an open issue with unsatisfactory salvage options and limited rationales to select among them. In the last years, several studies have highlighted that relapse is often associated with specific genomic and nongenomic mechanisms of immune escape. In this review we summarize the current knowledge about these modalities of immune evasion, focusing on the mechanisms that leverage antigen presentation and pathologic rewiring of the bone marrow microenvironment. We present examples of how this biologic information can be translated into specific approaches to treat relapse, discuss the status of the clinical trials for patients who relapsed after a transplant, and show how dissecting the complex immunobiology of allo-HCT represents a crucial step toward developing new personalized approaches to improve clinical outcomes.

Bronchiolitis obliterans (BO) is a form of graft-versus-host disease (GVHD) in the lung and manifests as moderate to severe airflow obstruction after hematopoietic stem cell transplantation (HCT). New-onset airflow obstruction on spirometry is considered diagnostic of bronchiolitis obliterans syndrome (BOS). BOS affects about 5% of all HCT recipients. In general, BO is thought of as a late complication of HCT, usually occurring after day 100 post-transplantation. However, the onset of airflow obstruction can be rapid and is most often irreversible even with treatment. We describe a patient who rapidly developed severe airflow obstruction less than one month after transplantation following the development of upper airway symptoms. Despite aggressive immunosuppression, the patient had no improvement in airflow obstruction. We hypothesize that early screening and treatment may help prevent BOS after HCT.

Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.

Five sessions presented at the European Respiratory Society Congress 2023 were selected by Assembly 8, consisting of thoracic surgeons and lung transplant professionals. Highlights covering management of adult spontaneous pneumothorax, malignant pleural effusion, infectious and immune-mediated complications after lung transplantation, as well as the pro and con debate on age limit in lung transplantation and results of the ScanCLAD study were summarised by early career members, supervised by the assembly faculty.

Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available. The purpose of this joint European Respiratory Society (ERS) and European Society for Blood and Marrow Transplantation task force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine and methodology, as well as patient advocates, formulated eight PICO (patient, intervention, comparison, outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the Grading of Recommendations Assessment, Development and Evaluation approach to develop recommendations. The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.

Immunocompromised (IC) patients are high risk for complications due to a high rate of antibiotic exposure. Antimicrobial stewardship interventions targeted to IC patients can be challenging due to limited data in this population and a high risk of severe infection-related outcomes. Here, the authors review immunocompromised antimicrobial stewardship barriers, metrics, and opportunities for antimicrobial use and testing optimization. Last, the authors highlight future steps in the field.

Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS.

Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled.

Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group.

Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS.

The resistance, plasticity and heterogeneity of cancer cells, including glioblastoma (GB) cells, have prompted the investigation of various agents for possible adjuncts and alternatives to existing therapies. This includes a macrolide antibiotic, azithromycin (AZI). It possesses intriguing anticancer properties in a range of cancer models in vitro, such as antiproliferative, pro-apoptotic, anti-autophagy and anti-angiogenic effects. In fact, AZI is renowned for its ability to eradicate cancer stem cells by inhibiting mitochondrial biogenesis and respiration. AZI-containing regimens in cancer patients for different purposes have shown favourable (i.e., attributed to its antibacterial activity) and unfavourable outcomes. Whilst its direct anticancer effects have yet to be clinically proven. To that end, this review provides a summary of AZI anticancer studies and delineates its potential activities in overcoming the challenges of GB.

Early administration of azithromycin after allogeneic hematopoietic stem cell transplantation was shown to increase the relapse of hematological malignancies. To determine the impact of azithromycin on the post-transplant gut ecosystem and its influence on relapse, we characterized overtime gut bacteriome, virome, and metabolome of 55 patients treated with azithromycin or a placebo. We describe four enterotypes and the network of associated bacteriophage species and metabolic pathways. One enterotype associates with sustained remission. One taxon from Bacteroides specifically associates with relapse, while two from Bacteroides and Prevotella correlate with complete remission. These taxa are associated with lipid, pentose, and branched-chain amino acid metabolic pathways and several bacteriophage species. Enterotypes and taxa associate with exhausted T cells and the functional status of circulating immune cells. These results illustrate how an antibiotic influences a complex network of gut bacteria, viruses, and metabolites and may promote cancer relapse through modifications of immune cells.

Bronchiolitis obliterans (BO) is a chronic disease that can arise as a complication of severe childhood pneumonia and can also impact the long-term survival of patients after lung transplantation. However, the precise molecular mechanism underlying BO remains unclear. We aimed to identify BO-associated hub genes and their molecular mechanisms.

