Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-ß/Smad or Wnt/ß-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Biallelic Variants in CCDC39 Gene Lead to Primary Ciliary Dyskinesia and Kartagener Syndrome.

Background: Primary ciliary dyskinesia (PCD) is a clinical syndrome characterized by cilia with an abnormal structure or function. Its main clinical manifestations comprise chronic bronchitis, cough, recurrent respiratory infections, situs inversus, and male infertility. Single-gene variants are widely assumed to be the main cause of this rare disease, and more than 40 genes have been described to be associated with its onset. CCDC39 is essential for assembling the inner dynein arms and dynein regulatory complex and is important in cilia motility. CCDC39 variants were reported as a monogenic etiology of PCD. Methods: This study investigated two unrelated Chinese patients diagnosed as PCD. The chest computed tomography scan was performed to identify PCD phenotypes of the two probands. Considering the effect of PCD on male fertility, routine semen analysis, sperm morphology examination, and scanning electron microscopy were performed to assess the semen characteristics of male proband in family 2 (F2 II-1), who had a history of infertility. Subsequently, the peripheral blood samples of probands were collected to perform whole-exome sequencing (WES) to explore the possible genetic causes of this disease. Results: Whole-exome sequencing revealed a homozygous CCDC39 variant in the female proband of family 1 (F1 II-1: c.286C>T:p.Arg96Ter) and two compound heterozygous CCDC39 variants in the male proband of family 2 (F2 II-1: c.732_733del: p.Ala245PhefsTer18; c.2800_2802dup:p.Val934dup). The two probands showed the typical PCD phenotypes, including chronic bronchitis, recurrent respiratory infections, and situs inversus. The male proband also showed oligoasthenoteratospermia with multiple morphological abnormalities of the sperm flagella. Additionally, CCDC39 protein level was significantly lower in the sperm of male proband than in the sperm from normal controls. Conclusion: We identified a homozygous variant reported previously and two compound heterozygous variants of CCDC39 possibly responsible for PCD pathogenesis, expanding the variant spectrum of Chinese PCD, Kartagener syndrome, and morphological abnormalities of the sperm flagella involving CCDC39.

Decreased eosinophil counts and elevated lactate dehydrogenase predict severe COVID-19 in patients with underlying chronic airway diseases.

BACKGROUND: Several predictors of COVID-19 severity have been reported. However, chronic airway inflammation characterised by accumulated lymphocytes or eosinophils may affect the pathogenesis of COVID-19. METHODS: In this retrospective cohort study, we reviewed the medical records of all patients with laboratory-confirmed COVID-19 with chronic bronchitis, chronic obstructive pulmonary disease (COPD) and asthma admitted to the Sino-French New City Branch of Tongji Hospital, a large regional hospital in Wuhan, China, from 26 January to 3 April. The Tongji Hospital Ethics Committee approved this study. RESULTS: There were 59 patients with chronic bronchitis, COPD and asthma. When compared with non-severe patients, severe patients were more likely to have decreased lymphocyte counts (0.6×109/L vs 1.1×109/L, p<0.001), eosinopaenia (<0.02×109/L; 73% vs 24%, p<0.001), increased lactate dehydrogenase (LDH) (471.0 U/L vs 230.0 U/L, p<0.001) and elevated interleukin 6 level (47.4 pg/mL vs 5.7 pg/mL, p=0.002) on admission. Eosinopaenia and elevated LDH were significantly associated with disease severity in both univariate and multivariate regression models including the above variables. Moreover, eosinophil count and LDH level tended to return to normal range over time in both groups after treatment and severe patients recovered slower than non-severe patients, especially in eosinophil count. CONCLUSIONS: Eosinopaenia and elevated LDH are potential predictors of disease severity in patients with COVID-19 with underlying chronic airway diseases. In addition, they could indicate disease progression and treatment effectiveness.

