Treatment Of Bronchiectasis Research Articles

The impact of Tanreqing injection on mucus hypersecretion and cough in bronchiectasis: A meta-analysis of randomized controlled trials.

Bronchiectasis clinically manifests airway mucus hypersecretion as mucopurulent sputum production and chronic cough. In the past decade, Tanreqing injection (TRQ) has been often used in clinical practice as an add-on treatment for bronchiectasis in China. Several in vivo studies have indicated that TRQ is effective in improving sputum expectoration and cough in acute exacerbation of bronchiectasis but results of individual studies are inconsistent. Therefore, systematically and critically evaluating the effectiveness and safety of TRQ on mucus hypersecretion and cough in bronchiectasis is necessary. Randomized controlled trials examining the treatment of bronchiectasis with TRQ were systematically searched from databases including PubMed, Cochrane Library, Embase, Web of Science, Chinese National Knowledge Infrastructure, Vip Information Database, Wanfang data, and Chinese Biomedical Literature Database, based on a preregistered protocol and adhering to Cochrane methods. Pertinent data were taken out from the included studies and a methodological quality assessment was done. R language (version 4.4.1) was used to perform the meta-analysis. Twenty randomized controlled trials involving 1544 patients were analyzed. The results demonstrated that TRQ significantly improved mucus hypersecretion, shortened the duration of cough and phlegm, reduced symptom scores, and enhanced both forced expiratory volume in 1 second and forced vital capacity. Additionally, TRQ effectively lowered inflammatory markers, including C-reactive protein, procalcitonin, white blood cell count, neutrophil count, interleukin-6, and tumor necrosis factor-alpha. Moreover, TRQ increased the partial pressure of oxygen and decreased carbon dioxide pressure. The findings suggest that TRQ positively impacts mucus hypersecretion and mucociliary clearance, leading to improvements in sputum production and cough during bronchiectasis exacerbations, without increasing the risk of adverse effects. TRQ may be considered a viable option for managing bronchiectasis and could serve as a novel mucus-modifying agent.

Bronchiectasis Exacerbations: Are We Doing Everything We Can?

At the European Respiratory Society (ERS) Congress 2024, two experts in bronchiectasis, Pieter Goeminne, Department of Respiratory Diseases, Vitaz Saint-Nicholas Hospitals, Belgium, and Michal Shteinberg, Pulmonology Institute and CF Center – Carmel Medical Center; Israel Institute of Technology; and The B. Rappaport Faculty of Medicine, Haifa, Israel, discussed bronchiectasis’ pathogenesis and exacerbations, along with unmet needs regarding diagnosis and treatment. Bronchiectasis is a chronic and progressive inflammatory disease with a rising prevalence. Commonly associated conditions/related comorbidities of bronchiectasis include post-infective diseases and other airway conditions (such as chronic obstructive pulmonary disease [COPD] and asthma), although the cause of bronchiectasis may remain unknown in over a third of patients. Development of bronchiectasis involves the intersection of four pathogenic components: chronic infections, airway ciliary dysfunction, chronic inflammation (mostly neutrophilic), and structural lung damage, commonly known as the ‘vicious vortex.’ In particular, bronchiectasis development, progression, and exacerbation also involve upregulated and dysregulated neutrophil function. Exacerbations in bronchiectasis are marked by symptoms of increased cough, sputum changes, decreased lung function, and fatigue, among others. Careful clinical examination and awareness of bronchiectasis symptoms are needed to properly diagnose and treat the initial condition and prevent exacerbations. Triggers for exacerbations can be endogenous, such as neutrophil or eosinophil increases, as well as exogenous, including the presence of infectious agents and pollution. Research regarding treatment for bronchiectasis is limited, but European guidelines recommend airway clearance techniques and antibiotics during exacerbations. To enable more targeted treatment for bronchiectasis from first occurrence, to limit exacerbations, and during an exacerbation, there are unmet needs for better identification of resistant genes, treatments for pathogens and inflammation, and biomarkers of exacerbation triggers.

