Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts.

BACKGROUND: Severe asthma is a complex heterogeneous disease associated with older age and obesity. The presence of eosinophilic (type 2) inflammation in some but not all patients with severe asthma predicts responsiveness to current treatments, but new treatment approaches will require a better understanding of non-type 2 mechanisms of severe asthma. We considered the possibility that systemic inflammation, which arises in subgroups of obese and older patients, increases the severity of asthma. Interleukin-6 (IL-6) is a biomarker of systemic inflammation and metabolic dysfunction, and we aimed to explore the association between IL-6 concentrations, metabolic dysfunction, and asthma severity. METHODS: In this cross-sectional analysis, patients were recruited from two cohorts: mainly non-severe asthmatics from the University of California San Francisco (UCSF) and mainly severe asthmatics from the Severe Asthma Research Program (SARP). We generated a reference range for plasma IL-6 in a cohort of healthy control patients. We compared the clinical characteristics of asthmatics with plasma IL-6 concentrations above (IL-6 high) and below (IL-6 low) the upper 95% centile value for plasma IL-6 concentration in the healthy cohort. We also compared how pulmonary function, frequency of asthma exacerbations, and frequency of severe asthma differed between IL-6 low and IL-6 high asthma populations in the two asthma cohorts. FINDINGS: Between Jan 1, 2005, and Dec 31, 2014, we recruited 249 patients from UCSF and between Nov 1, 2012, and Oct 1, 2014, we recruited 387 patients from SARP. The upper 95th centile value for plasma IL-6 concentration in the healthy cohort (n=93) was 3·1 pg/mL, and 14% (36/249) of UCSF cohort and 26% (102/387) of the SARP cohort had plasma IL-6 concentrations above this upper limit. The IL-6 high patients in both asthma cohorts had a significantly higher average BMI (p<0·0001) and a higher prevalence of hypertension (p<0·0001) and diabetes (p=0·04) than the IL-6 low patients. IL-6 high patients also had significantly worse lung function and more frequent asthma exacerbations than IL-6 low patients (all p values <0·0001). Although 80% (111/138) of IL-6 high asthmatic patients were obese, 62% (178/289) of obese asthmatic patients were IL-6 low. Among obese patients, the forced expiratory volume in 1 s (FEV1) was significantly lower in IL-6 high than in IL-6 low patients (mean percent predicted FEV1=70·8% [SD 19·5] vs 78·3% [19·7]; p=0·002), and the percentage of patients reporting an asthma exacerbation in the past 1-2 years was higher in IL-6 high than in IL-6 low patients (66% [73/111] vs 48% [85/178]; p=0·003). Among non-obese asthmatics, FEV1 values and the frequency of asthma exacerbations within the past 1-2 years were also significantly worse in IL-6 high than in IL-6 low patients (mean FEV1 66·4% [SD 23·1] vs 83·2% [20·4] predicted; p<0·0001; 59% [16/27] vs 34% [108/320]; p=0·01). INTERPRETATION: Systemic IL-6 inflammation and clinical features of metabolic dysfunction, which occur most commonly in a subset of obese asthma patients but also in a small subset of non-obese patients, are associated with more severe asthma. These data provide strong rationale to undertake clinical trials of IL-6 inhibitors or treatments that reduce metabolic dysfunction in a subset of patients with severe asthma. Plasma IL-6 is a biomarker that could guide patient stratification in these trials. FUNDING: NIH and the Parker B Francis Foundation.

A large subgroup of mild-to-moderate asthma is persistently noneosinophilic.

RATIONALE: Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic. OBJECTIVES: To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype. METHODS: We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments. MEASUREMENTS AND MAIN RESULTS: In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma. CONCLUSIONS: Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.

The H antigen at epithelial surfaces is associated with susceptibility to asthma exacerbation.

