Long-term Macrolide Research Articles

Epidemiology of bronchiectasis at a single center in Japan: a retrospective cohort study

BackgroundThe characteristics of bronchiectasis (BE) in Asia, including Japan, remain largely unknown. We aimed to provide insights into the clinical characteristics and treatment outcomes of BE, especially regarding nontuberculous mycobacteria (NTM) infection and its poorly understood impact on prognosis. We also aimed to clarify the effect of long-term macrolide antibiotic use in patients with BE, who had no history of exacerbations.MethodsIn this single-center, retrospective study, the medical records of patients who satisfied the BE criteria between January 1, 2012, and August 31, 2023, were reviewed. Severe exacerbations and mortality during the observation period were recorded. Baseline characteristics and overall survival of patients with and without NTM infection, and factors influencing the time to the first exacerbation and death were analyzed. Additionally, the effects of long-term macrolide antibiotic use in patients without a history of severe exacerbations were estimated.ResultsIn a cohort of 1044 patients with BE, the rate of severe exacerbation was 22.3%, with mortality rates of 3.2% over 3 years. Notably, the high prevalence of NTM infection (n = 410, 39.3%) in this cohort was distinctive. NTM infection was not associated with either the time to first severe exacerbation (p = 0.5676, adjusted hazard ratio = 1.11) or mortality (p = 0.4139, adjusted hazard ratio = 0.78). Compared with the NTM group, the non-NTM group had a higher proportion of elevated inflammatory markers, with significant differences in C-reactive protein levels (p = 0.0301) and blood neutrophil counts (p = 0.0273). Pseudomonas aeruginosa colonization was more frequent in the non-NTM group (p = 0.0003). Among patients with non-NTM infection and without a history of exacerbation in the past 2 years, 38.2% received long-term macrolide antibiotics that did not invariably prolong the time to first severe exacerbation (p = 0.4517, IPW p = 0.3555).ConclusionsThis study highlights BE epidemiology in Japan, noting that the presence of NTM infection may not necessarily worsen the prognostic outcomes and advising caution in the casual use of macrolides for milder cases without a history of exacerbations.Clinical trial registrationUMIN Clinical Trials Registry Number: UMIN000054726 (Registered on 21 June 2024).

Brensocatib in Patients With Bronchiectasis: Subgroup Analyses From the WILLOW Trial

Bronchiectasis is a chronic inflammatory airway disease. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces pulmonary inflammation by preventing the activation of neutrophil serine proteases. In the phase 2 WILLOW trial, brensocatib prolonged time to first exacerbation in patients with bronchiectasis. In this post-hoc analysis we compare clinical outcomes in patients from WILLOW according to baseline disease characteristics.Adults with bronchiectasis treated with brensocatib (10 or 25 mg) or placebo once-daily were analysed by baseline Bronchiectasis Severity Index (BSI) score (≤4 [mild], 5–8 [moderate], or ≥9 [severe]), exacerbation history (2 or ≥3 in the prior year), blood eosinophil count (<300 cells·µL−1or ≥300 cells·µL−1), long-term macrolide use (≥6 months; no or yes), andPseudomonas aeruginosaculture at screening (negative or positive). End points were time to first exacerbation, annualised exacerbation rate, change in lung function from baseline, and safety. All patients who received brensocatib were pooled and compared with placebo.Treatment with brensocatibversusplacebo was associated with a longer time to first exacerbation (hazard ratio [95% confidence interval], BSI: ≤4, 0.28 [0.08–0.96]; 5–8, 0.75 [0.35–1.60]; ≥9, 0.61 [0.35–1.04]; prior exacerbations: 2, 0.56 [0.34–0.90]; ≥3, 0.71 [0.32–1.59]; blood eosinophils/µL: <300, 0.66 [0.42–1.06]; ≥300, 0.49 [0.20–1.20]; long-term macrolide use: no, 0.60 [0.38–0.94]; yes, 0.60 [0.25–1.45];Pseudomonas aeruginosaculture: negative, 0.54 [0.32–0.92]; positive, 0.68 [0.37–1.27]). Safety results were similar across subgroups.Patients treated with brensocatib had a numerically longer time to first exacerbation and reduced annualised rate of exacerbationversusplacebo across all key baseline disease characteristics.