Patient-managed interventions for adults with bronchiectasis: evidence, challenges and prospects.

Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes.

CLINICAL MANAGEMENT OF CHRONIC ORANGUTAN RESPIRATORY DISEASE SYNDROME IN THREE ADULT MALE BORNEAN ORANGUTANS (PONGO PYGMAEUS).

Orangutan respiratory disease syndrome (ORDS) is a disease unique to orangutans (Pongo sp), characterized by chronic bacterial infection and inflammation of any region or combination of regions of the respiratory tract, including the sinuses, air sacs, cranial bones, airways, and lung parenchyma. Aggressive early intervention during a first episode may prevent progression to chronic disease. However, in the setting of an established chronic disease, intermittent acute exacerbations are associated with worsening symptoms and increased infection and inflammation. ORDS is ultimately fatal due to loss of respiratory function resulting from chronic structural damage. Utilizing potentially lifelong medications to slow the progression of chronic, destructive inflammation in the respiratory tract, chronic treatment is aimed at stabilizing the animals' respiratory function, decreasing the frequency of recurrent exacerbations, and improving their general well-being. Three adult male Bornean orangutans (Pongo pygmaeus) housed at an orangutan rehabilitation and reintroduction center in Indonesia have long histories of recurrent respiratory disease. Each underwent CT scans confirming ORDS with chronic airway disease prior to initiation of a long-term treatment protocol. Based on data-driven medical management of bronchiectasis in humans, the three orangutans have been treated with long-term combination regimens of oral azithromycin, nebulized salbutamol, and nebulized hypertonic saline. Follow-up CT scans in all three animals at least 1 yr following treatment initiation showed improvements throughout their respiratory tracts. The duration of each exacerbation period decreased, and the orangutans have longer symptom-free periods compared to before the start of treatment. At an average of 5 yr into the long-term treatment protocol, all three orangutans are thriving. Chronic medical management of ORDS modeled after human treatment of bronchiectasis has been efficacious in these three orangutans and encourages further study of this approach.

Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers.

Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Biomarkers in bronchiectasis.

Bronchiectasis is a heterogeneous disease with multiple aetiologies and diverse clinical features. There is a general consensus that optimal treatment requires precision medicine approaches focused on specific treatable disease characteristics, known as treatable traits. Identifying subtypes of conditions with distinct underlying biology (endotypes) depends on the identification of biomarkers that are associated with disease features, prognosis or treatment response and which can be applied in clinical practice. Bronchiectasis is a disease characterised by inflammation, infection, structural lung damage and impaired mucociliary clearance. Increasingly there are available methods to measure each of these components of the disease, revealing heterogeneous inflammatory profiles, microbiota, radiology and mucus and epithelial biology in patients with bronchiectasis. Using emerging biomarkers and omics technologies to guide treatment in bronchiectasis is a promising field of research. Here we review the most recent data on biomarkers in bronchiectasis.

Lung microbiome: new insights into bronchiectasis' outcome.

The present treatments for bronchiectasis, which is defined by pathological dilatation of the airways, are confined to symptom relief and minimizing exacerbations. The condition is becoming more common worldwide. Since the disease's pathophysiology is not entirely well understood, developing novel treatments is critically important. The interplay of chronic infection, inflammation, and compromised mucociliary clearance, which results in structural alterations and the emergence of new infection, is most likely responsible for the progression of bronchiectasis. Other than treating bronchiectasis caused by cystic fibrosis, there are no approved treatments. Understanding the involvement of the microbiome in this disease is crucial, the microbiome is defined as the collective genetic material of all bacteria in an environment. In clinical practice, bacteria in the lungs have been studied using cultures; however, in recent years, researchers use next-generation sequencing methods, such as 16S rRNA sequencing. Although the microbiome in bronchiectasis has not been entirely investigated, what is known about it suggests that Haemophilus, Pseudomonas and Streptococcus dominate the lung bacterial ecosystems, they present significant intraindividual stability and interindividual heterogeneity. Pseudomonas and Haemophilus-dominated microbiomes have been linked to more severe diseases and frequent exacerbations, however additional research is required to fully comprehend the role of microbiome in the evolution of bronchiectasis. This review discusses recent findings on the lung microbiota and its association with bronchiectasis.

