Allergic bronchopulmonary aspergillosis in a lung transplant recipient treated with mepolizumab.

Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction to Aspergillus spp. ABPA diagnosis may be challenging due to its non-specific presentation. Standard ABPA treatment consists of systemic corticosteroids and antifungal agents. Mepolizumab, a monoclonal antibody against interleukin-5 seems to be a promising treatment for ABPA. Data about ABPA following lung transplantation (LuTx) are scarce. LuTx recipients are at higher risk for adverse effects of ABPA treatment compared to the general population. Here we present a case of a LuTx recipient who was successfully treated with mepolizumab for ABPA following LuTx. Prolonged administration of high dose prednisone was thus avoided. To our knowledge, this is the first case describing mepolizumab administration following LuTx. Mepolizumab seems particularly attractive as a corticosteroid-sparing agent or as an alternative option to antifungal treatments, because of its excellent safety profile and low risk of drug interactions.

Antifungal drug penetration in soft tissue abscesses: a comparative analysis.

BACKGROUND: Invasive fungal infections (IFIs) are severe and difficult-to-treat infections affecting immunocompromised patients. Antifungal drug penetration at the site of infection is critical for outcome and may be difficult to achieve. Data about antifungal drug distribution in infected human tissues under real circumstances of IFI are scarce. METHODS: Multiple samples were obtained from soft tissue abscesses of a lung transplant patient with Candida albicans invasive candidiasis who underwent recurrent procedures of drainage, while receiving different consecutive courses of antifungal therapy [itraconazole (ITC), fluconazole, caspofungin]. Antifungal drug concentrations were measured simultaneously at the site of infection (surrounding inflammatory tissue and fluid content of the abscess) and in plasma for calculation of the tissue/plasma ratio (R). The concentration within the infected tissue was interpreted as appropriate if it was equal or superior to the MIC of the causal pathogen. RESULTS: A total of 30 tissue samples were collected for measurements of ITC (n = 12), fluconazole (n = 17) and caspofungin (n = 1). Variable concentrations were observed in the surrounding tissue of the lesions with median R of 2.79 (range 0.51-15.9) for ITC and 0.94 (0.21-1.37) for fluconazole. Concentrations ranges within the fluid content of the abscesses were 0.39-1.83 for ITC, 0.66-1.02 for fluconazole and 0.23 (single value) for caspofungin. The pharmacodynamic target (tissue concentration ≥ MIC) was achieved in all samples for all three antifungal drugs. CONCLUSIONS: This unique dataset of antifungal drug penetration in infected human soft tissue abscesses suggests that ITC, fluconazole and caspofungin could achieve appropriate concentrations in soft tissue abscesses.

Lung Transplantation for Primary Ciliary Dyskinesia and Kartagener Syndrome: A Multicenter Study.

Primary ciliary dyskinesia, with or without situs abnormalities, is a rare lung disease that can lead to an irreversible lung damage that may progress to respiratory failure. Lung transplant can be considered in end-stage disease. This study describes the outcomes of the largest lung transplant population for PCD and for PCD with situs abnormalities, also identified as Kartagener's syndrome. Retrospectively collected data of 36 patients who underwent lung transplantation for PCD from 1995 to 2020 with or without SA as part of the European Society of Thoracic Surgeons Lung Transplantation Working Group on rare diseases. Primary outcomes of interest included survival and freedom from chronic lung allograft dysfunction. Secondary outcomes included primary graft dysfunction within 72 h and the rate of rejection ≥A2 within the first year. Among PCD recipients with and without SA, the mean overall and CLAD-free survival were 5.9 and 5.2 years with no significant differences between groups in terms of time to CLAD (HR: 0.92, 95% CI: 0.27-3.14, p = 0.894) or mortality (HR: 0.45, 95% CI: 0.14-1.43, p = 0.178). Postoperative rates of PGD were comparable between groups; rejection grades ≥A2 on first biopsy or within the first year was more common in patients with SA. This study provides a valuable insight on international practices of lung transplantation in patients with PCD. Lung transplantation is an acceptable treatment option in this population.

