Mihaela Teodorescu

Body mass index and phenotype in subjects with mild- to-moderate persistent asthma

BACKGROUND Although obesity has been hypothesized to worsen asthma, data from studies of subjects with well-characterized asthma are lacking. OBJECTIVE We sought to evaluate the relationship between body mass index (BMI), asthma impairment, and response to therapy. METHODS BMI (in kilograms per meter squared) and asthma phenotypic and treatment response data were extracted from Asthma Clinical Research Network studies. The cross-sectional relationship between BMI and asthma impairment was analyzed, as was the longitudinal relationship between BMI and response to asthma controller therapies. RESULTS One thousand two hundred sixty-five subjects with mild-to-moderate persistent asthma were evaluated. Analyses of lean versus overweight/obese asthmatic subjects demonstrated small differences in FEV1 (3.05 vs 2.91 L, P = .001), FEV1/forced vital capacity ratio (mean, 83.5% vs 82.4%; P = .01), rescue albuterol use (1.1 vs 1.2 puffs per day, P = .03), and asthma-related quality of life (5.77 vs 5.59, P = .0004). Overweight/obese asthmatic subjects demonstrated a smaller improvement in exhaled nitric oxide levels with inhaled corticosteroid (ICS) treatment than did lean asthmatic subjects (3.6 vs 6.5 ppb, P = .04). With ICS/long-acting beta-agonist treatment, overweight/obese asthmatic subjects demonstrated smaller improvements in lung function than lean asthmatic subjects, with an 80 mL (P = .04) and 1.7% (P = .02) lesser improvement in FEV1 and FEV1/forced vital capacity ratio, respectively. Significant differences in therapeutic response to leukotriene modifiers between BMI categories were not observed. CONCLUSIONS Increased BMI is not associated with clinically significant worsening of impairment in subjects with mild-to-moderate persistent asthma. There is a modest association between increased BMI and reduced therapeutic effect of ICS-containing regimens in this patient population. Prospective studies evaluating the effect of being overweight or obese on treatment response in asthma are warranted.

Association of Obstructive Sleep Apnea Risk With Asthma Control in Adults

BACKGROUND Unrecognized obstructive sleep apnea (OSA) may lead to poor asthma control despite optimal therapy. Our objective was to evaluate the relationship between OSA risk and asthma control in adults. METHODS Patients with asthma seen routinely at tertiary-care clinic visits completed the validated Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ) and Asthma Control Questionnaire (ACQ). An ACQ score of >or= 1.5 defined not-well-controlled asthma, and an SA-SDQ score of >or= 36 for men and >or= 32 for women defined high OSA risk. Logistic regression was used to model associations of high OSA risk with not-well-controlled asthma (ACQ full version and short versions). RESULTS Among 472 subjects with asthma, the mean +/- SD ACQ (full version) score was 0.87 +/- 0.90, and 80 (17%) subjects were not well controlled. Mean SA-SDQ score was 27 +/- 7, and 109 (23%) subjects met the definition of high OSA risk. High OSA risk was associated, on average, with 2.87-times higher odds for not-well-controlled asthma (ACQ full version) (95% CI, 1.54-5.32; P = .0009) after adjusting for obesity and other factors known to worsen asthma control. Similar independent associations were seen when using the short ACQ versions. CONCLUSIONS High OSA risk is significantly associated with not-well-controlled asthma independent of known asthma aggravators and regardless of the ACQ version used. Patients who have difficulty achieving adequate asthma control should be screened for OSA.

Predictors of Habitual Snoring and Obstructive Sleep Apnea Risk in Patients With Asthma

BACKGROUND A high prevalence of obstructive sleep apnea (OSA) symptoms was reported in patients with asthma. Our goal was to evaluate factors associated with habitual snoring and OSA risk in these patients. METHODS Patients with asthma were surveyed at specialty clinics with the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ) and questions about the frequency of asthma symptoms (National Asthma Education and Prevention Program guidelines), followed by medical record review. SA-SDQ scores >or= 36 for men and >or= 32 for women defined high OSA risk. Logistic regression was used to model associations with habitual snoring and high OSA risk. RESULTS Among 244 patients, 37% snored habitually and 40% demonstrated high OSA risk. Independent predictors of habitual snoring included gastroesophageal reflux disease (GERD) [odds ratio (OR), 2.19; 95% confidence interval (CI), 1.19 to 4.02] and use of an inhaled corticosteroid (ICS) [OR, 2.66; 95% CI, 1.05 to 6.72]. High OSA risk was predicted by asthma severity step (OR, 1.59; 95% CI, 1.23 to 2.06), GERD (OR, 2.70; 95% CI, 1.51 to 4.83), and ICS use (OR, 4.05; 95% CI, 1.56 to 10.53). Linear, dose-dependent relationships of ICS with habitual snoring and high OSA risk were seen (p = 0.004 and p = 0.0006, respectively). Women demonstrated a 2.11 times greater odds for high OSA risk (95% CI, 1.10 to 4.09) when controlling for the above covariates. CONCLUSIONS Symptoms of OSA in patients with asthma are predicted by asthma severity, coexistent GERD, and use of an ICS in a dose-dependent fashion. The well-recognized male gender predominance for OSA symptoms is not apparent in these patients. Further exploration of these relationships may help to explain the increased prevalence of OSA in asthma and provide new insights into the reported female predominance of asthma morbidity.