Airway clearance management in people with bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

International guidelines recommend airway clearance management as one of the important pillars of bronchiectasis treatment. However, the extent to which airway clearance is used for people with bronchiectasis in Europe is unclear. The aim of the study was to identify the use of airway clearance management in patients with bronchiectasis across different countries and factors influencing airway clearance use. This was a prospective observational study using data from the European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) Registry between January 2015 and April 2022. Prespecified options for airway clearance management were recorded, including airway clearance techniques, devices and use of mucoactive drugs. 16 723 people with bronchiectasis from 28 countries were included in the study. The mean age was 67 years (interquartile range 57-74 years, range 18-100 years) and 61% were female. 72% of the participants reported daily sputum expectoration and 52% (95% CI 51-53%) of all participants reported using regular airway clearance management. Active cycle of breathing technique was used by 28% of the participants and airway clearance devices by 16% of participants. The frequency of airway clearance management and techniques used varied significantly between different countries. Participants who used airway clearance management had greater disease severity and worse symptoms, including a higher daily sputum volume, compared to those who did not use it regularly. Mucoactive drugs were also more likely to be used in participants with more severe disease. Access to specialist respiratory physiotherapy was low throughout Europe, but particularly low in Eastern Europe. Only a half of people with bronchiectasis in Europe use airway clearance management. Use of and access to devices, mucoactive drugs and specialist chest physiotherapy appears to be limited in many European countries.

Analysis of bronchiectasis patients who underwent video-assisted thoracoscopic surgery in a tertiary thoracic surgery center: Ten years of experience.

This study aimed to analyze our video-assisted thoracic surgery (VATS) experience in the surgical treatment of bronchiectasis and the reasons limiting VATS application. Two hundred one patients (106 males, 95 females; mean age: 39.7±14.1 years; range, 12 to 68 years) who underwent surgical treatment for bronchiectasis between January 2012 and October 2021 were included in the retrospective study. Three groups were created based on the surgical technique used: VATS, thoracotomy, and patients who were converted from VATS to thoracotomy. The most significant presenting symptoms were cough (43%) and excessive sputum expectoration (40%). Surgical intervention was applied to the left side of 60% of the patients, and the most common resection performed in all three groups was left lower lobectomy. The rate of conversion from VATS to thoracotomy was 28.8%, and it was found that dense pleural adhesions were the most common reason. Revision surgery was performed on a total of 11 (5.47%) patients. The frequency of revision surgery did not differ significantly among the three groups (p=0.943). The most common postoperative complication was prolonged air leakage. There was no statistically significant difference in postoperative complication rates among the groups (p=0.417). The rate of surgical treatment of bronchiectasis with VATS was observed to have increased from 11.1% to 77.7% in our clinic. In experienced hands, VATS can be safely applied in the surgical treatment of bronchiectasis.

The Efficacy and Safety of Inhaled Antibiotics for the Treatment of Bronchiectasis in Adults: Updated Systematic Review and Meta-Analysis