Comprehensive Care Management in Conjunction with Sputum Cytometry-Guided Pharmacotherapy in a Post-Discharge Clinic for Patients with COPD.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are amongst the most common reasons for hospital admission, and recurrent episodes occur frequently. Comprehensive care management (CCM) strategies have modest effect in preventing re-admissions. The objectives of this study were to examine the utility of optimizing anti-inflammatory therapy guided by sputum cytometry in the post-hospitalization setting, and to assess the feasibility and effectiveness of a clinic combining CCM and sputum-guided therapy. This is an observational study examining patients who received open-label CCM and sputum cytometry-guided pharmacotherapy in a COPD post-discharge clinic. Referral was based on high risk for readmission after hospitalization for AECOPD. The primary outcome was the change in COPD-related healthcare utilization before and after Visit 1, and this was analyzed with a mixed-effects negative binomial model controlling for age, number of follow-up clinic visits, pack years, current smoking and FEV1. Of 138 patients referred to the clinic, 73% attended at least one visit. Mean FEV1 was 42.8 (19.3) % predicted. Of the patients attending clinic, 42.6% produced an adequate sputum sample, and 32.7% had an abnormal sputum. By individual, infectious bronchitis was the most common (25.7%), followed by eosinophilic bronchitis (13.9%). Comparing the 6-months prior to and after the first clinic visit, there was a lower incidence rate ratio after visit 1 for COPD-related healthcare utilization (0.26 (95%CI 0.22,0.33; p < 0.001)). A COPD post-discharge clinic combining sputum-guided treatment and CCM was feasible and associated with a nearly 75% reduction in the incidence of COPD-related healthcare utilization.

Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested. METHODS: In this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production. RESULTS: We demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air-liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk. CONCLUSIONS: For the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease.

Expression Profiling Suggests Loss of Surface Integrity and Failure of Regenerative Repair as Major Driving Forces for Chronic Obstructive Pulmonary Disease Progression.

Chronic obstructive pulmonary disease (COPD) poses a major risk for public health, yet remarkably little is known about its detailed pathophysiology. Definition of COPD as nonreversible pulmonary obstruction revealing more about spatial orientation than about mechanisms of pathology may be a major reason for this. We conducted a controlled observational study allowing for simultaneous assessment of clinical and biological development in COPD. Sixteen healthy control subjects and 104 subjects with chronic bronchitis, with or without pulmonary obstruction at baseline, were investigated. Using both the extent of and change in bronchial obstruction as main scoring criteria for the analysis of gene expression in lung tissue, we identified 410 genes significantly associated with progression of COPD. One hundred ten of these genes demonstrated a distinctive expression pattern, with their functional annotations indicating participation in the regulation of cellular coherence, membrane integrity, growth, and differentiation, as well as inflammation and fibroproliferative repair. The regulatory pattern indicates a sequentially unfolding pathology that centers on a two-step failure of surface integrity commencing with a loss of epithelial coherence as early as chronic bronchitis. Decline of regenerative repair starting in Global Initiative for Chronic Obstructive Lung Disease stage I then activates degradation of extracellular-matrix hyaluronan, causing structural failure of the bronchial wall that is only resolved by scar formation. Although they require independent confirmation, our findings provide the first tangible pathophysiological concept of COPD to be further explored.Clinical trial registered with www.clinicaltrials.gov (NCT00618137).

Current smoking with or without chronic bronchitis is independently associated with goblet cell hyperplasia in healthy smokers and COPD subjects.

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log10 transformed values. Log10GCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log10 GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high log10GCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.

The Effect of Different Water Extracts from Platycodon grandiflorum on Selected Factors Associated with Pathogenesis of Chronic Bronchitis in Rats.