Role of Central/Peripheral Chemoreceptors and Their Interdependence in the Pathophysiology of Sleep Apnea

Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO(2)) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea.

Objective Measures of Disordered Sleep in Fibromyalgia

Objective. Patients with fibromyalgia syndrome (FM) complain of inadequate sleep, which could contribute to common symptoms including sleepiness, fatigue, or pain. However, measures that consistently and objectively distinguish FM patients remain elusive. Methods. Fifteen women with FM and 15 age- and gender-matched controls underwent 3 nights of polysomnography; Multiple Sleep Latency Tests to assess sleepiness; testing of auditory arousal thresholds during non-REM stage 2 and stage 4 sleep; overnight assessment of urinary free cortisol; and analysis of 24-hour heart rate variability. Results. On the second night of polysomnography, women with FM in comparison to controls showed more stage shifts (p = 0.04) but did not differ significantly on any other standard polysomnographic measure or on the Multiple Sleep Latency Tests. Alpha EEG power during deep non-REM sleep, alone or as a proportion of alpha power during remaining sleep stages, also failed to distinguish the groups, as did auditory arousal thresholds. Urinary free cortisol did not differ between FM and control subjects in a consistent manner. However, decreased short-term heart rate variability (HRV) and especially ratio-based HRV among FM subjects suggested diminished parasympathetic and increased sympathetic activity, respectively. Other HRV measures suggested decreased complexity of HRV among the FM subjects. Conclusion. Standard measures of sleep, a gold-standard measure of sleepiness, quantified alpha-delta EEG power, auditory arousal thresholds, and urinary free cortisol largely failed to distinguish FM and control subjects. However, HRV analyses showed more promise, as they suggested both increased sympathetic activity and decreased complexity of autonomic nervous system function in FM.

Association Between Asthma and Risk of Developing Obstructive Sleep Apnea

IMPORTANCE Obstructive sleep apnea (OSA) is more common among patients with asthma; whether asthma is associated with the development of OSA is unknown. OBJECTIVE To examine the prospective relationship of asthma with incident OSA. DESIGN, SETTING, AND PARTICIPANTS Population-based prospective epidemiologic study (the Wisconsin Sleep Cohort Study) beginning in 1988. Adult participants were recruited from a random sample of Wisconsin state employees to attend overnight polysomnography studies at 4-year intervals. Asthma and covariate information were assessed during polysomnography studies through March 2013. Eligible participants were identified as free of OSA (apnea-hypopnea index [AHI] of <5 events/h and not treated) by 2 baseline polysomnography studies. There were 1105 4-year follow-up intervals provided by 547 participants (52% women; mean [SD] baseline age, 50 [8] years). EXPOSURES Questionnaire-assessed presence and duration of self-reported physician-diagnosed asthma. MAIN OUTCOMES AND MEASURES The associations of presence and duration of asthma with 4-year incidences of both OSA (AHI of ≥5 or positive airway pressure treatment) and OSA concomitant with habitual daytime sleepiness were estimated using repeated-measures Poisson regression, adjusting for confounders. RESULTS Twenty-two of 81 participants (27% [95% CI, 17%-37%]) with asthma experienced incident OSA over their first observed 4-year follow-up interval compared with 75 of 466 participants (16% [95% CI, 13%-19%]) without asthma. Using all 4-year intervals, participants with asthma experienced 45 cases of incident OSA during 167 4-year intervals (27% [95% CI, 20%-34%]) and participants without asthma experienced 160 cases of incident OSA during 938 4-year intervals (17% [95% CI, 15%-19%]); the corresponding adjusted relative risk (RR) was 1.39 (95% CI, 1.06-1.82), controlling for sex, age, baseline and change in body mass index, and other factors. Asthma was also associated with new-onset OSA with habitual sleepiness (RR, 2.72 [95% CI, 1.26-5.89], P = .045). Asthma duration was related to both incident OSA (RR, 1.07 per 5-year increment in asthma duration [95% CI, 1.02-1.13], P = .01) and incident OSA with habitual sleepiness (RR, 1.18 [95% CI, 1.07-1.31], P = .02). CONCLUSIONS AND RELEVANCE Asthma was associated with an increased risk of new-onset OSA. Studies investigating the mechanisms underlying this association and the value of periodic OSA evaluation in patients with asthma are warranted.

Sleep quality and asthma control and quality of life in non-severe and severe asthma.

PurposeThe effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma.MethodsCross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded.ResultsBoth SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p = 0.02). The majority (88–100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates.ConclusionsThese results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances.