BackgroundInhaled antibiotics are conditionally recommended by international bronchiectasis guidelines for the treatment of patients with bronchiectasis but results of individual studies are inconsistent. A previous meta-analysis demonstrated promising results regarding the efficacy and safety of inhaled antibiotics in bronchiectasis. Subsequent publications have further supplemented the existing body of evidence in this area. Research questionTo what extent do inhaled antibiotics demonstrate both efficacy and safety as a treatment option for adults with bronchiectasis? Study design And methodsSystematic review and meta-analysis of randomised controlled trials of inhaled antibiotics in adult patients with bronchiectasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for eligible studies. Studies were included if they enrolled adults with bronchiectasis diagnosed by CT and trials had a treatment duration of at least 4 weeks. The primary endpoint was exacerbation frequency, with additional key efficacy endpoints including severe exacerbations, bacterial load, symptoms, quality of life and FEV1. Data were pooled through random-effects meta-analysis. Results20 studies involving 3468 patients were included. Inhaled antibiotics were associated with reduced number of subjects with exacerbations (risk ratio 0.85 95%CI 0.75-0.96), a slight reduction in exacerbation frequency (rate ratio 0.78 95%CI 0.68-0.91), a probable reduction in the frequency of severe exacerbations (rate ratio 0.48 95%CI 0.31-0.74) and a likely slight increase in time to first exacerbation (hazard ratio 0.80 95%CI 0.68-0.94). Inhaled antibiotics likely lead to a slight increase in the Quality of Life-Bronchiectasis Respiratory Symptom Score (2.51, 95%CI 0.44 to 4.31) and may reduce scores on the St. George’s Respiratory Questionnaire (-3.13, 95%CI -5.93 to -0.32). Bacterial load was consistently reduced but FEV1 was not changed with treatment. Evidence suggests little to no difference in adverse effects between groups (odds ratio 0.99 95%CI 0.75-1.30). Antibiotic resistant organisms were likely increased by treatment. InterpretationInhaled antibiotics result in a slight reduction in exacerbations, a probable reduction in severe exacerbations and a likely slight improvement in symptoms and quality of life in adults with bronchiectasis. Trial registrySystematic review registration number PROSPERO CRD42023384694

Clinical, Radiological, and Microbiologic Characteristics of Patients with Noncystic Fibrosis Bronchiectasis in a Tertiary Center at Jordan.

Only a small number of the investigations that were carried out in the Middle East attempted to characterize patients with NCFB. In order to characterize patients with NCFB, as well as their etiologies, microbiological profiles, and outcomes, we therefore carried out this investigation. This retrospective cohort study was carried out at the Jordan University Hospital (JUH), a tertiary facility located in Amman, Jordan. Non-cystic Fibrosis Bronchiectasis (NCFB) was defined as an HRCT scan typical for bronchiectasis along with a negative sweat chloride test to rule out cystic fibrosis. Patients' data were collected by the use of Electronic Medical Records (EMR) at our institution. Frequent exacerbation was defined as more than 2 exacerbations in 1 year of the onset of the diagnosis. A total of 79 patients were included, and 54.4% of them were female. The mean and standard deviation of the patient's age was 48.61 ± 19.62. The etiologies of bronchiectasis were evident in 79.7% of the sample. Asthma, Chronic Obstructive Pulmonary Diseases (COPD), and Kartagener syndrome were the most prevalent etiologies, accounting for related illnesses in 21.8%, 21.5%, and 13.9% of the patients, respectively. The most frequent bacteria cultured in our cohort were Pseudomonas and Candida Species. Moreover, 43 patients of the study cohort were frequent exacerbators, and 5 patients died. Our study supports the need to identify several bronchiectasis phenotypes linked to various causes. These findings provide information to clinicians for the early detection and treatment of bronchiectasis in Jordan.

Research Progress on Diagnosis and Treatment of Bronchiectasis with Massive Hemoptysis

Research Progress on Diagnosis and Treatment of Bronchiectasis with Massive Hemoptysis

Video-assisted thoracoscopic surgery for non-cystic fibrosis bronchiectasis in children.