The aim of this study was to assess the activity of extracts from Platycodon grandiflorum A. DC (PG) in a model of chronic bronchitis in rats. The research was carried out on three water extracts: E1 - from roots of field cultivated PG; E2 - from biotransformed roots of PG; E3 - from callus of PG. The extracts differed in saponins and inulin levels-the highest was measured in E3 and the lowest in E1. Identification of secondary metabolites was performed using two complementary LC-MS systems. Chronic bronchitis was induced by sodium metabisulfite (a source of SO2). Animals were treated with extracts for three weeks (100 mg/kg, intragastrically) and endothelial growth factor (VEGF), transforming growth factors (TGF-ß1, -ß2, -ß3), and mucin 5AC (MUC5AC) levels were determined in bronchoalveolar lavage fluid, whereas C reactive protein (CRP) level was measured in serum. Moreover, mRNA expression were assessed in bronchi and lungs. In SO2-exposed rats, an elevation of the CRP, TGF-ß1, TGF-ß2, VEGF, and mucin was found, but the extracts' administration mostly reversed this phenomenon, leading to control values. The results showed a strong anti-inflammatory effect of the extracts from PG.

Respiratory dysbiosis and population-wide temporal dynamics in canine chronic bronchitis and non-inflammatory respiratory disease.

The lungs of people and companion animals are now recognized to harbor diverse, low biomass bacterial communities. While these communities are difficult to characterize using culture-based approaches, targeted molecular methods such as 16S rRNA amplicon sequencing can do so using DNA extracted from samples such as bronchoalveolar lavage fluid (BALF). Previous studies identified a surprisingly uniform composition of the microbiota in the lungs of healthy research dogs living in a controlled environment, however there are no reports of the lung microbiota of client-owned dogs. Moreover, compositional changes in the lung microbiota depending on disease status have been reported in people, suggesting that similar events may occur in dogs, a species subject to several respiratory disease mechanisms analogous to those seen in people. To address these knowledge gaps, BALF samples from client-owned dogs presenting to the University of Missouri Veterinary Health Center for respiratory signs between 2014 and 2017 were processed for and subjected to 16S rRNA sequencing. Based on specific diagnostic criteria, dogs were categorized as Chronic Bronchitis (CB, n = 53) or non-CB (n = 11). Community structure was compared between groups, as well as to historical data from healthy research dogs (n = 16) of a uniform breed and environment. The lung microbiota detected in all client-owned dogs was markedly different in composition from that previously detected in research dogs and contained increased relative abundance of multiple canine fecal and environmental bacteria, likely due to aspiration associated with their clinical signs. While inter-sample diversity differed significantly between samples from CB and non-CB dogs, the variability within both groups made it difficult to discern reproducible bacterial classifiers of disease. During subsequent analyses to identify other sources of variability within the data however, population-wide temporal dynamics in community structure were observed, with substantial changes occurring in late 2015 and again in early 2017. A review of regional climate data indicated that the first change occurred during a historically warm and wet period, suggesting that changes in environmental conditions may be associated with changes in the respiratory microbiota in the context of respiratory disease. As the lung microbiota in humans and other animals is believed to result from repetitive micro-aspirations during health and in certain disease states associated with dyspnea and laryngeal dysfunction, these data support the increased colonization of the lower airways during compromised airway function, and the potential for temporal effects due to putative factors such as climate.

Exposure of normal and chronic bronchitis-like mucosa models to aerosolized carbon nanoparticles: comparison of pro-inflammatory oxidative stress and tissue injury/repair responses.

Carbon nanoparticles (CNP) are generated by incomplete combustion of diesel engines. Several epidemiological studies associated higher susceptibility to particulate matter related adverse respiratory outcomes with preexisting conditions like chronic bronchitis (CB). Therefore, we compared the effect of CNP exposure on primary bronchial epithelial cells (PBEC) developed in air-liquid interface (ALI) models of normal versus CB-like-mucosa.PBEC cultured at ALI represented normal mucosa (PBEC-ALI). To develop CB-like-mucosa (PBEC-ALI/CB), 1 ng/ml interleukin-13 was added to the basal media of PBEC-ALI culturing. PBEC-ALI and PBEC-ALI/CB were exposed to sham or to aerosolized CNP using XposeALI® system. Protein levels of CXCL-8 and MMP-9 were measured in the basal media using ELISA. Transcript expression of pro-inflammatory (CXCL8, IL6, TNF, NFKB), oxidative stress (HMOX1, SOD3, GSTA1, GPx), tissue injury/repair (MMP9/TIMP1) and bronchial cell type markers (MUC5AC, CC10) were assessed using qRT-PCR.Increased secretion of CXCL-8 and MMP-9 markers was detected 24 h post-exposure in both PBEC-ALI and PBEC-ALI/CB with more pronounced effect in the later. Pro-inflammatory and tissue injury markers were increased at both 6 h and 24 h post-exposure in PBEC-ALI/CB. Oxidative stress markers exhibited similar responses at 6 h and 24 h post-exposure in PBEC-ALI/CB. The club cell specific marker CC10 was increased by 300 fold in PBEC-ALI/CB and 20 fold in PBEC-ALI following CNP exposure.Our data indicates an earlier and stronger reaction of pro-inflammatory, oxidative stress and tissue injury markers in PBEC-ALI/CB models compared to PBEC-ALI models following CNP exposure. The findings may provide insight into the plausible mechanisms of higher susceptibility among predisposed individuals to nanoparticle exposure.