Impact of long-term macrolide therapy on the evaluation indicator of outpatient oral antimicrobial use according to the AWaRe classification

The WHO recently proposed a new indicator for judging the appropriateness of antimicrobial selection according to the AWaRe classification. Although macrolides are often administered for long-term macrolide therapy, the impact of this therapy on the indicator remains unclear. This study examined the impact of this therapy on the indicator for outpatient oral antimicrobial use. Using the JMDC claims database, outpatients who were prescribed an oral antimicrobial at least once between January and December 2022 (n = 2.66 million) were included in the study. The ratio of patient numbers and antimicrobial usage (AMU) were calculated based on age group (<15, 15–64, and ≥65 years) and prescription days (1–15, 16–30, 31–60, 61–90, and ≥91 days), and AMU of each drug was corrected for defined daily doses and classified according to the AWaRe. Patients with chronic airway disease for whom macrolides were prescribed for 91 days and more were defined as long-term macrolide therapy. Macrolides accounted for more than 30 % of total oral AMU in all age groups. In the elderly, 11.2 % of patients were prescribed macrolides for 91 days or more, accounting for 66.4 % of macrolide use. With regard to diseases that were associated with macrolide prescriptions, the percentage of patients prescribed for chronic airway diseases increased as the number of days of prescription increased. These results suggest that the impact of long-term macrolide therapy should be considered when assessing the appropriateness of outpatient oral AMU according to the AWaRe classification.

Effect of Statins on Patients With Osteoradionecrosis of the Jaw

BackgroundOsteoradionecrosis of the jaw (ORN) is a refractory late complication of radiation therapy. Radiation-induced fibrosis (RIF) is the most likely mechanism for developing ORN, and statins are effective against RIF. However, no reports have indicated the direct effectiveness of statins in treating ORN. PurposeThis study aimed to measure the association between statin exposure and ORN disease resolution. Study design, setting, sampleThis retrospective cohort study included patients with ORN diagnosed between January 2008 and December 2020 at the Hospital’s Department of Oral and Maxillofacial Surgery. Patients who were immunocompromised or followed up for < 6 months were excluded. Predictor variableThe predictor variable was statin exposure, which was defined as the use of statins for dyslipidemia by coincidence. Main outcome variableThe main outcome variable was ORN disease progression status (good prognosis). Patients who showed full recovery and improvement were included in the good prognosis group, and those who showed invariance and deterioration were included in the poor prognosis group. CovariatesWe analyzed the clinicodemographic including the age of onset, sex, history of smoking, alcohol consumption, history of chemotherapy, tumor site, association with dental treatment, location (maxilla or mandible), the time to ORN onset from radiation therapy, and stage of ORN, and treatment characteristics including hyperbaric oxygen therapy, long-term macrolide administration, and sequestrectomy. AnalysesWe analyzed the association between statin exposure/covariates and time to ORN improvement using bivariate and multivariate Cox regression. The significance level was set at p = 0.05. ResultsWe analyzed 102 patients, and the improvement rate was 32.4%. The favorable prognostic factors were statin exposure (adjusted hazard ratio [HR], 3.71; 95% confidence interval [CI], 1.62–8.50; p = 0.002), onset in the maxilla (HR, 2.15; 95% CI, 1.02–4.55; p = 0.045), and stage 1 of ORN (HR, 2.65; 95% CI, 1.20–5.83; p = 0.016). Conclusions and RelevanceIn this study, statin exposure, onset in the maxilla, and stage 1 of Lyons’s classification were favorable prognostic factors for ORN. Statins may be a novel and effective treatment for ORN.

Time to re-set our thinking about airways disease: lessons from history, the resurgence of chronic bronchitis / PBB and modern concepts in microbiology.