Pediatric bronchiectasis is a common respiratory disease in children. The use of video-assisted thoracoscopic surgery (VATS) for its treatment remains controversial. The objective of our study was to compare and analyze the clinical efficacy of thoracoscopic surgery and thoracotomy in the treatment of pediatric bronchiectasis and summarize the surgical treatment experience of VATS in children with bronchiectasis. Retrospective single-center cohort study. A retrospective analysis was conducted on the clinical data of 46 pediatric patients who underwent surgery with bronchiectasis at the Children's Hospital of Chongqing Medical University from May 2015 to May 2023. The patients were divided into two groups: the VATS group (25 cases) and the thoracotomy group (21 cases). Comparative analysis was performed on various parameters including basic clinical data, surgical methods, operation time, intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, length of hospital stay, incidence of complications, and follow-up information. There were no statistically significant differences between the two groups of patients in terms of age, weight, gender, etiology, duration of symptoms, site of onset, and comorbidities (p > 0.05). The operation time in the VATS group was longer than that in the thoracotomy group (p < 0.001). However, the VATS group had better outcomes in terms of intraoperative blood loss, transfusion status, postoperative pain, postoperative mechanical ventilation time, chest tube drainage time, and length of hospital stay (p < 0.05). The incidence of postoperative complications in the VATS group was lower than that in the thoracotomy group, although the difference was not statistically significant (p = 0.152). Follow-up data showed no statistically significant difference in the surgical treatment outcomes between the two groups (p = 0.493). The incidence of complications and mortality in surgical treatment of bronchiectasis is acceptable. Compared with thoracotomy surgery, VATS has advantages such as smaller trauma, less pain, faster recovery, and fewer complications. For suitable pediatric patients with bronchiectasis, VATS is a safe and effective surgical method.

Bronchiectasis Occurs Independently of Chronic Obstructive Pulmonary Disease in Alpha-1 Antitrypsin Deficiency.

Bronchiectasis occurs in patients with alpha-1 antitrypsin deficiency (AATD), but it is unknown whether an association exists independently of chronic obstructive pulmonary disease (COPD). We assessed whether bronchiectasis was associated with COPD in our cohort, and whether it has clinical significance for lung function decline, exacerbation rate, or symptoms. PiZZ, PiSZ, and PiMZ patients from the Birmingham AATD Research Database were studied. Demographics were recorded, along with the outcomes of symptoms, forced expiratory volume in 1 second (FEV1), transfer factor of carbon monoxide (TLCO), carbon monoxide transfer coefficient (KCO), and annualized exacerbation rate. Lung function decline was calculated for those with ≥3 measurements. Multivariate regression analyses were conducted to assess for associations of bronchiectasis with each outcome. A further binomial logistic regression model assessed for predictors of bronchiectasis diagnosis, including COPD. Those with alternative bronchiectasis causes were excluded from statistical models. A total of 1290 patients were eligible. PiZZ patients with bronchiectasis were older at presentation (54 versus 49 years, p<0.001), less likely to have smoked (65% versus 76.1%, p=0.001), and had higher modified Medical Research Council scores (mMRC) (mMRC 2 versus 0 odds ratio [OR] 1.97, 95% constant interval [CI] 1.20-3.25, p=0.008; mMRC 3 versus 0 OR 2.58 95% CI 1.59-4.19, p<0.001; mMRC 4 versus 0 OR 2.2 95% CI 1.23-3.92; p=0.008) than those without. The OR of bronchiectasis diagnosis was not associated with COPD diagnosis in any phenotype. Bronchiectasis was associated with lower serum alpha-1 antitrypsin levels in PiZZ patients (p=0.012). Bronchiectasis was not associated with a difference in FEV1 percentage predicted (pp)/year decline, KCO pp/year, TLCO pp/year decline, or exacerbation rate in multivariate analysis. Bronchiectasis exists in a significant minority of AATD patients independently of COPD and is associated with more severe shortness of breath. Appropriate treatment of bronchiectasis in AATD is essential.