Effects of stabilizing or increasing respiratory motor outputs on obstructive sleep apnea

To determine how the obstructive sleep apnea (OSA) patients pathophysiological traits predict the success of the treatment aimed at stabilization or increase in respiratory motor outputs, we studied 26 newly diagnosed OSA patients [apnea-hypopnea index (AHI) 42 ± 5 events/h with 92% of apneas obstructive] who were treated with O2 supplementation, an isocapnic rebreathing system in which CO2 was added only during hyperpnea to prevent transient hypocapnia, and a continuous rebreathing system. We also measured each patients controller gain below eupnea [change in minute volume/change in end-tidal Pco2 (ΔVe/ΔPetCO2)], CO2 reserve (eupnea-apnea threshold PetCO2), and plant gain (ΔPetCO2/ΔVe), as well as passive upper airway closing pressure (Pcrit). With isocapnic rebreathing, 14/26 reduced their AHI to 31 ± 6% of control (P < 0.01) (responder); 12/26 did not show significant change (nonresponder). The responders vs. nonresponders had a greater controller gain (6.5 ± 1.7 vs. 2.1 ± 0.2 l·min(-1)·mmHg(-1), P < 0.01) and a smaller CO2 reserve (1.9 ± 0.3 vs. 4.3 ± 0.4 mmHg, P < 0.01) with no differences in Pcrit (-0.1 ± 1.2 vs. 0.2 ± 0.9 cmH2O, P > 0.05). Hypercapnic rebreathing (+4.2 ± 1 mmHg PetCO2) reduced AHI to 15 ± 4% of control (P < 0.001) in 17/21 subjects with a wide range of CO2 reserve. Hyperoxia (SaO2 ∼95-98%) reduced AHI to 36 ± 11% of control in 7/19 OSA patients tested. We concluded that stabilizing central respiratory motor output via prevention of transient hypocapnia prevents most OSA in selected patients with a high chemosensitivity and a collapsible upper airway, whereas increasing respiratory motor output via moderate hypercapnia eliminates OSA in most patients with a wider range of chemosensitivity and CO2 reserve. Reducing chemosensitivity via hyperoxia had a limited and unpredictable effect on OSA.

Association of Obstructive Sleep Apnea Risk or Diagnosis with Daytime Asthma in Adults

Objective. Obstructive sleep apnea (OSA) worsens nocturnal asthma, but its potential impact on daytime asthma remains largely unassessed. We investigated whether the sleep disorder is associated with daytime, in addition to nighttime, asthma symptoms. Methods. Asthma patients at tertiary-care centers completed the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ), and an asthma control questionnaire. SA-SDQ scores ≥36 for males and ≥32 for females defined high OSA risk. Medical records were reviewed for established diagnosis of OSA and continuous positive airway pressure (CPAP) use. Results. Among 752 asthma patients, high OSA risk was associated similarly with persistent daytime and nighttime asthma symptoms (p < .0001 for each). A diagnosis of OSA was robustly associated with persistent daytime (p < .0001) in addition to nighttime (p = .0008) asthma symptoms. In regression models that included obesity and other known asthma aggravators, high OSA risk retained associations with persistent daytime (odds ratio [OR] = 1.96 [95% confidence interval [CI] = 1.31–2.94]) and nighttime (1.97 [1.32–2.94]) asthma symptoms. Diagnosed OSA retained an association with persistent daytime (2.08 [1.13–3.82]) but not with nighttime (1.48 [0.82–2.69]) asthma symptoms. CPAP use was associated with lower likelihood of persistent daytime symptoms (0.46 [0.23–0.94]). Conclusions. Questionnaire-defined OSA risk and historical diagnosis were each associated with persistent daytime asthma symptoms, to an extent that matched or exceeded associations with nighttime asthma symptoms. Unrecognized OSA may be a reason for persistent asthma symptoms during the day as well as the night.

Integrating the overlap of obstructive lung disease and obstructive sleep apnoea: OLDOSA syndrome

Obstructive lung diseases (OLD) such as asthma and chronic obstructive pulmonary disease (COPD) are very prevalent conditions. Disease phenotypes (e.g. chronic bronchitis, emphysema, etc.) often overlap, and significant confusion exists about their optimal nosologic characterization. Obstructive sleep apnoea (OSA) is also a common condition that features bidirectional interactions with OLD. OSA appears to be more commonly seen in patients with OLD, perhaps as a result of shared risk factors, for example obesity, smoking, increased airway resistance, local and systemic inflammation, anti‐inflammatory therapy. Conversely, OSA is associated with worse clinical outcomes in patients with OLD, and continuous positive airway pressure therapy has potential beneficial effects on this vicious pathophysiological interaction. Possible shared mechanistic links include increased parasympathetic tone, hypoxaemia‐related reflex bronchoconstriction/vasoconstriction, irritation of upper airway neural receptors, altered nocturnal neurohormonal secretion, pro‐inflammatory mediators, within and inter‐breath interactions between upper and lower airways, lung volume‐airway dependence, etc. While the term overlap syndrome has been defined as the comorbid association of COPD and OSA, the interaction between asthma and OSA has not been integrated yet nosologically; in this review, the latter will be called alternative overlap syndrome. In an effort to bolster further investigations in this area, an integrated, lumping nomenclature for OSA in the setting of OLD is proposed here—OLDOSA (obstructive lung disease and obstructive sleep apnoea) syndrome.