BO-associated transcriptome datasets (GSE52761, GSE137169, and GSE94557) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Additional bioinformatics analyses, such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI) analyses, were performed to determine functional roles and DEG-associated regulatory networks. Prediction of hub genes using the 12 algorithms available in the Cytohubba plugin of Cytoscape software was also performed. Verification was performed using the BO mouse model.

Our results revealed 57 DEGs associated with BO, of which 18 were down-regulated and 39 were up-regulated. The Cytohubba plugin data further narrowed down the 57 DEGs into 9 prominent hub genes (CCR2, CD1D, GM2A, TFEC, MPEG1, CTSS, GPNMB, BIRC2, and CTSZ). Genes such as CCR2, TFEC, MPEG1, CTSS, and CTSZ were dysregulated in 2,3-butanedione-induced BO mice, whereas TFEC, CTSS, and CTSZ were dysregulated in nitric acid-induced BO mouse models.

Our study identified and validated four novel BO biomarkers, which may allow further investigation into the development of distinct BO diagnostic markers and novel therapeutic avenues.

Allogeneic stem cell transplantation is a lifesaving treatment for many malignancies. Post-transplant patients may suffer from graft versus host disease in the acute and/or the chronic form(s). Post-transplantation immune deficiency due to a variety of factors is a major cause of morbidity and mortality. Furthermore, immunosuppression can lead to alterations in host factors that predisposes these patients to infections. Although patients who receive stem cell transplant are at an increased risk of opportunistic pathogens, which include fungi and viruses, bacterial infections remain the most common cause of morbidity. Here, we review bacterial pathogens that lead to pneumonias specifically in the chronic GVHD population.

Macrolide antibiotics are widely used antibacterial agents that are associated with autophagy inhibition. This study aimed to investigate the association between macrolide antibiotics and malignant tumors, as well as the effect on autophagy, reactive oxygen species (ROS) accumulation and integrated stress response (ISR). The meta-analysis indicated a modestly higher risk of cancer in macrolide antibiotic ever-users compared to non-users. Further experiments showed that macrolides block autophagic flux by inhibiting lysosomal acidification. Additionally, azithromycin, a representative macrolide antibiotic, induced the accumulation of ROS, and stimulated the ISR and the activation of transcription factor EB (TFEB) and TFE3 in a ROS-dependent manner. Finally, animal experiments confirmed that azithromycin promoted tumor progression in vivo, which could be receded by N-acetylcysteine, an inhibitor of ROS and ISR. Overall, this study reveals the potential role of macrolide antibiotics in malignant progression and highlights the need for further investigation into their effects.

Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications' underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.

Administration of azithromycin after allogeneic hematopoietic stem cell transplantation for hematologic malignancies has been associated with relapse in a randomized phase 3 controlled clinical trial. Studying 240 samples from patients randomized in this trial is a unique opportunity to better understand the mechanisms underlying relapse, the first cause of mortality after transplantation. We used multi-omics on patients' samples to decipher immune alterations associated with azithromycin intake and post-transplantation relapsed malignancies. Azithromycin was associated with a network of altered energy metabolism pathways and immune subsets, including T cells biased toward immunomodulatory and exhausted profiles. In vitro, azithromycin exposure inhibited T-cell cytotoxicity against tumor cells and impaired T-cell metabolism through glycolysis inhibition, down-regulation of mitochondrial genes, and up-regulation of immunomodulatory genes, notably SOCS1. These results highlight that azithromycin directly affects immune cells that favor relapse, which raises caution about long-term use of azithromycin treatment in patients at high risk of malignancies. The ALLOZITHRO trial was registered at www.clinicaltrials.gov as #NCT01959100.

Bronchiolitis obliterans syndrome (BOS)-chronic graft-versus-host disease (cGVHD) affecting the lungs-is an uncommon complication of allogeneic hematopoietic cell transplant (HCT). The epidemiology and complications of lower respiratory tract infections (LRTIs) and community-acquired respiratory viruses (CARVs) in these patients are poorly understood.

We aim to characterize the epidemiology of LRTIs in patients with BOS complicating HCT. We also aim to explore the association of LRTIs and CARV detection on lung function in BOS patients.

Adult patients with BOS at Stanford Health Care between January 2010 and December 2019 were included in this retrospective cohort study. LRTI diagnosis was based on combined clinical, microbiologic, and radiographic criteria, using consensus criteria where available.