Outcomes of SARS-CoV-2 infection among lung transplant recipients: A single center retrospective study.

BACKGROUND: Lung transplant recipients (LTRs) are at increased risk for coronavirus disease 2019 (COVID-19)-associated complications. METHODS: We aimed to describe the outcomes of polymerase chain reaction-documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LTRs followed at our institution from March 2020 to July 2022. The primary outcome investigated was hospitalization or death from COVID-19-related symptoms within 28 days from diagnosis. RESULTS: Overall, 60 cases were included, of which 18 (30%) reached the primary outcome. Only one patient (2%) died. Anti-spike monoclonal antibodies (mAbs) were administered as early treatment in 36 patients (casirivimab/imdevimab = 2, sotrovimab = 31, and tixagevimab/cilgavimab = 3). Multivariate analysis revealed that age >60 years (p = .003; odds ratio [OR] 9.41; confidence interval [CI] 2.52-41.05) was associated with a higher risk for the primary outcome, while administration of mAbs as early treatment (p = .030; OR 0.23; CI 0.06-0.87) was associated with a lower risk. No effect of vaccination and SARS-CoV-2 variant was observed. Forced expiratory volume in 1 s and forced vital capacity values did not decrease among 37 patients who had spirometry performed 1 month after COVID-19. CONCLUSIONS: We observed a relatively low morbidity and mortality of COVID-19 in LTR. mAb administration was associated with a better outcome.

Impact of COVID-19 on long-term lung function in lung transplant recipients: A single-center retrospective cohort study.

Available data are limited concerning long-term lung function (LF) evolution after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in lung transplant (LT) recipients. The aim of this study is to determine the effect of first SARS-CoV-2 infection on long-term LF in LT recipients. We analyzed spirometry results of LT recipients followed at our institution (March 2020 to July 2022) at 3, 6, and 12 months after first SARS-CoV-2 infection. Overall, 42 LT patients of our cohort (70%) with COVID-19 were included for long-term LF analysis. Forced expiratory volume in 1 s (FEV1 ) declined significantly at 3 months (-4.5%, -97 mL, 95% CI [-163; -31], p < .01), but not at 6 and 12 months (-3.9%, -65 mL, 95% CI [-168; +39], p = .21). Results were quite similar for the forced vital capacity. Spirometry values declined significantly at 3 months after COVID-19 in LT recipients, presented a mixed decline at 6 months, and no significant decline at 12 months.

[When to consider lung transplantation?] / Quand penser à la transplantation pulmonaire ?

Pulmonary transplantation remains the ultimate therapeutic option for selected patients with an advanced pulmonary disease and terminal respiratory insufficiency when all other therapeutic options have been exhausted. The optimal time-frame to proceed to a first discussion and evaluation about lung transplantation may be difficult to determine. This article describes the pathway of a patient towards lung transplantation and summarizes the criteria, which may help to timely identify eligibility for this therapeutic modality. We will focus mainly on the 2021 update of the International Society for Heart and Lung Transplantation (ISHLT) recommendations for the selection of lung transplant candidates.

La transplantation pulmonaire reste l'ultime option thérapeutique pour des patients sélectionnés présentant une maladie pulmonaire avancée au stade d'insuffisance respiratoire terminale, une fois les autres traitements reconnus épuisés. Le moment idéal pour une première discussion et l'évaluation d'une transplantation pulmonaire peut être difficile à identifier. Cet article décrit le parcours d'un patient vers la transplantation pulmonaire et résume les différents facteurs qui permettent d'identifier son éligibilité pour ce traitement. Nous nous focalisons notamment sur les recommandations pour la sélection des receveurs de transplantation pulmonaire mises à jour en 2021 par l'International Society for Heart and Lung Transplantation (ISHLT).

[Phage therapy for respiratory infections]. / Phagothérapie pour traiter les infections respiratoires.

The crisis of antibiotic resistance represents a global public health challenge, affecting particularly patients with respiratory infections. The use of (bacterio)phages for the treatment of bacterial infections (phage therapy) seems safe but its effectiveness has not yet been proven by controlled clinical trials. Nevertheless, phage therapy is regaining interest, encouraged by published cases treated successfully with personalized phage combinations as well as significant advances at a preclinical level. Standardized approaches in phage production and treatment administration, as well as future translational studies, are needed to improve our understanding and explore the potential of phage therapy.