Eosinophilic bronchitis, eosinophilic granuloma, and eosinophilic bronchopneumopathy in 75 dogs (2006-2016).

BACKGROUND: Eosinophilic lung disease is a poorly understood inflammatory airway disease that results in substantial morbidity. OBJECTIVE: To describe clinical findings in dogs with eosinophilic lung disease defined on the basis of radiographic, bronchoscopic, and bronchoalveolar lavage fluid (BAL) analysis. Categories included eosinophilic bronchitis (EB), eosinophilic granuloma (EG), and eosinophilic bronchopneumopathy (EBP). ANIMALS: Seventy-five client owned dogs. METHODS: Medical records were retrospectively reviewed for dogs with idiopathic BAL fluid eosinophilia. Information abstracted included duration and nature of clinical signs, bronchoscopic findings, and laboratory data. Thoracic radiographs were evaluated for the pattern of infiltrate, bronchiectasis, and lymphadenomegaly. RESULTS: Thoracic radiographs were normal or demonstrated a bronchial pattern in 31 dogs assigned a diagnosis of EB. Nine dogs had intraluminal mass lesions and were bronchoscopically diagnosed with EG. The remaining 35 dogs were categorized as having EBP based on radiographic changes, yellow green mucus in the airways, mucosal changes, and airway collapse. Age and duration of cough did not differ among groups. Dogs with EB were less likely to have bronchiectasis or peripheral eosinophilia, had lower total nucleated cell count in BAL fluid, and lower percentage of eosinophils in BAL fluid compared to dogs in the other 2 groups. In contrast to previous reports, prolonged survival (>55 months) was documented in dogs with EG. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with eosinophilic lung disease can be categorized based on imaging, bronchoscopic and BAL fluid cytologic findings. Further studies are needed to establish response to treatment in these groups.

Total flavonoids from sea buckthorn ameliorates lipopolysaccharide/cigarette smoke-induced airway inflammation.

The total flavonoids from sea buckthorn (TFSB) exhibit a potent anti-inflammatory activity; however, the effect of TFSB on respiratory inflammatory disease is not fully known. The present study evaluated the potential of TFSB to prevent airway inflammation and the underlying mechanism. The results showed that TFSB remarkably inhibited lipopolysaccharide/cigarette smoke extract (LPS/CSE)-induced expression of IL-1ß, IL-6, CXCL1, and MUC5AC at both mRNA and protein levels in HBE16 bronchial epithelial cells. TFSB also decreased the production of PGE2 through inhibition the expression of COX2 in LPS/CSE-stimulated HBE16 cells. Furthermore, bronchoalveolar fluid and histological analyses revealed that LPS/cigarette smoke exposure-induced elevated cell numbers of neutrophils and macrophages in bronchoalveolar fluid, inflammatory cell infiltration, and airway remodeling were remarkably attenuated by TFSB in mice. Immunohistochemical results also confirmed that TFSB decreased the expression of IL-1ß, IL-6, COX2, CXCL1, and MUC5AC in LPS/CS-exposed mice. Mechanistically, TFSB blocked LPS/CSE-induced activation of ERK, Akt, and PKCα. Molecular docking further confirmed that the main components in TFSB including quercetin and isorhamnetin showed potent binding affinities to MAPK1 and PIK3CG, two upstream kinases of ERK and Akt, respectively. In summary, TFSB exerts a potent protective effect against LPS/CS-induced airway inflammation through inhibition of ERK, PI3K/Akt, and PKCα pathways, suggesting that TFSB may be a novel therapeutic agent for respiratory diseases.