Fifty-five patients with BOS were included. BOS was diagnosed at a median of 19.2 (IQR 12.5-24.7) months after HCT, and patients were followed for a median of 29.3 (IQR 9.9-53.2) months from BOS diagnosis. Twenty-two (40%) patients died after BOS diagnosis; 17 patients died from complications of cGVHD (including respiratory failure and infection) and 5 died from relapsed disease. Thirty-four (61.8%) patients developed at least one LRTI. Viral LRTIs were most common, occurring in 29 (52.7%) patients, primarily due to rhinovirus. Bacterial LRTIs-excluding Nocardia and non-tuberculous mycobacteria (NTM)-were the second most common, occurring in 21 (38.2%) patients, mostly due to Pseudomonas aeruginosa. Fungal LRTIs, NTM, and nocardiosis occurred in 14 (25.5%), 10 (18.2%), and 4 (7.3%) patients, respectively. Median time to development of the first LRTI after BOS diagnosis was 15.3 (4.7-44.7) months. Twenty-six (76.5%) of the 34 patients who developed LRTIs had infections due to more than one type of organism-fungi, viruses, Nocardia, NTM, and other bacteria-over the observation period. Patients with at least one LRTI had significantly lower forced expiratory volume in one second percent predicted (FEV1%) (37% vs. 53%, p = 0.0096) and diffusing capacity of carbon monoxide (DLCO) (45.5% predicted vs. 69% predicted, p = 0.0001). Patients with at least one LRTI trended toward lower overall survival (OS) (p = 0.0899) and higher non-relapse mortality (NRM) (p = 0.2707). Patients with a CARV detected or LRTI diagnosed after BOS-compared to those without any CARV detected or LRTI diagnosed-were more likely to have a sustained drop in FEV1% from baseline of at least 10% (21 [61.8%] versus 7 [33.3%]) and a sustained drop in FEV1% of at least 30% (12 [36.4%] versus 2 [9.5%]).

LRTIs are common in BOS and associated with lower FEV1%, lower DLCO, and a trend toward decreased OS and higher NRM. Patients with LRTIs or CARVs (even absent lower respiratory tract involvement) were more likely to have substantial declines in FEV1% over time than those without. The array of organisms-including P. aeruginosa, mold, Nocardia, NTM, and CARVs-seen in BOS reflects the unique pathophysiology of this form of cGVHD, involving both systemic immunodeficiency and structural lung disease. These patterns of LRTIs and their outcomes can be used to guide clinical decisions and inform future research.

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1-4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1-4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

Bronchiolitis obliterans syndrome (BOS) is a devastating complication that occurs after transplantation. Although azithromycin is currently used for the treatment of BOS, the evidence is sparse and controversial. The aim of this meta-analysis is to evaluate the effects of azithromycin on forced expiratory volume in 1 second (FEV1) and patient's survival.

PubMed, Embase, Cochrane library, Web of Science databases, and the ClinicalTrials.gov registry were systematically searched from inception until December 2020 for relevant original research articles. Random-effects models were used to calculate pooled-effect estimates.

Searches identified 15 eligible studies involving 694 participants. For FEV1 (L), there was a significant increase after short-term (≤12 weeks; P = .00) and mid-term (12-24 weeks; P = .01) administration of azithromycin. For FEV1 (%) compared to baseline, there was a significant increase after short-term (≤12 weeks) administration of azithromycin (P = .02), while there were no statistically significant differences in the medium and long term. When pooled FEV1% was predicted, it exhibited a similar trend to FEV1 (%) compared to baseline. In addition, we discovered that azithromycin reduced the risk of death (hazard ratio = 0.26; 95% confidence interval = 0.17 to 0.40; P = .00) in patients with BOS post-lung transplantation.

Azithromycin therapy is both effective and safe for lung function improvement in patients with posttransplant BOS after the short- and medium-term administration. Additionally, it has been demonstrated a significant survival benefit among patients with BOS post-lung transplant. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed to confirm the effect of azithromycin on patients with posttransplant BOS.

Hematologic malignancies are cancers of the blood, bone marrow and lymph nodes and represent a heterogenous group of diseases that affect people of all ages. Treatment generally involves chemotherapeutic or targeted agents that aim to kill malignant cells. In some cases, hematopoietic stem cell transplantation (HCT) is required to replenish the killed blood and stem cells. Both disease and therapies are associated with pulmonary complications. As survivors live longer with the disease and are treated with novel agents that may result in secondary immunodeficiency, airway diseases and respiratory infections will increasingly be encountered. To prevent airways diseases from adding to the morbidity of survivors or leading to long-term mortality, improved understanding of the pathogenesis and treatment of viral bronchiolitis, BOS, and bronchiectasis is necessary.