La crise de l'antibiorésistance représente un enjeu considérable en santé publique, touchant particulièrement les patients avec des infections respiratoires. L'utilisation des (bactério)phages pour le traitement des infections bactériennes semble sécuritaire mais son efficacité n'a pas encore été formellement démontrée dans des essais cliniques contrôlés. La phagothérapie regagne de l'intérêt comme traitement personnalisé pour les patients qui ne répondent pas aux traitements standards, comme en témoignent les multiples cas publiés ainsi que des découvertes significatives au niveau préclinique. Des approches standardisées concernant la production et l'administration des phages ainsi que des études translationnelles sont nécessaires afin d'améliorer notre compréhension et d'explorer le potentiel de la phagothérapie.

[Short telomere syndrome in adults: a rare entity that should be evoked]. / Syndrome des télomères courts chez l'adulte†: une entité rare qu'il faut savoir évoquer.

Short telomere syndrome (STS) is a group of rare, often underrecognized, diseases caused by defects in telomere-maintenance genes, leading to abnormal telomere shortening and associated with diverse multi-organ manifestations. In pediatric patients, STS typically presents with mucocutaneous or gastrointestinal lesions, bone marrow failure and neoplasia. In adulthood, aplastic bone marrow disease, liver disease and pulmonary fibrosis are classic clinical manifestations. At present, medical treatment options for STS remain limited. Danazol, a synthetic androgenic hormone, can slow down telomere shortening and thus limit the progression of the disease. Finally, hematopoietic, hepatic and pulmonary transplantation, sometimes combined, may be discussed in a multidisciplinary setting in certain situations.

Le syndrome des télomères courts (STC) est un groupe de maladies rares dues à un défaut dans les gènes de maintenance des télomères, provoquant leur raccourcissement anormal et des manifestations cliniques multiorganiques. Dans l'enfance, le STC se présente par des lésions mucocutanées et gastro-intestinales, une insuffisance médullaire et des néoplasies. À l'âge adulte, une atteinte médullaire aplasiante, hépatique, et une fibrose pulmonaire sont des manifestations cliniques classiques. Les options thérapeutiques pour le STC restent limitées. Le danazol, une hormone androgène synthétique, permet, parfois, de freiner le raccourcissement télomérique et de limiter la progression de la maladie. Finalement, les transplantations hématopoïétique, hépatique et pulmonaire sont discutées dans certaines situations de manière multidisciplinaire.

Bronchial anastomosis dehiscence and stenosis caused by donor-transmitted Mycoplasma hominis infection in a lung transplant recipient: Case report and literature review.

Pulmonary infection by Mycoplasma hominis (M hominis) in lung transplant (LTx) recipients is an uncommon yet potentially severe complication. Bronchial dehiscence in the context of M hominis infection has not been previously reported. In this report, we discuss a case of donor-derived M hominis infection in a LTx recipient with bilateral bronchial anastomoses dehiscence and stenosis. The infection was managed using a multidisciplinary approach: repeat surgical revision of the necrotic anastomosis; targeted antibiotic therapy with the combination of oral and inhaled fluoroquinolones, and oral doxycycline and continuous ventilatory support. Response to therapy was monitored through repeat bronchoscopy and serial quantitative PCR assays for M hominis in bronchoalveolar lavage and aspiration. The rare nature of M hominis infection after LTx, its difficult detection in conventional cultures and innate resistance to beta-lactams make diagnosis and timely treatment of this organism challenging. We recommend that transplant centers have a low threshold for screening for Mycoplasma infection, particularly in patients with unsatisfactory postoperative course and little response to broad-spectrum antimicrobial and antifungal coverage. Monitoring with PCR may help to adapt the duration of antibiotic therapy.

Acute Rejection in the Modern Lung Transplant Era.