In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary disease' (COPD) has minimally changed in recent decades while 'the incidence of bronchiectasis' is on the rise. The current focus on producing guidelines for these two airway 'diseases' has hindered progress in both treatment and prevention. The elephant in the room is that neither COPD nor bronchiectasis is a disease but rather a consequence of progressive untreated airway inflammation. To make this case, it is important to review the evolution of our understanding of airway disease and how a pathological appearance (bronchiectasis) and an arbitrary physiological marker of impaired airways (COPD) came to be labelled as 'diseases'. Valuable insights into the natural history of airway disease can be obtained from the pre-antibiotic era. The dramatic impacts of antibiotics on the prevalence of significant airway disease, especially in childhood and early adult life, have largely been forgotten and will be revisited as will the misinterpretation of trials undertaken in those with chronic (bacterial) bronchitis. In the past decades, paediatricians have observed a progressive increase in what is termed 'persistent bacterial bronchitis' (PBB). This condition shares all the same characteristics as 'chronic bronchitis', which is prevalent in young children during the pre-antibiotic era. Additionally, the radiological appearance of bronchiectasis is once again becoming more common in children and, more recently, in adults. Adult physicians remain sceptical about the existence of PBB; however, in one study aimed at assessing the efficacy of antibiotics in adults with persistent symptoms, researchers discovered that the majority of patients exhibiting symptoms of PBB were already on long-term macrolides. In recent decades, there has been a growing recognition of the importance of the respiratory microbiome and an understanding of the ability of bacteria to persist in potentially hostile environments through strategies such as biofilms, intracellular communities, and persister bacteria. This is a challenging field that will likely require new approaches to diagnosis and treatment; however, it needs to be embraced if real progress is to be made.

Bronchiectasis management in adults: state of the art and future directions.

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent randomised clinical trials.

Long-Term Erythromycin Treatment Alters the Airway and Gut Microbiota: Data from Chronic Obstructive Pulmonary Disease Patients and Mice with Emphysema

Introduction: Although long-term macrolide antibiotics could reduce the recurrent exacerbation of chronic obstructive pulmonary disease (COPD), the side effect of bacterial resistance and the impact on the microbiota remain concerning. We investigated the influence of long-term erythromycin treatment on the airway and gut microbiota in mice with emphysema and patients with COPD. Methods: We conducted 16S rRNA gene sequencing to explore the effect of erythromycin treatment on the lung and gut microbiota in mice with emphysema. Liquid chromatography-mass spectrometry was used for lung metabolomics. A randomized controlled trial was performed to investigate the effect of 48-week erythromycin treatment on the airway and gut microbiota in COPD patients. Results: The mouse lung and gut microbiota were disrupted after cigarette smoke exposure. Erythromycin treatment depleted harmful bacteria and altered lung metabolism. Erythromycin treatment did not alter airway or gut microbial diversity in COPD patients. It reduced the abundance of pathogens, such as Burkholderia, in the airway of COPD patients and increased levels of symbiotic bacteria, such as Prevotella and Veillonella. The proportions of Blautia, Ruminococcus, and Lachnospiraceae in the gut were increased in COPD patients after erythromycin treatment. The time to the first exacerbation following treatment was significantly longer in the erythromycin treatment group than in the COPD group. Conclusion: Long-term erythromycin treatment reduces airway and gut microbe abundance in COPD patients but does not affect microbial diversity and restores microbiota balance in COPD patients by reducing the abundance of pathogenic bacteria.

Brensocatib in non-cystic fibrosis bronchiectasis: ASPEN protocol and baseline characteristics.

Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369). The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ≥2 exacerbations in the prior 12 months. It was designed to evaluate the impact of two brensocatib doses (10 mg and 25 mg) on exacerbation rate over a 52-week treatment period versus placebo. Comprehensive clinical data, including demographics, disease severity, lung function, Pseudomonas aeruginosa status and quality of life, were collected at baseline. 1682 adults from 35 countries were randomised from December 2020 to March 2023. Mean age was 61.3 years and 64.7% were female. ∼70% had moderate-to-severe Bronchiectasis Severity Index (BSI) scores, 29.3% had ≥3 exacerbations in the prior 12 months and 35.7% were positive for P. aeruginosa. Mean BSI scores were highest in Australia/New Zealand (8.3) and lowest in Latin America (5.9). Overall, the most common aetiology was idiopathic (58.4%). In P. aeruginosa-positive versus P. aeruginosa-negative patients, lung function was lower, with greater long-term macrolide (21.5% versus 14.0%) and inhaled corticosteroid use (63.5% versus 53.9%). There was wide regional variation in long-term antibiotic use in patients with bronchiectasis and P. aeruginosa. ASPEN baseline characteristics and treatment profiles were representative of a global bronchiectasis population.

