Bronchial asthma is a heterogeneous respiratory condition characterized by chronic airway inflammation, airway hyperresponsiveness and airway structural changes (known as remodeling). The clinical ...symptoms can be evoked by (non)specific triggers, and their intensity varies over time. In the past, treatment was mainly focusing on symptoms’ alleviation; in contrast modern treatment strategies target the underlying inflammation, even during asymptomatic periods. Components of airway remodeling include epithelial cell shedding and dysfunction, goblet cell hyperplasia, subepithelial matrix protein deposition, fibrosis, neoangiogenesis, airway smooth muscle cell hypertrophy and hyperplasia. Among the other important, and frequently forgotten aspects of airway remodeling, also loss of epithelial barrier integrity, immune defects in anti-infectious defence and mucociliary clearance (MCC) dysfunction should be pointed out. Mucociliary clearance represents one of the most important defence airway mechanisms. Several studied in asthmatics demonstrated various dysfunction in MCC – e.g., ciliated cells displaying intracellular disorientation, abnormal cilia and cytoplasmic blebs. Moreover, excessive mucus production and persistent cough are one of the well-recognized features of severe asthma and are also associated with defects in MCC. Damaged airway epithelium and impaired function of the ciliary cells leads to MCC dysfunction resulting in higher susceptibility to infection and inflammation. Therefore, new strategies aimed on restoring the remodeling changes and MCC dysfunction could present a new therapeutic approach for the management of asthma and other chronic respiratory diseases.
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•Bronchial asthma is a complex multi-facetted disease which develops as a consequence of the interplay between genes and factors or triggers from the external and internal environment.•Immune defects, epithelial barrier dysfunction and mucociliary clearance dysfunction are important features of bronchial asthma and should be considered in the context of airway remodeling.•So far, only selected molecules used in asthma treatment showed some capacity to affect and modify remodeling process, but more studies are needed.•New therapeutic options for allergies and bronchial asthma should be aimed at the restoration of the mucociliary clearance and epithelial barrier function.•Therapeutic modulation of associated immune deficiencies could decrease the susceptibility of asthma patients to respiratory infections and thus help to prevent exacerbations.
Acute otitis media is one of the most commonly-diagnosed childhood infections. This study assessed the efficacy of a novel vaccine that contained polysaccharides from 11 different
Streptococcus ...pneumoniae serotypes each conjugated to
Haemophilus influenzae-derived protein D in prevention of acute otitis media.
4968 infants were randomly assigned to receive either pneumococcal protein D conjugate or hepatitis A vaccine at the ages of 3, 4, 5, and 12–15 months and were followed-up until the end of the second year of life. Middle-ear fluid was obtained for bacteriological culture and serotyping in children who presented with abnormal tympanic membrane or presence of middle-ear effusion, plus two predefined clinical symptoms. The primary endpoint was protective efficacy against the first episode of acute otitis media caused by vaccine pneumococcal serotypes. Analysis was per protocol.
From 2 weeks after the third dose to 24–27 months of age, 333 clinical episodes of acute otitis media were recorded in the protein D conjugate group (n=2455) and 499 in the control group (n=2452), giving a significant (33·6% 95% CI 20·8–44·3) reduction in the overall incidence of acute otitis media. Vaccine efficacy was shown for episodes of acute otitis media caused by pneumococcal vaccine serotypes (52·6% 35·0–65·5 for the first episode and 57·6% 41·4–69·3 for any episode). Efficacy was also shown against episodes of acute otitis media caused by non-typable
H influenzae (35·3% 1·8–57·4). The vaccine reduced frequency of infection from vaccine-related cross-reactive pneumococcal serotypes by 65·5%, but did not significantly change the number of episodes caused by other non-vaccine serotypes.
These results confirm that using the
H influenzae-derived protein D as a carrier protein for pneumococcal polysaccharides not only allowed protection against pneumococcal otitis, but also against acute otitis media due to non-typable
H influenzae. Whether this approach would also allow improved protection against lower respiratory tract infections warrants further investigation.
This experimental study evaluated the anti-asthmatic capacity of the dihydroxyflavone chrysin in the settings of ovalbumin (OVA)-induced allergic inflammation.
