Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Chlamydia pneumoniae (TWAR) is a recently recognized third species of the genus Chlamydia that causes acute respiratory disease. It is distinct from the other two chlamydial species that infect humans, C. trachomatis and C. psittaci, in elementary body morphology and shares less than 10% of the DNA homology with those species. The organism has a global distribution, with infection most common among children between the ages of 5 and 14 years. In children, TWAR infection is usually mild or asymptomatic, but it may be more severe in adults. Pneumonia and bronchitis are the most common clinical manifestations of infection, and TWAR is responsible for approximately 10% of cases of pneumonia and 5% of cases of bronchitis in the United States. The microimmunofluorescence serologic assay is specific for TWAR and can distinguish between recent and past infections. The organism can be isolated in cell culture; however, PCR techniques have recently facilitated its detection in tissues and clinical specimens.

/pdf/chlamydia-pneumoniae-twar-4q1jwy7gjd.pdf

Chlamydia pneumoniae (TWAR)

Intracellular parasitism by bacterial pathogens is a complex, multi-factorial process that has been exploited successfully by a wide variety of organisms. Members of the Order Chlamydiales are obligate intracellular bacteria that are transmitted as metabolically inactive particles and must differentiate, replicate, and re-differentiate within the host cell to carry out their life cycle. Understanding the developmental cycle has been greatly advanced by the availability of complete genome sequences, DNA microarrays, and advanced cell biology techniques. Measuring transcriptional changes throughout the cycle has allowed investigators to determine the nature of the temporal gene expression changes required for bacterial growth and development.

http://bmg.fc.ul.pt/Disciplinas/Regula_e_Diferenc/artigos/AbdelRahman05.pdf

The chlamydial developmental cycle.

It is estimated that in 1995, 16.4 million people in the United States suffered from chronic obstructive pulmonary disease (COPD) (226). COPD is also the fourth most common cause of death in the United States (14). Both the prevalence of and mortality from this disease have been increasing worldwide (118, 226, 330). COPD is defined physiologically by the presence of irreversible or partially reversible airway obstruction in patients with chronic bronchitis and/or emphysema (14). Chronic bronchitis is defined clinically by the presence of cough with sputum production for most days of at least 3 months a year for 2 consecutive years (200). Other causes of chronic cough need to be excluded. Emphysema is defined pathologically as permanent dilation of the airspaces distal to the terminal bronchioles, accompanied by destruction of the alveolar septa in the absence of fibrosis (292). More than 80% of COPD cases encountered in the Western world are related to tobacco smoke exposure. Occupational exposures and alpha-1 antitrypsin deficiency are uncommon precedents for the development of COPD (177, 234).

Several potential contributions of bacterial infection to the etiology, pathogenesis, and clinical course of COPD can be identified (219). However, the precise role of bacterial infection in COPD has been a source of controversy for several decades (175, 296, 307). Opinion regarding the contribution of bacteria to the pathogenesis of COPD has ranged from the idea that it has a preeminent role (along with mucus hypersecretion) as embodied in the British hypothesis in the 1950s and 1960s, to the idea that it is a mere epiphenomenon in the 1970s and 1980s (200, 296, 307). In the last decade, new research techniques have become available, and traditionally noninfectious diseases such as peptic ulcer have been shown to be of infectious origin (240). This has renewed interest in the area of bacteria and COPD, and these new research methodologies should lead to a precise delineation of the contribution of bacterial infection to this disease.

Five potential pathways by which bacteria could contribute to the course and pathogenesis of COPD can be identified. (i) Childhood lower respiratory tract infection impairs lung growth, reflected in smaller lung volumes in adulthood. (ii) Bacteria cause a substantial proportion of acute exacerbations of chronic bronchitis which cause considerable morbidity and mortality. (iii) Chronic colonization of the lower respiratory tract by bacterial pathogens amplifies the chronic inflammatory response present in COPD and leads to progressive airway obstruction (vicious circle hypothesis). (iv) Bacterial pathogens invade and persist in respiratory tissues, alter the host response to cigarette smoke, or induce a chronic inflammatory response and thus contribute to the pathogenesis of COPD. (v) Bacterial antigens in the lower airway induce hypersensitivity that enhances airway hyperreactivity and induces eosinophilic inflammation. Evidence supporting these roles will be discussed in this review, with an emphasis on information gained from newer research techniques in the last decade. The second part of this review will discuss each of the major pathogens, with emphasis on recent developments related specifically to infections in COPD.