Acute cellular rejection (ACR) remains a common complication after lung transplantation. Mortality directly related to ACR is low and most patients respond to first-line immunosuppressive treatment. However, a subset of patients may develop refractory or recurrent ACR leading to an accelerated lung function decline and ultimately chronic lung allograft dysfunction. Infectious complications associated with the intensification of immunosuppression can also negatively impact long-term survival. In this review, we summarize the most recent evidence on the mechanisms, risk factors, diagnosis, treatment, and prognosis of ACR. We specifically focus on novel, promising biomarkers which are under investigation for their potential to improve the diagnostic performance of transbronchial biopsies. Finally, for each topic, we highlight current gaps in knowledge and areas for future research.

Endobronchial coil spring fiducial markers for CyberKnife® stereotactic body radiation therapy.

BACKGROUND AND OBJECTIVE: SBRT is an alternative treatment for early-stage inoperable lung cancer. Metallic FM allow to increase tumour tracking precision by CyberKnife®. Currently used techniques for FM placement have many limitations; transthoracic insertion has a high risk for pneumothorax, endovascular insertion requires expertise and dedicated angiography infrastructure and endobronchial linear-gold FM dislocate frequently. This is the first study to assess the safety and efficacy of cs-FM endobronchial insertion under fluoroscopy with or without R-EBUS assessment. METHODS: We retrospectively evaluated all consecutive patients undergoing endobronchial cs-FM placement for at least one PPL <25 mm between 10.2015 and 12.2019. TBB of the PPL were performed in case of a typical R-EBUS signal. PPL tracking accuracy by CyberKnife, complications, cs-FM migration rate and procedure duration were analysed. RESULTS: A total of 52 patients were treated during 55 procedures and 207 cs-FM were placed in 70 PPL. Tracking was successful for 65 of 70 (93%) PPL. R-EBUS was performed for 33 (47%) PPL and TBB for 9 (13%) PPL. Bronchospasm occurred once and any other complications were observed. Migration of cs-FM occurred in 16 of 207 (8%) cs-FM. Migration was more frequent when the target was in a previously irradiated area (P = 0.022). The median bronchoscopy duration was 31.5 min (n = 48 procedures). CONCLUSION: Bronchoscopic cs-FM placement is a rapid and safe procedure. It is associated with a low migration rate and allows precise SBRT delivery. Previous irradiation of the PPL was associated with a higher migration rate.

[Revolution in the treatment of cystic fibrosis]. / Révolution dans le traitement de la mucoviscidose.

Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly respiratory. Until recently, treatments only concerned the consequences of the disease. But a new type of molecules called «â€…modulators ¼, is already available to some patients and targets the origin of the disease. «â€…Modulators ¼ are divided into «â€…potentiators ¼, which improve the transport of chloride by the CFTR protein, and «â€…correctors ¼, increasing the amount of CFTR proteins. An oral triple therapy combining a potentiator and two correctors has just been approved in the USA and will treat 85 % of patients. The clinical benefit of «â€…modulators ¼ is remarkable, and these drugs are revolutionizing the treatment of Cystic Fibrosis.

La mucoviscidose est une maladie génétique entraînant une absence ou des dysfonctions de la protéine Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), un canal chlore présent à la surface des épithélia, notamment respiratoire. Jusqu'à récemment, les traitements ne concernaient que les conséquences de la maladie. Mais un nouveau type de molécules appelées «â€…modulateurs ¼ est déjà à la disposition de certains patients et cible l'origine de la maladie. Les «â€…modulateurs ¼ sont divisés en «â€…potentiateurs ¼, permettant d'améliorer le transport du chlore par la protéine CFTR, et en «â€…correcteurs ¼, augmentant la quantité de protéines CFTR. Une trithérapie orale combinant un potentiateur et deux correcteurs vient d'être approuvée aux États-Unis et permettra de traiter 85 % des patients. Le bénéfice clinique des «â€…modulateurs ¼ est remarquable et ces médicaments bouleversent le traitement de la mucoviscidose.

Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung.

BACKGROUND: Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling. OBJECTIVE: This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation. METHODS: Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture. RESULTS: We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg, Staphylococcus, Pseudomonas, and Corynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg, Prevotella, Streptococcus, and Veillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition. CONCLUSIONS: Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.