RATIONALE: Acute asthma exacerbations, precipitated by viral infections, are a significant cause of morbidity, but not all patients with asthma are equally susceptible. OBJECTIVES: To explore susceptibility factors for asthma exacerbations, we considered a role for histoblood group antigens because they are implicated in mechanisms of gastrointestinal viral infection, specifically the O-secretor mucin glycan phenotype. We investigated if this phenotype is associated with susceptibility to asthma exacerbation. METHODS: We performed two consecutive case-control studies in subjects with asthma who were either prone or resistant to asthma exacerbations. Exacerbation-prone cases had frequent use of prednisone for an asthma exacerbation and frequent asthma-related healthcare utilization, whereas exacerbation-resistant control subjects had rarely reported asthma exacerbations. The frequency of different mucin glycan phenotypes, defined by the presence or absence of H (O), A, B, or AB antigens, was compared in cases and control subjects. MEASUREMENTS AND MAIN RESULTS: In an initial study consisting of 49 subjects with asthma (23 cases and 26 control subjects), we found that having the O-secretor phenotype was associated with a 5.8-fold increase in the odds of being a case (95% confidence interval, 1.7-21.0; P = 0.006). In a replication study consisting of 204 subjects with asthma (101 cases and 103 control subjects), we found that having the O-secretor phenotype was associated with a 2.3-fold increased odds of being a case (95% confidence interval, 1.2-4.4; P = 0.02). CONCLUSIONS: The O-secretor mucin glycan phenotype is associated with susceptibility to asthma exacerbation. Clinical trial registered at www.clinicaltrials.gov (NCT00201266).

Objective airway monitoring improves asthma control in the cold and flu season: a cluster randomized trial.

BACKGROUND: The goals of asthma care are reductions in risk and impairment, but achieving these goals requires collaborative work between patients and their clinicians. The purpose of this study was to improve inhaled corticosteroid (ICS) adherence and asthma control by cueing therapeutic communication between patients with asthma and their primary care clinicians. METHODS: We conducted a prospective, cluster-randomized, controlled effectiveness trial to assess the effect of providing visually standardized, interpreted peak flow graphs (CUE intervention) to patients and their clinicians on ICS adherence and asthma control. Asthma control outcomes were analyzed by season to account for seasonal variations in exacerbation frequency. RESULTS: Although mean log-transformed ICS adherence was not significantly different between the two groups, there was a trend toward preserved adherence in the intervention group over time (P = .16). Intervention patients required fewer courses of oral steroids during winter (9% vs 23%, P < .001) and spring (3% and 17%, P < .001) compared with control subjects. Intervention patients also had fewer periods of worsening symptoms (65% vs 89%, P < .001) and fewer urgent care visits (10% vs 23%, P < .001) during winter compared with control subjects. Post hoc analysis showed significant improvement in the intervention group with respect to ICS adherence during winter months (P < .05), the likely explanation for the reduction in prednisone use and symptoms. Day-to-day peak flow variability in the intervention group fell consistently throughout the study from an average of 32% at baseline to 23% at final measurement (P < .001), indicating less airway reactivity over time. CONCLUSIONS: Our findings provide evidence of the value of peak flow monitoring for patients with asthma during seasons of greatest vulnerability, the cold/flu season. The peak flow information apparently led to improvements in ICS adherence resulting in less need for prednisone rescue and fewer episodes of worsening symptoms.

Barriers to patient-clinician collaboration in asthma management: the patient experience.