/pdf/bacterial-infection-in-chronic-obstructive-pulmonary-disease-3excqsafks.pdf

Bacterial Infection in Chronic Obstructive Pulmonary Disease in 2000: a State-of-the-Art Review

Estimating the amount and cost of excess antibiotic use in ambulatory practice and identifying the conditions that account for most excess use are necessary to guide intervention and policy decisions. Data from the 1998 National Ambulatory Medical Care Survey, a sample survey of United States ambulatory physician practices, was used to estimate primary care office visits and antibiotic prescription rates for acute respiratory infections. Weight-averaged antibiotic costs were calculated with use of 1996 prescription marketing data and adjusted for inflation. In 1998, an estimated 76 million primary care office visits for acute respiratory infections resulted in 41 million antibiotic prescriptions. Antibiotic prescriptions in excess of the number expected to treat bacterial infections amounted to 55% (22.6 million) of all antibiotics prescribed for acute respiratory infections, at a cost of approximately $726 million. Upper respiratory tract infections (not otherwise specified), pharyngitis, and bronchitis were the conditions associated with the greatest amount of excess use. This study documents that the amount and cost of excessive antibiotic use for acute respiratory infections by primary care physicians are substantial and establishes potential target rates for antibiotic treatment of selected conditions.

/pdf/excessive-antibiotic-use-for-acute-respiratory-infections-in-gty509hoda.pdf

Excessive Antibiotic Use for Acute Respiratory Infections in the United States

Objective. —To study the clinical characteristics of respiratory tract illness caused by Chlamydia pneumoniae . Design. —Prospective clinical, bacteriologic, and serologic study. Secondarily, a matched comparison of patients with and without evidence of C pneumoniae infection (serologic titers ≥1:64 and Setting. —Four primary care (family practice) clinics in Madison, Wis, and nearby towns. Patients. —The study included 365 white males and females (mean age, 34.2 years). Main Outcome Measures. —Association of acute C pneumoniae infection with signs and symptoms of respiratory illness and the relationship of C pneumoniae antibody titer with wheezing at the time of enrollment in the study, and with the diagnosis of asthmatic bronchitis. Results. —Nine (47%) of 19 patients with acute C pneumoniae infection had bronchospasm during respiratory illness, and there was a strong quantitative association of C pneumoniae titer with wheezing at the time of enrollment in the study ( P =.01). In the matched study, C pneumoniae antibody was significantly associated with asthmatic bronchitis after, but not before, respiratory illness (odds ratio, 7.2; 95% confidence interval, 2.2 to 23.4). Four infected patients had newly diagnosed asthma after illness, and four others had exacerbation of previously diagnosed asthma. There was no serologic evidence of coexisting Mycoplasma pneumoniae, Chlamydia trachomatis , or respiratory viral infection in 96% of patients with asthmatic bronchitis and asthma. Conclusions. —Some Cpneumoniae antibody titers, although not diagnostic of chlamydial infection by present criteria, probably represent acute reinfection or ongoing chronic infection. Repeated or prolonged exposure to C pneumoniae may have a causal association with wheezing, asthmatic bronchitis, and asthma. ( JAMA . 1991;266:225-230)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=386460&pdfFileName=jama_266_2_031.pdf

Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.

Learning objectives Reading this article will familiarize the reader with (1) the unique chlamydial intracellular life cycle and the propensity for human chlamydial infections to become persistent and to result in immunopathologic (inflammatory) damage in target organs and (2) current evidence linking Chlamydia pneumoniae ( Cpn ) infection to obstructive lung diseases (asthma and chronic obstructive pulmonary disease, COPD). Potential therapeutic implications of the Cpn -asthma association are also discussed. Data sources All Medline articles (January 1985 to March 1999) that cross-referenced the exploded MESH headings "lung diseases, obstructive" and " Chlamydia pneumoniae " (N = 76). Additional referenced articles, published abstracts, book chapters, and conference proceedings were also utilized. Study selection (1) Case reports and case series that identified Cpn infection in asthma and/or COPD and (2) epidemiologic studies of markers for Cpn infection in asthma and/or COPD that included one or more control groups. Results Of 18 controlled epidemiologic studies (over 4000 cases/controls), 15 found significant associations between Cpn infection and asthma using organism detection (polymerase chain reaction (PCR) testing (n = 2 studies) or fluorescent antigen testing (n = 1)), Cpn -specific secretory IgA (sIgA) antibody testing (n = 1), and/or specific serum IgE (n = 2), IgA (n = 4), IgG (n = 3) or other antibody criteria (n = 7). Eight case reports and 13 case series of Cpn infection in asthma (over 100 patients) also include descriptions of improvement or complete disappearance of asthma symptoms after prolonged antibiotic therapy directed against Cpn. Significant associations with COPD (over 1000 cases/controls) were reported in 5 of 6 studies. Results of treating chronic chlamydial infections in COPD patients have not been reported. Conclusions Although the full clinical significance of these Cpn -obstructive lung disease associations remains to be established, reports of asthma improvement after treatment of Cpn infection deserve further investigation. Clinicians who manage asthma should be aware of this information since it may help to manage difficult cases. The hypothesis that Cpn infection in COPD can amplify smoking-associated inflammation and worsen fixed obstruction also deserves further study.