Clinical significance of post-prophylaxis cytomegalovirus infection in lung transplant recipients.

Cytomegalovirus (CMV) disease has been associated with the development of chronic lung allograft dysfunction (CLAD) after transplantation. However, the relevance of CMV replication occurring after the discontinuation of antiviral prophylaxis on the development of CLAD has not been fully established. Patients who underwent lung transplantation during 2004-2014 were included. All patients received antiviral prophylaxis for 3-6 months, followed by monitoring of CMV replication during the first year post-transplantation (preemptive therapy). Risk factors for the development of CLAD were assessed by Cox models. A linear regression model with an interaction coefficient between time and CMV infection was used to evaluate the influence of CMV infection on the evolution of FEV1 . Overall, 69 patients were included, 30/69 (43%) patients developed at least 1 episode of significant CMV infection, and 8/69 (11.5%) patients developed CMV disease. After a median follow-up of 3.67 years, 25/69 (36%) patients developed CLAD and 14/69 (20%) patients died. In the univariate Cox analysis, significant CMV infection (HR 1.177, P = .698), CMV disease (HR 1.001, P = .998), and duration of CMV replication (HR 1.004, P = .758) were not associated with CLAD. Only bacterial pneumonia tended to be associated with CLAD in the multivariate model (HR 2.579, P = .062). We did not observe a significant interaction between CMV replication and evolution FEV1 (interaction coefficient 0.006, CI 95% [-0.084 to 0.096], P = .890). In this cohort of lung transplant recipients receiving antiviral prophylaxis and monitored by preemptive therapy post-prophylaxis, CMV infection did not have impact on long-term allograft lung function.

Acute Cellular Rejection: Is It Still Relevant?

Despite significant progress in the field of transplant immunology, acute cellular rejection (ACR) remains a very frequent complication after lung transplantation (LTx), with almost 30% of LTx recipients experiencing at least one episode of treated ACR during the first year of follow-up. Most episodes respond to the first-line immunosuppressive treatment and are rarely a direct cause of death. However, the association of ACR with later adverse outcomes, such as chronic lung allograft dysfunction, bronchial stricture, and infectious complications associated with the intensification of immunosuppression, negatively impacts long-term survival. The burden imposed on patients and health-care resources is even higher in cases of refractory or recurrent ACR, which accelerates lung function decline. Although important laboratory and clinical research conducted over the last two decades has improved our understanding of the mechanisms underlying ACR, there are still many uncertainties about the risk factors for ACR, the optimal monitoring strategies, and the prediction of long-term outcomes. These knowledge gaps contribute to the large variability in clinical practice among LTx centers, which renders multicenter studies of ACR challenging. In this review, we summarize current evidence on the epidemiology, pathogenesis, and risk factors of ACR. We describe diagnostic and therapeutic approaches that are currently used in the clinical practice and also review promising diagnostic tools that are under investigation. Associations between ACR and other adverse outcomes of LTx are examined. Finally, within each topic of discussion, we highlight the main areas of controversy and opportunities for future research.

Airway Microbiota Determines Innate Cell Inflammatory or Tissue Remodeling Profiles in Lung Transplantation.

RATIONALE: In lung transplant recipients, long-term graft survival relies on the control of inflammation and tissue remodeling to maintain graft functionality and avoid chronic lung allograft dysfunction. Although advances in clinical practice have improved transplant success, the mechanisms by which the balance between inflammation and remodeling is maintained are largely unknown. OBJECTIVES: To assess whether host-microbe interactions in the transplanted lung determine the immunologic tone of the airways, and consequently could impact graft survival. METHODS: Microbiota DNA and host total RNA were isolated from 203 bronchoalveolar lavages obtained from 112 patients post-lung transplantation. Microbiota composition was determined using 16S ribosomal RNA analysis, and expression of a set of genes involved in prototypic macrophage functions was quantified using real-time quantitative polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: We show that the characteristics of the pulmonary microbiota aligned with distinct innate cell gene expression profiles. Although a nonpolarized activation was associated with bacterial communities consisting of a balance between proinflammatory (e.g., Staphylococcus and Pseudomonas) and low stimulatory (e.g., Prevotella and Streptococcus) bacteria, "inflammatory" and "remodeling" profiles were linked to bacterial dysbiosis. Mechanistic assays provided direct evidence that bacterial dysbiosis could lead to inflammatory or remodeling profiles in macrophages, whereas a balanced microbial community maintained homeostasis. CONCLUSIONS: The crosstalk between bacterial communities and innate immune cells potentially determines the function of the transplanted lung offering novel pathways for intervention strategies.