Patients at risk of nontuberculous mycobacterial pulmonary disease who need testing evaluated using a modified Delphi process by European experts

BackgroundIdentifying patients at risk of nontuberculous mycobacterial pulmonary disease (NTM-PD) is challenging. Delays in NTM-PD identification and management are associated with declining lung function and increased morbidity and mortality.Study design and methodsEuropean NTM-PD experts (n=12) participated in a three-round modified Delphi process to score symptoms and comorbidities potentially associated with NTM-PD as reasons to test for nontuberculous mycobacteria.ResultsExperts reached a consensus on the symptoms and comorbidities that should and should not prompt testing for nontuberculous mycobacteria. Requirements for testing were scored as high (mean ≥7), medium (mean ≥4–&lt;7) or low (mean &lt;4). Nontuberculous mycobacteria testing should be undertaken when multiple suggestive symptoms are present simultaneously in all patients except those with cancer (7.3–8.8), or when radiology is indicative of NTM-PD (≥8.9). Symptoms of persistent sputum production, recurrent respiratory infection and haemoptysis should prompt testing for nontuberculous mycobacteria, particularly in those with underlying respiratory diseases. Symptomatic patients with bronchiectasis or previous tuberculosis/NTM-PD or those being prescribed or undergoing long-term macrolide therapy for a respiratory condition should also be tested. Testing is not warranted in patients without an underlying respiratory disorder or in those without a history of respiratory disorders unless presenting with multiple symptoms.ConclusionsAssessing patients’ risk of NTM-PD is challenging. This Delphi consensus process provides insight into symptoms and clinical characteristics that should prompt NTM-PD assessment. Timely testing and diagnosis would enable initiation of appropriate management.

The Effectiveness and Safety of Long-Term Macrolide Therapy for COPD in Stable Status: A Systematic Review and Meta-Analysis.

Background: Chronic obstructive pulmonary disease (COPD) is a prevalent condition with fewer treatments available as the severity increases. Previous systematic reviews have demonstrated the benefits of long-term macrolide use. However, the therapeutic differences between different macrolides and the optimal duration of use remain unclear. Methods: A systematic review and meta-analysis were conducted to assess the effectiveness of long-term macrolide use in reducing COPD exacerbations, compare the therapeutic differences among macrolides, and determine the appropriate treatment duration. Four databases (PubMed, Cochrane Library, Web of Science, and ICHU-SHI) were searched until 20 March 2023, and a random-effects model was used to calculate the pooled effect. Results: The meta-analysis included nine randomized controlled trials involving 1965 patients. The analysis revealed an odds ratio (OR) of 0.34 (95% confidence interval [CI] 0.19, 0.59, p < 0.001) for the reduction in exacerbation frequency. Notably, only azithromycin or erythromycin showed suppression of COPD exacerbations. The ORs for reducing exacerbation frequency per year and preventing hospitalizations were -0.50 (95% CI: -0.81, -0.19; p = 0.001) and 0.60 (95% CI: 0.3, 0.97; p = 0.04), respectively. Statistical analyses showed no significant differences between three- and six-month macrolide prescriptions. However, studies involving a twelve-month prescription showed an OR of 0.27 (95% CI: 0.11, 0.68; p = 0.005; I2 = 81%). Although a significant improvement in St George's Respiratory Questionnaire (SGRQ) total scores was observed with a mean difference of -4.42 (95% CI: -9.0, 0.16; p = 0.06; I2 = 94%), the minimal clinically important difference was not reached. While no adverse effects were observed between the two groups, several studies have reported an increase in bacterial resistance. Conclusions: Long-term use of azithromycin or erythromycin suppresses COPD exacerbations, and previous studies have supported the advantages of a 12-month macrolide prescription over a placebo.

The Impact of Long-Term Macrolide Exposure on the Gut Microbiome and Its Implications for Metabolic Control.

Long-term low-dose macrolide therapy is now widely used in the treatment of chronic respiratory diseases for its immune-modulating effects, although the antimicrobial properties of macrolides can also have collateral impacts on the gut microbiome. We investigated whether such treatment altered intestinal commensal microbiology and whether any such changes affected systemic immune and metabolic regulation. In healthy adults exposed to 4 weeks of low-dose erythromycin or azithromycin, as used clinically, we observed consistent shifts in gut microbiome composition, with a reduction in microbial capacity related to carbohydrate metabolism and short-chain fatty acid biosynthesis. These changes were accompanied by alterations in systemic biomarkers relating to immune (interleukin 5 [IL-5], IL-10, monocyte chemoattractant protein 1 [MCP-1]) and metabolic (serotonin [5-HT], C-peptide) homeostasis. Transplantation of erythromycin-exposed murine microbiota into germ-free mice demonstrated that changes in metabolic homeostasis and gastrointestinal motility, but not systemic immune regulation, resulted from changes in intestinal microbiology caused by macrolide treatment. Our findings highlight the potential for long-term low-dose macrolide therapy to influence host physiology via alteration of the gut microbiome. IMPORTANCE Long-term macrolide therapy is widely used in chronic respiratory diseases although its antibacterial activity can also affect the gut microbiota, a key regulator of host physiology. Macrolide-associated studies on the gut microbiota have been limited to short antibiotic courses and have not examined its consequences for host immune and metabolic regulation. This study revealed that long-term macrolides depleted keystone bacteria and impacted host regulation, mediated directly by macrolide activity or indirectly by alterations to the gut microbiota. Understanding these macrolide-associated mechanisms will contribute to identifying the risk of long-term exposure and highlights the importance of targeted therapy for maintenance of the gut microbiota.