The parameters that were used to assess ...the anti-asthmatic activity of chrysin included the specific airway resistance to histamine, the sensitivity to a chemically induced cough and the activity of chrysin on the ciliary beat frequency (CBF) of the respiratory epithelium. The anti-inflammatory potential was confirmed by the measurement of cytokine concentrations Th2 (IL-4, IL-5 and IL-13), Th1 (Granulocyte-macrophage colony-stimulating factor GM-CSF, INF-γ and IL-12), leucocyte count in the bronchoalveolar lavage fluid (BALF) and growth factor TBF-β1 in lung homogenate.
Chronic administration of chrysin (30 mg/kg/day for 21 days) to OVA-sensitised guinea pigs showed bronchodilatory activity comparable to that of long-acting β 2 receptors agonist (LABA) salmeterol. Chrysin revealed antitussive efficiency but was not able to abolish the negative effect of OVA on CBF. Chrysin managed to ameliorate the progression of chronic airway inflammation by decreasing the count of eosinophils, lymphocytes and basophils, IL-5, L-13, GM-CSF, INF-γ in BALF, and TGF-β1 in lung homogenate.
The acquired results support the complex anti-asthmatic profile of chrysin. The flavone may represent an attractive compound for further studies concerning the prevention or treatment of asthma.
Aim To compare the sequences of the tcd C gene between Clostridioides difficile (C. difficile ) strains identified as PCR ribotype 176 and the reference strain C. difficile PCR ribotype 027 and to ...evaluate the use of the Xpert C. difficile /Epi assay for their differentiation.
Methods A total of 45 strains were grown from storage beads. DNA of sufficient quality and quantity for sequencing was extracted from 9 samples. Single consensus sequences of PCR ribotype 176 strains and PCR ribotype 001, PCR ribotype 070 (a control group) were mapped to a reference genome of strain CDI-01 (PCR ribotype 027).
Results Four strains (out of seven; 57%) characterized as PCR ribotype 176 had 100% identity of the tcd C gene with the reference strain. The average length of the tcd C gene in these four strains (PCR ribotype 176) was 643 bp, which is 36 bp shorter than the reference genome. Three strains (PCR ribotype 176) had a percentage identity of the tcd C gene in the range of 99.37-100%. Strains 25 (PCR ribotype 001) and 28 (PCR ribotype 070) had a similarity in the range of 95.39-95.63% as a result of different ribotype to the reference strain.
Conclusion PCR ribotype 176 strains have almost the same tcd C gene sequence as PCR ribotype 027, resulting in misidentification of this PCR ribotype by the Xpert C. difficile /Epi assay. Information about presumptive positive results based on deletion in the tcdC gene should be treated with caution or disregarded
Clostridium difficile infection remains a major healthcare burden. Until the recent introduction of fidaxomicin, antimicrobial treatments were limited to metronidazole and vancomycin. The emergence ...of epidemic C. difficile PCR ribotype 027 and its potential link to decreased antibiotic susceptibility highlight the lack of large-scale antimicrobial susceptibility and epidemiological data available. We report results of epidemiological and antimicrobial susceptibility investigations of C. difficile isolates collected prior to fidaxomicin introduction, establishing important baseline data. Thirty-nine sites in 22 countries submitted a total of 953 C. difficile isolates for PCR ribotyping, toxin testing, and susceptibility testing to metronidazole, vancomycin, fidaxomicin, rifampicin, moxifloxacin, clindamycin, imipenem, chloramphenicol, and tigecycline. Ninety-nine known ribotypes were identified. Ribotypes 027, 014, 001/072, and 078 were most frequently isolated in line with previous European studies. There was no evidence of resistance to fidaxomicin, and reduced susceptibility to metronidazole and vancomycin was also scarce. Rifampicin, moxifloxacin, and clindamycin resistance (13%, 40%, and 50% of total isolates, respectively) were evident in multiple ribotypes. There was a significant correlation between lack of ribotype diversity and greater antimicrobial resistance (measured by cumulative resistance score). Well-known epidemic ribotypes 027 and 001/072 were associated with multiple antimicrobial resistance, but high levels of resistance were also observed, particularly in 018 and closely related emergent ribotype 356 in Italy. This raises the possibility of antimicrobial exposure as the underlying reason for their appearance, and highlights the need for ongoing epidemiological and antimicrobial resistance surveillance.