Research Progress and Reflections on Traditional Chinese Medicine in the Treatment of Bronchiectasis

Research Progress and Reflections on Traditional Chinese Medicine in the Treatment of Bronchiectasis

Bronchiectasis with Trans Mediastinal Herniation of Left Upper Lobe in 3-Year-Old Child: A Case Report

BACKGROUND: Bronchiectasis is a disorder characterized by destruction of smooth muscle and elastic tissue due to inflammation which leads to permanent dilation of bronchi and bronchioles. It may develop in association with Cystic Fibrosis, a single severe episode or recurrent episodes of pneumonia and exposure to tuberculosis. The principal conditions associated with bronchiectasis are obstruction and infection. Infections primarily originate from issues with airway clearance, which cause bronchi and bronchioles to enlarge irreversibly. Vertical airways are notably affected, while distal bronchi and bronchioles are more severely affected. The degree of disease activity and chronicity may affect the histological findings. Childhood bronchiectasis can proceed to severe consequences including persistent bacterial bronchitis, in developing nations like India due to a lack of effective diagnosis and treatment as a result of poor health care infrastructure in the rural areas as well as limited awareness on the part of general public and health care professionals. THE CASE: A 3.5-year-old Indian boy presented with productive cough and cold for 8 days associated with low grade fever. Patient was admitted through Out Patient Department (OPD) due to respiratory distress and facial swelling. Clinical exam revealed presence of crepitation, wheeze and pectus carinatum. Patient has history of multiple hospital admissions due to pneumonia and respiratory distress. There is history of exposure to tuberculosis. His mother had been diagnosed with tuberculosis when the child was 3 months old. She received anti-tubercular drugs and is now cured. HRCT thorax reveals collapse of basal segment of right lung, trans-mediastinal space shift of left upper lobe and bi-lateral bronchiectatic changes which include unusually thickened enlarged airways exhibiting the characteristic tram-track appearance. Echocardiogram findings show thickened pericardium, mild pericardial collection and trace tricuspid valve regurgitation. The case is unique since it is quite rare for a young child to have such a severe form of bronchiectasis. CONCLUSION: Diagnosis can be done with the help of radiological and clinical examination. However, High Resolution Computed Tomography (HRCT) scan is the investigation of choice. Early management is a key factor in minimizing more serious complication like severe hemoptysis and cor pulmonale. Current treatment modalities include antibiotics, bronchodilators, anti-inflammatory drugs and chest physical therapy. Severe cases may require injectable antibiotics. Bronchiectasis was thought to be an orphan disease that seldom progressed to severe consequences, especially after the introduction of newer antimicrobials. There exist guidelines that advocate treatments for bronchiectasis, and reports of therapy have been shown to be linked with clinical success. However, such guidelines do not exist in India at present. This case is noteworthy as it portrays bronchiectasis in an Indian child that has proceeded to the severe complication of transmediastinal herniation, demonstrating that it is relatively common albeit under-diagnosed in developing countries. Though is an irreversible disease in adults, in children if detected early there is almost complete restoration of pulmonary function and adequate exercise tolerance. Early diagnosis with suitable pharmacological and non-pharmacological management is critical for a positive outcome and prevention of sequelae like persistent bacterial bronchitis.

Bronchiectasis

Bronchiectasis is a final common pathway of a wide variety of underlying conditions including infectious, autoimmune, allergic, genetic and inflammatory conditions. Patients experience a chronic disease with variable clinical symptoms and course, but most experience cough, sputum production and recurrent exacerbations. Symptoms of bronchiectasis lead to poor quality of life and exacerbations are the major driver of morbidity and mortality. Patients are often chronically infected with bacteria with the most common being Pseudomonas aeruginosa and Haemophilus influenzae. Treatment of bronchiectasis includes standardised testing to identify the underlying cause with targeted treatment if immune deficiency, allergic bronchopulmonary aspergillosis or non-tuberculous mycobacterial infection, for example, are identified. Airway clearance is the mainstay of therapy for patients with symptoms of cough and sputum production. Frequently exacerbating patients may benefit from long term antibiotic or mucoactive therapies. Bronchiectasis is a heterogeneous disease and increasingly precision medicine approaches are advocated to target treatments most appropriately and to limit the emergence of antimicrobial resistance.