The Mechanism of Action and Clinical Efficacy of Low-Dose Long-Term Macrolide Therapy in Chronic Rhinosinusitis.

Various chronic inflammatory airway diseases can be treated with low-dose, long-term (LDLT) macrolide therapy. LDLT macrolides can be one of the therapeutic options for chronic rhinosinusitis (CRS) due to their immunomodulatory and anti-inflammatory actions. Currently, various immunomodulatory mechanisms of the LDLT macrolide treatment have been reported, as well as their antimicrobial properties. Several mechanisms have already been identified in CRS, including reduced cytokines such as interleukin (IL)-8, IL-6, IL-1β, tumor necrosis factor-α, transforming growth factor-β, inhibition of neutrophil recruitment, decreased mucus secretion, and increased mucociliary transport. Although some evidence of effectiveness for CRS has been published, the efficacy of this therapy has been inconsistent across clinical studies. LDLT macrolides are generally believed to act on the non-type 2 inflammatory endotype of CRS. However, the effectiveness of LDLT macrolide treatment in CRS is still controversial. Here, we reviewed the immunological mechanisms related to CRS in LDLT macrolide therapy and the treatment effects according to the clinical situation of CRS.

Effect of medical treatment on eradication of biofilms in chronic rhinosinusitis

Background: Long-term macrolides and intranasal corticosteroids have evidence-based recommendations. It has been reported that macrolide therapy caused objective and subjective improvements which correlated to the duration of therapy. Topical nasal steroids are the mainstay of treatment in CRS. It is proposed that intranasal steroid may increase the restoration of normal epithelium. Methods: Sample size of 24 in each group is sufficient to detect the difference between positivity rate with 80% power and 5% level of significance clinically diagnosed cases of CRS with nasal polyps in age group of 18-60 years were taken. Outcome was measured with multiple scoring systems like SNOT-20, CT scoring, endoscopic scoring system. Results: Significant improvement was seen in the SNOT-20 scores with p value of 0.011 and endoscopic scores with p value of 0.001 in group having macrolides along with steroids pre-operatively however the scores post-surgery didn’t show any significant change in both groups. The efficacy of macrolide with nasal steroidal spray or nasal spray alone showed no further benefit in the subjective outcome measures post operatively. Also, no statistically significant eradication of biofilms or decrease in density could be appreciated in both groups. Furthermore, there was no significant difference in recurrence rate. Conclusions: Our result demonstrated the subjective improvement in patients of macrolide group post treatment which could be attributed to its anti-inflammatory effect. Even though macrolides in combination with nasal spray reflected some improvement in the secondary outcomes but the primary outcome of eradication of biofilms couldn’t be achieved.

Bronchiectasis exacerbation: a narrative review of causes, risk factors, management and prevention.

Bronchiectasis exacerbations are significant events in the natural course of the disease and determine long-term clinical outcomes. This review aims to discuss the definition, causes, risk factors, management and prevention of bronchiectasis exacerbations. The PubMed database was searched for relevant articles published in English between January 1990 and March 2022 using keywords "bronchiectasis" and "exacerbation". Causes of bronchiectasis exacerbation are multifactorial; it can be associated with bacterial and viral pathogens, host inflammatory responses, and external environmental effects. In addition, recent advances in bronchiectasis research highlight the phenotype of patients who are more prone to exacerbations, including those with chronic Pseudomonas aeruginosa infection, worse symptoms, greater lung inflammation and comorbid airway diseases. Once bronchiectasis exacerbations occur, antibiotics are the mainstay treatment. Preventing exacerbations is of paramount importance because frequent exacerbations are linked to a detrimental disease course and higher mortality. To prevent frequent exacerbations, clinicians should attempt to understand the risk factors for exacerbation that are amenable to therapeutic intervention: so called "treatable traits". Treatments are personalised but include improving mucociliary clearance by physiotherapy and mucoactive therapy, reducing airway infection by inhaled antibiotics, and inflammation by long-term macrolide or in specific subpopulations, inhaled corticosteroids (ICS). Novel approaches to prevent exacerbations including direct anti-inflammatory therapies are in development for bronchiectasis. Future research is needed to better manage and prevent exacerbations in patients with bronchiectasis, although recent studies have characterised frequent exacerbator phenotype and enhanced our understanding of various aspects of exacerbations.

Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review

Primary ciliary dyskinesia (PCD) is a genetic and congenital disease associated with an abnormal ciliary ultrastructure and function and is estimated to affect 1 in 15,000-20,000 individuals. A PCD diagnosis can be achieved by genotyping. Here, we performed whole-exome analysis for the diagnosis of PCD and described the detailed clinical characteristics of the case. A 39-year-old Japanese woman with sinusitis and bronchiectasis without situs inversus had had upper and lower respiratory symptoms since childhood and had received long-term macrolide therapy without an accurate diagnosis. A moderate deterioration of cilia function was observed by high-speed video microscopy analysis; additionally, the number of cells with moving cilia was fewer than that in patients without PCD. Electron microscopy revealed no apparent structural abnormalities. We performed whole-exome analysis and identified novel biallelic variants of SPEF2 in the homozygous state (c.1860_1861insCT). We confirmed the absence of SPEF2 protein expression in the cilia of the nasal mucosa using fluorescent immunostaining. Accordingly, she was diagnosed as having PCD with the SPEF2 variant. The present case suggests that the deterioration of cilia function is moderate, the number of respiratory cells with moving cilia might be reduced, and the respiratory condition could be severe in patients with PCD with the SPEF2 variant.

Non-typeable Haemophilus influenzae airways infection: the next treatable trait in asthma?

Asthma is a complex, heterogeneous condition that affects over 350 million people globally. It is characterised by bronchial hyperreactivity and airways inflammation. A subset display marked airway neutrophilia, associated with worse lung function, higher morbidity and poor response to treatment. In these individuals, recent metagenomic studies have identified persistent bacterial infection, particularly with non-encapsulated strains of the Gram-negative bacterium Haemophilus influenzae. Here we review knowledge of non-typeable H. influenzae (NTHi) in the microbiology of asthma, the immune consequences of mucosal NTHi infection, various immune evasion mechanisms, and the clinical implications of NTHi infection for phenotyping and targeted therapies in neutrophilic asthma. Airway neutrophilia is associated with production of neutrophil chemokines and proinflammatory cytokines in the airways, including interleukin (IL)-1β, IL-6, IL-8, IL-12, IL-17A and tumour necrosis factor. NTHi adheres to and invades the lower respiratory tract epithelium, inducing the NLR family pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes. NTHi reduces expression of tight-junction proteins, impairing epithelial integrity, and can persist intracellularly. NTHi interacts with rhinoviruses synergistically via upregulation of intracellular cell adhesion molecule 1 and promotion of a neutrophilic environment, to which NTHi is adapted. We highlight the clinical relevance of this emerging pathogen and its relevance for the efficacy of long-term macrolide therapy in airways diseases, we identify important unanswered questions and we propose future directions for research.

Diffuse Panbronchiolitis: Report of a Rare Disease from India

Initially described by a group of Japanese clinicians and pulmonary pathologists to distinguish it from other chronic obstructive lung diseases, diffuse panbronchiolitis (DPB) is an uncommon disorder which has been reported largely from the eastern world. It is imperative to recognise this condition because of its potentially treatable nature. Recently, long-term macrolide therapy has revolutionised its management. Herein, we describe a 65-year-old male who was being managed as a case of chronic bronchitis before this diagnosis was suspected and proved.

Paranasal sinus actinomycosis treated with a combination of surgery and long-term low-dose macrolide.