Chlamydia pneumoniae, asthma, and COPD: what is the evidence?

Background Chlamydia pneumoniae infection can cause acute respiratory illnesses (including sinusitis, bronchitis, and pneumonia) that are sometimes associated with wheezing. Little is known about whether acute infection in a previously unexposed, nonasthmatic individual can produce persistent wheezing leading to a diagnosis of chronic asthma. Objective We sought to determine whether patients with acute C. pneumoniae respiratory tract infections would develop chronic asthma. Methods A consecutive series of 163 primary care outpatient adolescents and adults (average age 43, 45% male) who had acute wheezing illnesses or chronic asthma were evaluated for C. pneumoniae infection by serologic testing. A subgroup of these patients also had nasopharyngeal cultures for C. pneumoniae . Results Twenty patients (12%) were diagnosed with C. pneumoniae infection defined by serology (15), culture isolation (3), or both (2). Of these 20, 10 patients wheezed for the first time and 6 of them subsequently developed chronic asthma (5) or chronic bronchitis (1) along with a serologic profile suggesting chronic infection. The other 10 patients diagnosed with C. pneumoniae infection already had a diagnosis of chronic asthma. In these patients initial serologic findings suggested chronic rather than acute infection. Conclusions Acute C. pneumoniae respiratory tract infections in previously unexposed, an asthmatic individuals can result in chronic asthma. Patients previously diagnosed with chronic asthma should be evaluated for possible chronic C. pneumoniae infection.

Can Acute Chlamydia pneumoniae Respiratory Tract Infection Initiate Chronic Asthma

BACKGROUND Some diseases previously believed to be noninfectious, eg, peptic ulcer disease, are now known to be caused by chronic infection. Recently, chronic Chlamydia pneumoniae infection has been suggested as a cause for adult-onset asthma. The purpose of this study was to determine whether antichlamydial treatment would affect the natural history of this disease. METHODS An open-label, before-after treatment trial was performed in a community-based, primary care office. Forty-six patients (mean age 47.7 years; range 17 to 78) with moderate to moderately severe, stable, chronic asthma were treated a median of 4 weeks (range 3 to 9) with oral doxycycline (100 mg twice daily), azithromycin (1000 mg once weekly), or erythromycin (1000 mg daily). Post-treatment pulmonary function and asthma symptoms were compared with baseline values. Follow-up was an average of 6 months (range 1.5 to 36) post-treatment. RESULTS Four patients with C pneumoniae respiratory tract infection developed chronic asthma, which disappeared after treatment in each case. Of the remaining 42 seroreactive patients who were treated a mean of 6 years after the development of chronic asthma, one half had either complete remission or major clinical improvement (3 and 18 patients, respectively). This improvement was significantly more likely to occur in patients with early disease (P = .01) and before the development of fixed obstruction (P < .01). CONCLUSIONS Antimicrobial therapy appeared to "cure" or significantly improve asthma in approximately one half of treated adults, and the response pattern was consistent with chlamydial pathogenesis. C pneumoniae infection in asthma may be clinically important and should be investigated further.

Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial.

Background Patient engagement throughout research is a way to generate more relevant patient-important research questions, methods and results with the ultimate aim of facilitating translation of research into practice. Tokenism is defined as the practice of making perfunctory or symbolic efforts to engage communities or patients. Objective We wanted to explore how tokenism might influence engaging patients in research to help researchers work towards more genuine engagement. Methods The Community Clinician Advisory Group and Patient and Clinician Engagement program held a workshop at the 2015 North American Primary Care Research Group meeting titled 'How Do We Move beyond Tokenism in Patient Engagement?' Patients, clinicians and academic researchers contributed examples of genuine and token engagement characteristics based on personal experience and knowledge. Data were iteratively collated and categorized into domains and items. Results Examples of genuine and token engagement were categorized into three domains: Methods/Structure of engagement, Intent and Relationship building. Members with experience in patient-engaged research projects felt that longitudinal engagement was a key element to effectively translating research into local community and practice. Conclusions The group (i) highly valued genuine intent and relationship building as elements to combat tokenism; (ii) noted that early genuine attempts at engagement may superficially resemble tokenism as researchers build enduring and trusting relationships with patient/community partners and (iii) emphasized the importance of seeking and utilizing patient experiences throughout research. These observations may contribute to more formal methods to help researchers (and reviewers) evaluate where engagement processes sit along the 'genuine-token' continuum.

David L. Hahn

Papers

Association of Chlamydia pneumoniae (strain TWAR) infection with wheezing, asthmatic bronchitis, and adult-onset asthma.

Chlamydia pneumoniae, asthma, and COPD: what is the evidence?

Can Acute Chlamydia pneumoniae Respiratory Tract Infection Initiate Chronic Asthma

Treatment of Chlamydia pneumoniae infection in adult asthma: a before-after trial.

Tokenism in patient engagement.