BI 1291583: a novel selective inhibitor of cathepsin C with superior in vivo profile for the treatment of bronchiectasis

BackgroundAirway inflammation in chronic inflammatory lung diseases (e.g. bronchiectasis) is partly mediated by neutrophil-derived serine protease (NSP)/antiprotease imbalance. NSPs are activated during neutrophil myelopoiesis in bone marrow by cathepsin C (CatC; DPP1). CatC is therefore an attractive target to reduce NSP activity in the lungs of patients with bronchiectasis, restoring the protease/antiprotease balance. We report results from the preclinical pharmacological assessment of the novel CatC inhibitor BI 1291583.MethodsBinding kinetics of BI 1291583 to human CatC were determined by surface plasmon resonance. In vitro inhibition of human CatC activity was determined by CatC-specific fluorescent assay, and selectivity was assessed against related cathepsins and unrelated proteases. Inhibition of NSP neutrophil elastase (NE) production was assessed in a human neutrophil progenitor cell line. In vivo inhibition of NE and NSP proteinase 3 (PR3) in bronchoalveolar lavage fluid (BALF) neutrophils after lipopolysaccharide (LPS) challenge and distribution of BI 1291583 was determined in a mouse model.ResultsBI 1291583 bound human CatC in a covalent, reversible manner, selectively and fully inhibiting CatC enzymatic activity. This inhibition translated to concentration-dependent inhibition of NE activation in U937 cells and dose-dependent, almost-complete inhibition of NE and PR3 activity in BALF neutrophils in an in vivo LPS-challenge model in mice. BI 1291583 exhibited up to 100 times the exposure in the target tissue bone marrow compared with plasma.ConclusionBI 1291583-mediated inhibition of CatC is expected to restore the protease–antiprotease balance in the lungs of patients with chronic airway inflammatory diseases such as bronchiectasis.

Immunological Approaches to The Pathogenesis and Treatment of Bronchiectasis

Bronchiectasis is characterized by a constant and abnormal expansion of the airways of the lungs (bronchi) and/or a violation of the tone of the muscle layer of the bronchial wall due to inflammation, sclerosis, dystrophy, hypoplasia. Bronchiectasis is a very common disease that is the main cause of respiratory problems. A deficiency in the host's immune response to bacterial infection is considered to be the main condition for the development of bronchiectasis. In addition, many patients have no identifiable cause and are defined as having an idiopathic disease. This can lead to the development of a chronic respiratory tract infection and subsequent inflammation. Patients tend to have persistent disease despite aggressive use of antibiotics and optimal sputum clearance techniques. New therapies based on the manipulation of the immune response are becoming available and offer significant promise for the treatment of this condition

Basic, translational and clinical aspects of bronchiectasis in adults.

Bronchiectasis is a common progressive respiratory disease with recognisable radiological abnormalities and a clinical syndrome of cough, sputum production and recurrent respiratory infections. Inflammatory cell infiltration into the lung, in particular neutrophils, is central to the pathophysiology of bronchiectasis. Herein we explore the roles and relationships between infection, inflammation and mucociliary clearance dysfunction in the establishment and progression of bronchiectasis. Microbial and host-mediated damage are important processes underpinning bronchiectasis and the relative contribution of proteases, cytokines and inflammatory mediators to the propagation of inflammation is presented. We also discuss the emerging concept of inflammatory endotypes, defined by the presence of neutrophilic and eosinophilic inflammation, and explore the role of inflammation as a treatable trait. Current treatment for bronchiectasis focuses on treatment of underlying causes, enhancing mucociliary clearance, controlling infection and preventing and treating complications. Data on airway clearance approaches via exercise and mucoactive drugs, pharmacotherapy with macrolides to decrease exacerbations and the usefulness of inhaled antibiotics and bronchodilators are discussed, finishing with a look to the future where new therapies targeting host-mediated immune dysfunction hold promise.