Safety of Drugs during Pregnancy and Breastfeeding in Cystic Fibrosis Patients.

Health management of cystic fibrosis (CF) patients should be maximized during pregnancy and breastfeeding because of its significant impact on the maternal and newborn outcomes. Thus, numerous drugs will have to be continued during pregnancy and lactation. Most of the drugs representing CF treatment lines cross the placenta or are excreted into human milk. Research addressing the risks and benefits of drugs used in CF patients during pregnancy and lactation is often incomplete or challenged by limited methodology, which often leads to conflicting or inconclusive results. Yet, potential treatment benefits for CF pregnant patients most often outbalance potential risks for the unborn child.

Radial Ultrasound-Assisted Transbronchial Biopsy: A New Diagnostic Approach for Non-Resolving Pulmonary Infiltrates in Neutropenic Hemato-Oncological Patients.

The role of radial-endobronchial ultrasound (R-EBUS) assisted transbronchial biopsy (TBB) for the diagnosis of peripheral pulmonary lesions is well established. However, no study has addressed its safety and value in hemato-oncological patients presenting with non-resolving infiltrates during persistent febrile neutropenia. To assess safety and feasibility of R-EBUS assisted TBB in severe thrombocytopenic and neutropenic patients. Over a period of 18 months, eight patients were assessed with R-EBUS assisted TBB after adequate platelet transfusion. This technique allowed precise localisation and sampling of the pulmonary lesions in seven of eight patients. In the seven patients, R-EBUS assisted TBB enabled treatment optimization. Invasive fungal infection was diagnosed in four patients, idiopathic acute fibrinous and organising pneumonia in three patients, and a granulomatous inflammation of undetermined origin in one patient. Importantly, no complications, such as bleeding, were observed. R-EBUS assisted TBB is a promising and safe procedure for the evaluation of nonresolving pulmonary infiltrates in febrile neutropenic hemato-oncological patients.

Pulmonary biomarkers in COPD exacerbations: a systematic review.

Exacerbations of COPD (ECOPD) represent a major burden for patients and health care systems. Innovative sampling techniques have led to the identification of several pulmonary biomarkers. Although some molecules are promising, their usefulness in clinical practice is not yet established. Medline and Highwire databases were used to identify studies evaluating pulmonary sampled biomarkers in ECOPD. We combined 3 terms for ECOPD, 3 for biomarkers and 6 for the sampling method. Seventy-nine studies were considered eligible for inclusion in the review and were analyzed further. Pulmonary biomarkers sampled with non-invasive, semi-invasive and invasive methods were evaluated for their potential to illustrate the disease's clinical course, to correlate to clinical variables and to predict clinical outcomes, ECOPD etiology and response to treatment. According to published data several pulmonary biomarkers assessed in ECOPD have the potential to illustrate the natural history of disease through the modification of their levels. Among the clinically relevant molecules, those that have been studied the most and appear to be promising are spontaneous and induced sputum biomarkers for reflecting clinical severity and symptomatic recovery, as well as for directing towards an etiological diagnosis. Current evidence on the clinical usefulness of exhaled breath condensate and bronchoalveolar lavage biomarkers in ECOPD is limited. In conclusion, pulmonary biomarkers have the potential to provide information on the mechanisms underlying ECOPD, and several correlate with clinical variables and outcomes. However, on the basis of published evidence, no single molecule is adequately validated for wide clinical use. Clinical trials that incorporate biomarkers in decisional algorithms are required.