David L. Hahn

Evidence for Chlamydia pneumoniae infection in steroid-dependent asthma

BACKGROUND Chlamydia pneumoniae is an obligate intracellular respiratory pathogen capable of persistent infection. Seroepidemiologic studies and the results of open-label antimicrobial treatment of patients with non-steroid-dependent asthma have suggested a potential role for C. pneumoniae in asthma. OBJECTIVE To evaluate the results of antimicrobial treatment in patients with uncontrolled steroid-dependent asthma and serologic evidence suggesting C. pneumoniae infection. METHODS Three nonsmoking asthmatic patients (aged 13 to 65 years) whose symptoms remained poorly controlled despite daily administration of inhaled and oral steroid (10 to 40 mg/d). All met serologic criteria for current or recent C. pneumoniae infection. RESULTS After prolonged treatment (6 to 16 weeks) with clarithromycin or azithromycin all three patients were able to discontinue oral steroids. All three patients have remained well controlled with inhaled antiasthma therapy only during 3 to 24 months of postantibiotic therapy observation. CONCLUSIONS In adolescent and adult asthmatic patients, Chlamydia pneumoniae infection may contribute to symptoms of asthma that are poorly controlled by steroids. Serologic evidence for C. pneumoniae infection should be sought in such patients. A trial of appropriate antibiotic therapy may be helpful in those patients with high titers of anti-C. pneumoniae IgG antibodies.

Can acute Chlamydia pneumoniae respiratory tract infection initiate chronic asthma

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, nonasthmatic individuals can result in chronic asthma. Patients previously diagnosed with chronic asthma should be evaluated for possible chronic C. pneumoniae infection.

Serologic markers for Chlamydia pneumoniae in asthma.

BACKGROUND Chlamydia pneumoniae infection has been reported as a possible etiologic agent in asthma, which in primary care settings often appears to be initiated by acute respiratory infections. OBJECTIVE To determine if serologic markers for C. pneumoniae are associated with adult asthma that first became symptomatic after an acute respiratory illness (asthma associated with infection: AAWI). METHODS Serum samples from 164 primary care outpatients, mean age 44 years, (68 with AAWI; 36 with atopic, occupational or exercise-induced asthma (non-AAWI); 16 nonasthmatic patients with acute bronchitis; and 44 asymptomatic nonasthmatic controls) were tested for the presence of C. pneumoniae-specific IgG and IgA antibodies. Levels of chlamydial heat shock protein 60 (CHSP60) antibody were also measured. Those positive for CHSP60 were tested for C. pneumoniae-specific IgE antibodies by immunoblotting. RESULTS Statistically significant differences in IgG and IgA seroreactivity were noted between groups: acute bronchitis and AAWI had the highest levels (93% to 94% IgG seroreactivity, 69% to 75% IgA seroreactivity) whereas non-AAWI and asymptomatic controls had the lowest levels (61% to 84% IgG seroreactivity, 31% to 43% IgA seroreactivity, P < .02 after adjustment for age, sex and smoking). CHSP60 antibodies were significantly more prevalent in AAWI than in non-AAWI (19% versus 3%, P = .02). IgE antibodies against C. pneumoniae 60, 62, and/or 70 kD antigens were detected in 5 of 13 CHSP60 positive AAWI patients. Persistent IgG, IgA, and CHSP60 seroreactivities were noted in all seropositive asthma patients with serial serum samples. CONCLUSIONS Serologic markers of C. pneumoniae infection were associated with acute bronchitis and with asthma that first became symptomatic following respiratory illness. Serologic responses to C. pneumoniae may be useful in the classification and diagnosis of asthma.

Secondary Outcomes of a Pilot Randomized Trial of Azithromycin Treatment for Asthma

Objectives: The respiratory pathogen Chlamydia pneumoniae (C. pneumoniae) produces acute and chronic lung infections and is associated with asthma. Evidence for effectiveness of antichlamydial antibiotics in asthma is limited. The primary objective of this pilot study was to investigate the feasibility of performing an asthma clinical trial in practice settings where most asthma is encountered and managed. The secondary objectives were to investigate (1) whether azithromycin treatment would affect any asthma outcomes and (2) whether C. pneumoniae serology would be related to outcomes. This report presents the secondary results. Design: Randomized, placebo-controlled, blinded (participants, physicians, study personnel, data analysts), allocation-concealed parallel group clinical trial. Setting: Community-based health-care settings located in four states and one Canadian province. Participants: Adults with stable, persistent asthma. Interventions: Azithromycin (six weekly doses) or identical matching placebo, plus usual community care. Outcome Measures: Juniper Asthma Quality of Life Questionnaire (Juniper AQLQ), symptom, and medication changes from baseline (pretreatment) to 3 mo posttreatment (follow-up); C. pneumoniae IgG and IgA antibodies at baseline and follow-up. Results: Juniper AQLQ improved by 0.25 (95% confidence interval; −0.3, 0.8) units, overall asthma symptoms improved by 0.68 (0.1, 1.3) units, and rescue inhaler use decreased by 0.59 (−0.5, 1.6) daily administrations in azithromycin-treated compared to placebo-treated participants. Baseline IgA antibodies were positively associated with worsening overall asthma symptoms at follow-up (p = 0.04), but IgG was not (p = 0.63). Overall asthma symptom improvement attributable to azithromycin was 28% in high IgA participants versus 12% in low IgA participants (p for interaction = 0.27). Conclusions: Azithromycin did not improve Juniper AQLQ but appeared to improve overall asthma symptoms. Larger community-based trials of antichlamydial antibiotics for asthma are warranted.