We describe the epidemiology of invasive Haemophilus influenzae disease during 2007-2014 in 12 European countries and assess overall H. influenzae disease trends by serotype and patient age. Mean ...annual notification rate was 0.6 cases/100,000 population, with an increasing annual trend of 3.3% (95% CI 2.3% to 4.3%). The notification rate was highest for patients <1 month of age (23.4 cases/100,000 population). Nontypeable H. influenzae (NTHi) caused 78% of all cases and showed increasing trends among persons <1 month and >20 years of age. Serotype f cases showed an increasing trend among persons >60 years of age. Serotype b cases showed decreasing trends among persons 1-5 months, 1-4 years, and >40 years of age. Sustained success of routine H. influenzae serotype b vaccination is evident. Surveillance systems must adopt a broad focus for invasive H. influenzae disease. Increasing reports of NTHi, particularly among neonates, highlight the potential benefit of a vaccine against NTHi.
Whole-genome sequencing of Clostridium difficile across Europe demonstrates 2 distinct transmission patterns. Healthcare-associated ribotypes showed genetic clustering by country and region, and ...widespread fluoroquinolone resistance. However, multiple common ribotypes showed no within-country clustering, consistent with Europe-wide dissemination via nonhealthcare routes/sources.
Abstract
Background
Rates of Clostridium difficile infection vary widely across Europe, as do prevalent ribotypes. The extent of Europe-wide diversity within each ribotype, however, is unknown.
Methods
Inpatient diarrheal fecal samples submitted on a single day in summer and winter (2012-2013) to laboratories in 482 European hospitals were cultured for C. difficile, and isolates the 10 most prevalent ribotypes were whole-genome sequenced. Within each ribotype, country-based sequence clustering was assessed using the ratio of the median number of single-nucleotide polymorphisms between isolates within versus across different countries, using permutation tests. Time-scaled Bayesian phylogenies were used to reconstruct the historical location of each lineage.
Results
Sequenced isolates (n = 624) were from 19 countries. Five ribotypes had within-country clustering: ribotype 356, only in Italy; ribotype 018, predominantly in Italy; ribotype 176, with distinct Czech and German clades; ribotype 001/072, including distinct German, Slovakian, and Spanish clades; and ribotype 027, with multiple predominantly country-specific clades including in Hungary, Italy, Germany, Romania, and Poland. By contrast, we found no within-country clustering for ribotypes 078, 015, 002, 014, and 020, consistent with a Europe-wide distribution. Fluoroquinolone resistance was significantly more common in within-country clustered ribotypes (P = .009). Fluoroquinolone-resistant isolates were also more tightly clustered geographically with a median (interquartile range) of 43 (0-213) miles between each isolate and the most closely genetically related isolate, versus 421 (204-680) miles in nonresistant pairs (P < .001).
Conclusions
Two distinct patterns of C. difficile ribotype spread were observed, consistent with either predominantly healthcare-associated acquisition or Europe-wide dissemination via other routes/sources, for example, the food chain.
Clostridium difficile
infection (CDI) has been primarily treated with metronidazole or vancomycin. High recurrence rates, the emergence of epidemic PCR ribotypes (RTs) and the introduction of ...fidaxomicin in Europe in 2011 necessitate surveillance of antimicrobial resistance and CDI epidemiology. The
Clos
ER study monitored antimicrobial susceptibility and geographical distribution of
C. difficile
RTs pre- and post-fidaxomicin introduction. From 2011 to 2016, 28 European countries submitted isolates or faecal samples for determination of PCR ribotype, toxin status and minimal inhibitory concentrations (MICs) of metronidazole, vancomycin, rifampicin, fidaxomicin, moxifloxacin, clindamycin, imipenem, chloramphenicol and tigecycline. RT diversity scores for each country were calculated and mean MIC results used to generate cumulative resistant scores (CRSs) for each isolate and country. From 40 sites, 3499 isolates were analysed, of which 95% (3338/3499) were toxin positive. The most common of the 264 RTs isolated was RT027 (mean prevalence 11.4%); however, RT prevalence varied greatly between countries and between years. The fidaxomicin geometric mean MIC for years 1–5 was 0.04 mg/L; only one fidaxomicin-resistant isolate (RT344) was submitted (MIC ≥ 4 mg/L). Metronidazole and vancomycin geometric mean MICs were 0.46 mg/L and 0.70 mg/L, respectively. Of prevalent RTs, RT027, RT017 and RT012 demonstrated resistance or reduced susceptibility to multiple antimicrobials. RT diversity was inversely correlated with mean CRS for individual countries (Pearson coefficient r = − 0.57). Overall,
C. difficile
RT prevalence remained stable in 2011–2016. Fidaxomicin susceptibility, including in RT027, was maintained post-introduction. Reduced ribotype diversity in individual countries was associated with increased antimicrobial resistance.
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