This review focuses on viral bronchitis, BOS and bronchiectasis in people with hematological malignancy. Literature was reviewed from Pubmed for the areas covered.

Airway disease impacts significantly on hematologic malignancies. Viral bronchiolitis, BOS and bronchiectasis are common respiratory manifestations in hematological malignancy. Strategies to identify patients early in their disease course may improve the efficacy of treatment and halt progression of lung function decline and improve quality of life.

Macrolide antibiotics are one of the most commonly used broad-spectrum antibiotics. They have an inhibitory effect on a variety of respiratory pathogens; besides, they have non-anti-infective effects, including anti-inflammatory, regulating airway secretion, immune regulation, and other effects. A growing number of studies have shown that the non-anti-infective effects of macrolides have important and potential value in the treatment of pediatric chronic airway diseases; the therapy was described as "long-term, low-dose usage"; unfortunately, there is no guideline or consensus that applies to children. To better carry out the mechanism and clinical research of non-anti-infective effect and promote its rational use in children, the authors summarize the evidence of the usage of long-term, low-dose macrolide antibiotic therapy (LLMAT) in the treatment of chronic airway diseases in children and the progress in recent years. IMPACT: This review summarizes the evidence (mostly in recent 5 years) of the usage of long-term, low-dose macrolide antibiotic therapy in the treatment of chronic airway diseases. The recent studies and guidelines support and enrich the point that long-term, low-dose macrolide antibiotic therapy has potential benefit for children with severe asthma, CF, non-CF bronchiectasis, and BO, which provides clinical references and is of clinical interest. Long-term, low-dose macrolide antibiotic therapy has good safety, and no serious events have been reported; however, potential cardiac side effects and macrolide resistance should be clinically noted.

Noninfectious lung diseases contribute to nonrelapse mortality. They constitute a spectrum of diseases that can affect the parenchyma, airways, or vascular pulmonary components and specifically exclude cardiac and renal causes. The differential diagnoses of these entities differ as a function of time after hematopoietic cell transplantation. Specific diagnosis, prognosis, and optimal treatment remain challenging, although progress has been made in recent decades.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

Bronchiolitis obliterans syndrome (BOS) is one of the most severe complications and the leading cause of late mortality and morbidity after lung transplantation (LT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). No approved treatment for BOS is available. This review aimed to systematically identify and summarise the findings regarding the relationship between FEV₁ decline and mortality in patients who developed BOS following LT or allo-HSCT.

A systematic literature search was performed in the Medline, Embase and Cochrane reviews databases. Of the 501 potential studies identified 25 met inclusion criteria and were analysed.

Overall, 13 studies reported a relationship between FEV₁ and mortality, and 12 studies reported both mortality and FEV₁ results but did not investigate the relationship between them. There was heterogeneity in the analyses, which investigated the relationship between FEV₁ decline and mortality across the studies in terms of levels of lung functioning, comparison to a control group, treatment, and statistical methodology; nevertheless, a clear and consistent increase in the risk of death associated with FEV₁ decrease was seen in the analysed studies.

The systematic literature review identified studies and findings that support a relationship between FEV₁ and mortality, with a decrease in FEV₁ being statistically associated with increased risk of death. Knowing that lower FEV₁ levels are associated with higher mortality rates may help assess the condition of a patient with BOS and monitor future treatment effectiveness. However, more evidence is needed to further investigate this relationship and to verify its clinical usefulness.

Approximately 2,500 pediatric hematopoietic cell transplants (HCTs), most of which are allogeneic, are performed annually in the United States for life-threatening malignant and nonmalignant conditions. Although HCT is undertaken with curative intent, post-HCT complications limit successful outcomes, with pulmonary dysfunction representing the leading cause of nonrelapse mortality. To better understand, predict, prevent, and/or treat pulmonary complications after HCT, a multidisciplinary group of 33 experts met in a 2-day National Institutes of Health Workshop to identify knowledge gaps and research strategies most likely to improve outcomes. This summary of Workshop deliberations outlines the consensus focus areas for future research.

Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible overtreatment and may interfere with the graft-versus-malignancy immune response. Here we summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet National Institutes of Health diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist. In this report, we (1) review current knowledge regarding clinical risk factors for chronic GVHD, (2) review what is known about chronic GVHD risk assignment biomarkers, (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents, and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development, including trial design and statistical considerations. We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early-phase preemptive therapy trials represent the most urgent priorities for advancing this novel area of research.

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.