Chlamydia pneumoniae-Specific IgE Is Prevalent in Asthma and Is Associated with Disease Severity

Background Several Chlamydia pneumoniae (Cp) biomarkers have been associated with asthma but Cp-specific IgE (Cp IgE) has not been investigated extensively. Our objective was to investigate Cp IgE in community adult asthma patients. Methods (1) Prevalence of Cp IgE (measured by immunoblotting) and Cp DNA (by polymerase chain reaction) in peripheral blood, and biomarker associations with asthma severity. (2) Case-control studies of Cp IgE association with asthma using healthy blood donor (study 1) and non-asthmatic clinic patient (study 2) controls. Results Of 66 asthma subjects (mean age 40.9 years, range 5–75, 59% male, 45% ever-smokers) 33 (50%) were Cp IgE positive and 16 (24%) were Cp DNA positive (P = 0.001 for association of Cp IgE and DNA). Cp IgE was detected in 21% of mild intermittent asthma v 79% of severe persistent asthma (test for trend over severity categories, P = 0.002). Cp IgE detection was significantly (P = 0.001) associated with asthma when compared to healthy blood donor controls but not when compared to clinic controls. Conclusions Half of this sample of community asthma patients had detectable IgE against C. pneumoniae. Cp IgE was strongly and positively associated with asthma severity and with asthma when healthy blood donor controls were used. These results support the inclusion of Cp IgE as a biomarker in future studies of infectious contributions to asthma pathogenesis.

Azithromycin for Bronchial Asthma in Adults: An Effectiveness Trial

Background: Macrolides have antimicrobial and anti-inflammatory properties that may be useful in the treatment of chronic asthma. Methods: We performed a randomized, placebo-controlled, double-blinded effectiveness trial of 12 weekly doses of adjunctive azithromycin, with follow-up to 1 year after randomization, in adults with persistent asthma. Measurements included overall asthma symptoms, asthma quality of life (AQL), and asthma control. Eligible subjects who declined to participate in randomization were offered enrollment into a parallel open-label (OL) azithromycin treatment arm. Results: Of 304 adult asthma patients screened, 97 (32%) were enrolled: 38 were randomized to azithromycin, 37 were randomized to placebo, and 22 opted in as OL subjects. OL subjects had higher rates of severe persistent asthma compared with randomized subjects (32% vs 8%, respectively; P = .012). At 1 year, compared with the placebo arm, subjects randomized to azithromycin were more likely to have an AQL score ≥1 unit increase compared with baseline, but this difference was not statistically significant (36% vs 21% for placebo; P = .335). Compared with placebo, OL subjects had significant improvements in overall asthma symptoms from baseline (P = .0196), AQL (P = .0006), and asthma control (P = .0148). Conclusions: Adults with asthma who were randomized to azithromycin did not show statistically significant improvement in asthma outcomes, although the study was underpowered to detect clinical improvement in 15% (number needed to treat = 7). Adults with severe persistent asthma who elected OL treatment documented clinical improvements in asthma symptoms, AQL, and asthma control that persisted after completion of OL azithromycin (number needed to treat = 2).

Importance of Evidence Grading for Guideline Implementation: The Example of Asthma

The goal of evidence-based clinical guidelines is to improve the value of health care by recommending treatments with favorable benefit/harm ratios. Achieving this goal requires use of evidence-grading systems that explicitly address strength of evidence in terms of external validity (generalizability), internal validity, and patient-oriented outcomes. To be clinically useful, guidelines should also incorporate patient preferences, particularly when evidence is weak. The National Heart, Lung and Blood Institute recently published Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3). This special report addresses the extent to which current guidelines adhere to the principles enunciated above by using EPR-3 as the prime example. EPR-3 used an unconventional evidence-grading system that emphasized precision and consistency (statistical significance, large sample sizes, and/or consistency of results) at the expense of patient-oriented outcomes and generalizability (applicability to the general population). EPR-3 did not report information on numbers needed to treat or numbers needed to harm, which are useful in eliciting patient preferences via shared decision making. Asthma guidelines (and others) are limited by lack of a generalizable research base, flawed evidence grading, and lack of attention to patient preferences. An evidence-grading system based on applicable populations, patient-oriented outcomes, and shared decision making might improve physician and patient guideline adherence and improve asthma outcomes.