Actinomycosis is a bacterial infection caused by actinomyces. Although almost 50% of cases are related to the head and neck region, those in the nose and paranasal sinuses (PNS) are rare. Actinomycosis of the PNS is presumed to be typically caused by dental caries, dental manipulation, and maxillofacial trauma, which facilitate the penetration of oral pathogens into the sinus, and should thus be treated by the combination of surgical removal and potent antibiotics for at least two months. The current use of these antibiotics might be redundant, considering the nature of actinomycosis of the PNS, which does not invade the mucosal surface. We herein report a 67-year-old female treated with endoscopic sinus surgery (ESS) and diagnosed with actinomycosis of the PNS by pathological findings. She had no history of dental impairment or treatment. She was given routine perioperative prophylactic antibiotics (cefazolin) during the surgery, followed by low-dose clarithromycin. The mucosa of the PNS normalized without any discharge by three months after the operation. The patient is a valuable example that should prompt reconsideration of the commonly accepted pathogenesis and treatment of actinomycosis of the PNS.

An observational study of Pseudomonas aeruginosa in adult long-term ventilation.

IntroductionPseudomonas aeruginosa increases morbidity and mortality in respiratory disease. To date the long-term ventilation population does not have clear guidelines regarding its management.MethodWe undertook a retrospective observational study in a regional long-term ventilation population (837 patients). We defined the primary outcome as P. aeruginosa isolation. In addition positive cultures for copathogens (Serratia, Proteus species, Stenotrophomonas, Burkholderia cepacia complex and nontuberculous mycobacteria) were recorded. Logistic regression and odds ratios were calculated.Results17.6% of the cohort isolated P. aeruginosa, and this pathogen was cultured more frequently in patients with a tracheostomy (logistic regression coefficient 2.90, p≤0.0001) and cystic fibrosis/bronchiectasis (logistic regression coefficient 2.48, p≤0.0001). 6.3% of patients were ventilated via tracheostomy. In the P. aeruginosa positive cohort 46.9% of patients were treated with a long-term macrolide, 36.7% received a nebulised antibiotic and 21.1% received both. Tracheostomised P. aeruginosa positive patients received a nebulised antibiotic more frequently (OR 2.63, 95% CI 1.23–5.64, p=0.013). Copathogens were isolated in 33.3% of the P. aeruginosa cohort. In this cohort patients with a tracheostomy grew a copathogen more frequently than those without (OR 2.75, 95% CI 1.28–5.90).ConclusionsP. aeruginosa isolation is common within the adult long-term ventilation population and is significantly associated with tracheostomy, cystic fibrosis and bronchiectasis. Further research and international guidelines are needed to establish the prognostic impact of P. aeruginosa and to guide on antimicrobial management. The increased risk of P. aeruginosa should be considered when contemplating long-term ventilation via tracheostomy.

Assessment of Long-Term Macrolide Exposure on the Oropharyngeal Microbiome and Macrolide Resistance in Healthy Adults and Consequences for Onward Transmission of Resistance.

While the use of long-term macrolide therapy to prevent exacerbations in chronic respiratory diseases is widespread, its impact on the oropharyngeal microbiota and macrolide resistance, and the potential for onward transmission of resistance to close contacts are poorly understood. We determined the effects of long-term exposure to azithromycin or erythromycin on phenotypic and genotypic macrolide resistance within the oropharyngeal microbiome of healthy adults and their close contacts in a randomized, single-blinded, parallel-group trial of 4 weeks of twice-daily oral 400 mg erythromycin ethylsuccinate or twice-daily oral 125 mg azithromycin. Using oropharyngeal swabs collected from 20 index healthy adults and 20 paired close contacts, the oropharyngeal microbial composition and macrolide resistance in streptococci were assessed by 16S rRNA sequencing and antibiotic susceptibility testing of oropharyngeal cultures, respectively, at baseline and weeks 4 and 8 (washout). Targeted quantitative PCR of antibiotic resistance genes was performed to evaluate paired changes in resistance gene levels in index patients and close contacts and to relate the potential transmission of antibiotic resistance. Neither azithromycin nor erythromycin altered oropharyngeal microbiota characteristics significantly. Proportional macrolide resistance in oropharyngeal streptococci increased with both erythromycin and azithromycin, remaining above baseline levels for the azithromycin group at washout. Levels of resistance genes increased significantly with azithromycin[erm(B) and mef] and erythromycin (mef), returning to baseline levels at washout only for the erythromycin group. We found no evidence of onward transmission of resistance to close contacts, as indicated by the lack of concomitant changes in resistance gene levels detected in close contacts. (This study has been registered with the Australian and New Zealand Clinical Trials Registry under identifier ACTRN12617000278336.).