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice.

Cigarette smoke is well recognized to cause injury to the airways and the alveolar walls over time. This injury usually requires many years of exposure, suggesting that the lungs may rapidly develop responses that initially protect it from this repetitive injury. Our studies tested the hypotheses that smoke induces an inflammatory response and changes in mRNA profiles that are dependent on sex and the health status of the lung, and that the response of the lungs to smoke differs after 1 day compared to 5 days of exposure. Male and female wildtype (WT) and Scnn1b-transgenic (ßENaC) mice, which have chronic bronchitis and emphysematous changes due to dehydrated mucus, were exposed to cigarette smoke or sham air conditions for 1 or 5 days. The inflammatory response and gene expression profiles were analyzed in lung tissue. Overall, the inflammatory response to cigarette smoke was mild, and changes in mediators were more numerous after 1 than 5 days. ßENaC mice had more airspace leukocytes than WT mice, and smoke exposure resulted in additional significant alterations. Many genes and gene sets responded similarly at 1 and 5 days: genes involved in oxidative stress responses were upregulated while immune response genes were downregulated. However, certain genes and biological processes were regulated differently after 1 compared to 5 days. Extracellular matrix biology genes and gene sets were upregulated after 1 day but downregulated by 5 days of smoke compared to sham exposure. There was no difference in the transcriptional response to smoke between WT and ßENaC mice or between male and female mice at either 1 or 5 days. Taken together, these studies suggest that the lungs rapidly alter gene expression after only one exposure to cigarette smoke, with few additional changes after four additional days of repeated exposure. These changes may contribute to preventing lung damage.

Effect of LysM+ macrophage depletion on lung pathology in mice with chronic bronchitis.

Macrophages (MΦ) are key sentinels of respiratory exposure to inhaled environmental stimuli. In normal "healthy" tissues, MΦ are believed to be a dormant cell type that, upon exposure to stress-causing stimuli, may get activated to exhibit pro- or anti-inflammatory roles. To test whether stress present in chronic bronchitic (CB) airways triggers MΦ to manifest protective or detrimental responses, the DTA+ (LysM-regulated Diphtheria Toxin A expressing) strain with partial MΦ-deficiency was crossed with the Scnn1b-Tg mouse model of CB and the progenies were studied at 4-5 weeks of age. Compared with DTA- littermates, the DTA+ mice had ~50% reduction in bronchoalveolar lavage (BAL) MΦ, and the recovered MΦ were immature, phenotypically distinct, and functionally defective. DTA+/Scnn1b-Tg mice exhibited a similar depletion of LysM+ MΦ offset by a significant increase in LysM- MΦ in the BAL. In DTA+/Scnn1b-Tg mice, lung disease was more severe than in DTA-/Scnn1b-Tg littermates, as indicated by an increased incidence of mucus plugging, mucous cells, airway inflammation, higher levels of cytokines/chemokines (KC, TNF-α, MIP-2, M-CSF, IL-5, and IL-17), and worsened alveolar airspace enlargement. DTA+/Scnn1b-Tg mice exhibited increased occurrence of lymphoid nodules, which was concomitant with elevated levels of immunoglobulins in BAL. Collectively, these data indicate that numerical deficiency of MΦ in stressed airspaces is responded via compensatory increase in the recruitment of immature MΦ and altered non-MΦ effector cell-centered responses, for example, mucus production and adaptive immune defense. Overall, these data identify dynamic roles of MΦ in moderating, rather than exacerbating, the severity of lung disease in a model of CB.

Clinical Outcome of Eosinophilic Airway Inflammation in Chronic Airway Diseases Including Nonasthmatic Eosinophilic Bronchitis.