Airflow limitation, asthma, and Chlamydia pneumoniae-specific heat shock protein 60

BACKGROUND Chlamydia pneumoniae has been associated with asthma. It has also been suggested that C pneumoniae infection may lead to lung remodeling in a subset of asthmatic patients. Seroreactivity against Chlamydia trachomatis heat shock protein 60 (hsp60), a highly conserved, immunoreactive chaperone protein, is associated with immunopathologic abnormalities, leading to blinding trachoma and tubal infertility. This suggests that the host response to infection may affect chronic inflammatory damage to the eye and the fallopian tubes. The pathogenesis of C trachomatis disease associations is thought to include molecular mimicry (autoimmunity), direct activation of the innate immune response via the CD14/toll-like receptor 4 complex, or both. OBJECTIVE To study whether airflow limitation in asthma in C pneumoniae-exposed individuals is associated with a specific antibody response to the C pneumoniae hsp60 molecule and not with a genus-specific response to the hsp60 molecule. METHODS In a case-control study, we evaluated 138 C pneumoniae-exposed primary care patients (86 adult asthmatic cases and 52 nonasthmatic controls) for seroreactivity against a C pneumoniae-specific hsp60 fragment and against the C trachomatis hsp60 molecule. We analyzed associations with asthma and irreversible lung remodeling as measured by means of postbronchodilator forced expiratory volume in 1 second. RESULTS Twenty-seven percent of asthmatic patients were C pneumoniae hsp60 seropositive vs 8% of controls (P < .01). Controlling for age, sex, and smoking, C pneumoniae hsp60 seropositivity was associated with lower postbronchodilator forced expiratory volume in 1 second in asthmatic patients (P < .05). No comparable associations were present for C trachomatis hsp60. CONCLUSIONS In individuals with evidence of previous exposure to C pneumoniae infection, a host antibody response against a C pneumoniae hsp60 fragment but not against C trachomatis hsp60 was associated with airflow limitation in adults with asthma.

Chlamydia Infection and Pneumonia

As outlined in Table II this review has delineated similarities and differences in the epidemiology, pathogenesis, clinical symptoms, and immune responses to chlamydial pneumonias. Each organism may induce unique immune responses, as different pneumonia syndromes result from infection with different chlamydiae. Understanding such species differences in the context of one disease may help establish common principles applicable to understanding the pathogenesis of these chlamydial infections. Clearly, the use of murine models for C. trachomatis pneumonia has described important immune mediators, and whether these mediators are equally applicable to recently developed C. pneumoniae animal models awaits to be seen. In either case,the immune response to pneumonia may be different in humans, and future studies therefore must define immune mediators in human chlamydial pneumonias.

Clinician and Staff Perspectives on Participating in Practice-based Research (PBR): A Report from the Wisconsin Research and Education Network (WREN)

Background: The success of practice-based research (PBR) depends on the willingness of clinicians and staff to incorporate meaningful and useful research protocols into already demanding clinic schedules. The impact of participation on those who implement multiple projects and how to address the issues that arise during this complex process remain incompletely described. This article reports a qualitative evaluation of the experiences of primary care clinicians and clinic staff who participated in multiple PBR projects with the Wisconsin Research and Education Network (WREN). Also included are their suggestions to researchers and clinicians for future collaborations. Methods: For program evaluation purposes, WREN conducted 4 focus groups at its 2014 annual meeting. The main focus group question was, “How has participation in PBR affected you and your clinic?” A total of 27 project members from 13 clinics participated in 4 groups (physicians, nurses, managers, and other clinical staff). The 2-hour sessions were recorded, transcribed, and analyzed to identify recurring themes. Results: Five major focus group themes emerged: receptivity to research, outcomes as a result of participation, barriers to implementation, facilitators of success, and advice to researchers and colleagues. Focus group members find research valuable and enjoy participating in projects that are relevant to their practice, even though many barriers exist. They indicated that research participation produces clinical changes that they believe result in improved patient care. They offered ways to improve the research process, with particular emphasis on collaborative early planning, project development, and communication before, during, and after a project. Conclusions: Clinics that participate in WREN projects remain willing to risk potential work constraints because of immediate or impending benefits to their clinical practice and/or patient population. Including a broader array of clinic personnel in the communication processes, especially in the development of relevant research ideas and planning for clinic implementation and ongoing participation in research projects, would address many of the barriers identified in implementing PBR. The themes and supporting quotes identified in this evaluation of WREN projects may inform researchers planning to collaborate with primary care clinics and clinicians and staff considering participating in research endeavors.