OBJECTIVE: To describe what adult patients with asthma report about their experiences with their own self-management behavior and working with their clinicians to control asthma. METHODS: The study sample consisted of 104 patients with persistent asthma participating in a clinical trial on asthma monitoring. All subjects were seen by primary care clinicians of a large, academic medical center. This qualitative post hoc analysis examined the views of adults with asthma about their asthma-related health care. Patients attended monthly visits as part of their study participation, during which data were derived from semistructured interviews. All patients included in this analysis participated in the study for 1 year. At the end of study participation, patients were asked to complete an evaluation of their clinician's communication behavior. All study clinicians were also asked to complete a self-evaluation of their own communication behavior. RESULTS: Five major themes of barriers to successful self-management were identified, including personal constraints, social constraints, communication failures, medication issues, and health care system barriers to collaboration with their clinicians. Patients most frequently reported lack of communication surrounding issues relating to day-to-day management of asthma (31%) and home management of asthma (24%). Clinicians generally rated themselves well for consistency in showing nonverbal attentiveness (89%) and maintaining interactive conversations (93%). However, only 30% of clinicians reported consistency in helping patients make decisions about asthma management and only 33% of clinicians reported consistency in tailoring medication schedules to the patient's routines. CONCLUSION: These findings emphasize the difficulties of establishing and maintaining a therapeutic partnership between patients and clinicians. The results underscore the need for system-wide interventions that promote the success of a therapeutic patient-clinician relationship in order to achieve long-term success in chronic disease management.

Improving chronic care of type 2 diabetes using teams of interprofessional learners.

PURPOSE: To improve the care and outcomes of adult patients with type 2 diabetes by teaching interprofessional teams of learners the principles and practices of the Improving Chronic Illness Care Model. METHOD: The study population consisted of 384 adult patients with type 2 diabetes. The study design was a nonrandomized, parallel-group, clinical trial conducted during 18 months in the University of California, San Francisco internal medicine clinics. Interprofessional team care provided by primary care internal medicine residents, nurse practitioner students, and pharmacy students was compared with usual care by internal medicine residents only. Processes of care, clinical status, and health utilization were measured in both patient groups. Learner outcomes also were assessed and compared. RESULTS: At study completion, intervention patients more frequently received assessments of glycosolated hemoglobin (79% versus 67%; P=.01), LDL-C (69% versus 55%; P=.009), blood pressure (86% versus 79%; P=.08), microalbuminuria (40% versus 30%; P=.05), smoking status assessment (43% versus 31%; P=.02), and foot exams (38% versus 20%; P=.0005). Intervention patients had more planned general medicine visits (7.9+/-6.2 versus 6.2+/-5.7; P=.006) than did control patients. Interprofessional learners rated themselves significantly higher on measures of accomplishment, preparation, and success for chronic care than did the usual care learners. CONCLUSIONS: Interprofessional team care by learners was effective in improving quality of care for adult patients with diabetes treated in general medicine clinics. The chronic illness framework resulted in more appropriate health care utilization.

Individualized asthma self-management improves medication adherence and markers of asthma control.

BACKGROUND: Adherence to inhaled anti-inflammatory therapy and self-management skills are essential parts of the asthma treatment plan to improve asthma control and prevent exacerbations. Whether self-management education improves long-term medication adherence is less clear. OBJECTIVE: A 24-week prospective, randomized controlled trial was performed to study the effect of self-management education on long-term adherence to inhaled corticosteroid (ICS) therapy and markers of asthma control. METHODS: After stabilization on ICS medication during a run-in phase, 95 adults with moderate-to-severe asthma were recruited from a large metropolitan community, and 84 were randomized to individualized self-management education, including self-monitoring of symptoms and peak flow or usual care with self-monitoring alone. The key components of the 30-minute intervention were asthma information, assessment, and correction of inhaler technique; an individualized action plan based on self-monitoring data; and environmental control strategies for relevant allergen and irritant exposures. The intervention was personalized based on pulmonary function, allergen skin test reactivity, and inhaler technique and reinforced at 2-week intervals. RESULTS: Participants randomized to the self-management intervention maintained consistently higher ICS adherence levels and showed a 9-fold greater odds of more than 60% adherence to the prescribed dose compared with control subjects at the end of the intervention (P = .02) and maintained a 3-fold greater odds of higher than 60% adherence at the end of the study. Perceived control of asthma improved (P = .006), nighttime awakenings decreased (P = .03), and inhaled beta-agonist use decreased (P = .01) in intervention participants compared with control subjects. CONCLUSION: Our results show that individualized asthma self-management education attenuates the usual decrease in medication adherence and improves clinical markers of asthma control.