We enrolled patients with confirmed sputum eosinophilia who had visited our tertiary referral hospital between 2012 and 2015. We evaluated the incidence and predictors of exacerbations in patients with nonasthmatic eosinophilic bronchitis (NAEB), and investigated predictors of improvement in eosinophilic inflammation in chronic airway diseases with or without persistent airflow limitation. In total, 398 patients with sputum eosinophilia were enrolled. Of these, 152 (38.2%) had NAEB. The incidence rate of exacerbations requiring treatment with antibiotics, systemic corticosteroids, or hospital admission was 0.13 per patient-year (95% CI, 0.06-0.19) in NAEB. Inhaled corticosteroid (ICS) did not affect the risk of exacerbations, even in an analysis of propensity score. One hundred seventy-six patients had chronic airway diseases; in 37 of these (21.0%), sputum eosinophilia had improved at the 1-year follow-up. Patients who had persistent airflow limitation were less likely to show an improvement in eosinophilic inflammation (aOR, 0.26; 95% CI, 0.09-0.77) when they were treated with ICSs for less than 75% of the follow-up days. Exacerbations requiring systemic corticosteroids, antibiotics, or hospitalization did occur, although infrequently, in NAEB patients. Among patients with chronic airway diseases, those with persistent airflow limitation were less likely to show an improvement in eosinophilic airway inflammation.

[Follicular bronchiolitis: report of 3 cases and literature review].

Objective: To improve understanding of the characteristics of follicular bronchiolitis(FB). Methods: The clinical data of 3 patients with FB confirmed by thoracoscopic lung biopsy were retrospectively analyzed. A literature search was performed with "follicular bronchiolitis" as the key word in China Knowledge Resource Integrated Database, Wanfang and PubMed, Ovid Database. The time interval was from January 1947 to December 2015. Related articles of FB were retrieved and the clinical, radiographic characteristics and prognosis were analyzed. Results: Among the 3 patients, 1 was male and 2 were female, aging 32-55 years. Two patients were asymptomatic, and 1 patient presented with fever, cough and dyspnea. Two patients showed normal pulmonary ventilatory function with decreased diffusive function, and 1 patient showed normal pulmonary function. The predominant HRCT findings were bilateral multiple small nodules and cystic opacities, patchy ground-glass opacities, reticular opacities and traction bronchiectasis. The pathological examination by thoracoscopic biopsy revealed bronchiolar and peribronchiolar lymphoid follicles. All patients were treated with corticosteroids, with 2 patients receiving immunosuppressants. Follow-up HRCT after 1-2 months showed no improvement, and further follow-up HRCT after 2-4 years revealed no change in 2 patients while the other patient had increased pulmonary nodules and cystic opacities. Seventeen articles concerning FB with complete records were included in the literature review. A total of 64 patients were reported in these articles. The typical images were bilateral multiple small nodules and ground-glass opacities, reticular opacities, and cystic opacities. The majority of patients improved after treatment of corticosteroids and (or) immunosuppressants. But our 3 cases showed no improvement. Conclusions: FB is a rare small airway disease which has non-specific clinical manifestations and pulmonary function. The most common imaging findings are bilateral multiple small nodules, with cystic opacities, ground-glass opacities, and reticular opacities. Surgical thoracoscopic biopsy can get ideal specimen which is useful for diagnosis. The curative effects of corticosteroids or immunosuppressants on FB need to be further clinically investigated.

Early investigational antibiotics for the treatment of acute exacerbations of chronic bronchitis.

INTRODUCTION: Acute exacerbations in patients with chronic bronchitis are a leading cause of hospitalizations and death. Bacteria contribute significantly to such exacerbations. The aim of this review was to explore the potential role of investigational antibiotics in the treatment of these episodes. Areas covered: The available literature in PubMed database, in websites related to investigational drugs and in websites of the producing companies has been searched. The in vitro activity against pathogens involved in acute exacerbations of chronic bronchitis and the pharmacokinetic profile of antibiotics currently under development were taken into consideration for inclusion in the review. Expert opinion: Several novel antimicrobial agents have completed preclinical and Phase I studies and were well-tolerated. Further investigation is mandatory in order to evaluate their future in treatment of chronic bronchitis exacerbations and discover potential advantages compared to already approved antimicrobials.

Propensity of pneumococcal carriage serotypes to infect the lower airways of children with chronic endobronchial infections.

BACKGROUND: Chronic endobronchial infections in children are responsible for a high disease burden. Streptococcus pneumoniae is frequently isolated; however, few publications have described serotypes associated with non-invasive lower airway infection. METHODS: Paired nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL) fluids were collected from children undergoing bronchoscopy for chronic cough. NP swabs were also collected from asymptomatic children in otitis media surveillance studies (controls). Specimens were processed and lower airway infection defined (⩾104 colony forming units/mL BAL) as previously described. Serotype-specific odds ratios (ORs) were calculated (as described for invasive pneumococcal disease) to indicate propensity for infection. RESULTS: From 2007-2015, paired specimens were processed from 435 children with protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) or bronchiectasis. S. pneumoniae lower airway infection was detected in 95 children: 27% with PBB and 20% with CSLD/bronchiectasis. Most (91%) children were vaccinated with ⩾2 doses of 7-valent, 10-valent or 13-valent pneumococcal conjugate vaccine. Paired NP and BAL serotype distributions were very similar; prevalent serotypes (>10 isolates) were 19A (9%), 19F, 6C, 35B, 15B, 16F, 15A, 15C, 23A, 23F and 11A. For 21 serotypes found in both NP and BAL specimens, ORs for infection were low; range 0.46 (serotype 23B) to 2.15 (serotype 6A). In the 2008-2013 surveillance studies, NP swabs were collected from 1565 asymptomatic children; 74% were pneumococcal carriers. For 21 of 22 serotypes found in both control NP swabs and BAL specimens, ORs for infection were similarly low; range 0.33 (serotype 23B) to 3.29 (serotype 22F); none was significantly different from 1. The exception was serotype 7B with OR 8.84 (95% CI 1.46, 38.1). CONCLUSIONS: Most NP carriage serotypes have a similar propensity to cause lower airway infection in children with suppurative lung diseases. Further development of pneumococcal vaccines is needed to prevent non-invasive disease caused by commonly carried serotypes.

Synchronous dynamic research on respiratory and intestinal microflora of chronic bronchitis rat model.

OBJECTIVES: To investigate the mechanism of the Chinese medicine theory that Fei (Lung) and Dachang (Large Intestine) are exteriorly and interiorly related via synchronous observation on the dynamic changes of the respiratory and intestinal microflora. METHODS: Forty specific pathogen free Sprague-Dawley rats were selected and randomly divided into blank (10 rats) and chronic bronchitis model groups (30 rats). The blank group rats were put into the smoke-free environment and the model group rats were put into the smoke environment in order to establish pulmonary disease (chronic bronchitis) model. Then the corresponding changes of the respiratory and intestinal microflflora of the model on 20th, 50th and 70th days were synchronously observed. RESULTS: The respiratory tract microflflora showed an increase in the total aerobic and Staphylococcus aureus and reduced anaerobic amount signifificantly on 20th day in the respiratory tract microflflora (P<0.05 or 0.01). On 50th day, total aerobic, total anaerobic amount and bififidobacterium signifificantly increased (P<0.05). On 70th day, Staphylococcus aureus reduced and lactobacillus increased signifificantly (P<0.01). The intestinal microflflora showed an increase in the total aerobic, Clostridium perfringens, enterobacter and enterococcus significantly increased on 20th day (P<0.05 or 0.01). Staphylococcus aureus on 50th day increased significantly (P<0.05). Total aerobic and enterococcus increased, total anaerobic and Clostridium perfringens reduced signifificantly on 70th day (P<0.05 or 0.01). CONCLUSION: The microecosystem of respiratory tract and intestine of rat model during the pathological process showed a dynamic disorder, indicating an interaction between the lung and large intestine which may be one of the connotations as they exteriorly and interiorly related.