The association between the interpregnancy interval and autism spectrum disorder in a Canadian cohort.

OBJECTIVES: Two studies reported an increased risk of autistic disorder in children conceived less than 12 months after a previous birth. Our objective was to examine the association between the interpregnancy interval (IPI) and autism spectrum disorder (ASD) in a Canadian cohort. METHODS: Using administrative datasets housed at the Manitoba Centre for Health Policy, we identified pairs of first- and second-born singleton siblings born between 1988 and 2005. Diagnoses of ASD were ascertained by searching physician billing claims, hospital discharge abstracts, education data, and a database containing information on individuals identified for a 2002-2007 ASD surveillance program in Manitoba. Logistic regression models were fit to examine the association between the IPI and ASD in 41,050 second-born siblings where the first-borns did not have ASD, using IPIs of ≥ 36 months as the reference category and specifying three case groups. Case Group 1 included individuals with at least one ASD code (n = 490); Case Group 2 included those with two or more ASD codes (n = 375); and Case Group 3 comprised individuals with a record in the ASD surveillance program database (n = 141). RESULTS: The adjusted odds ratios (ORs) for IPIs shorter than 12 months ranged from 1.22 (95% CI: 0.91-1.63) for Case Group 1 to 1.72 (95% CI: 0.96-3.06) for Case Group 3. When the case groups were restricted to individuals with more severe ASD, the ORs increased and were significant for Case Groups 1 and 2. CONCLUSION: Our findings also support an association between short IPIs and more severe ASD.

Components of the COPD Assessment Test (CAT) associated with a diagnosis of COPD in a random population sample.

The aim of this study was to determine if components of the COPD Assessment Test (CAT), a validated health status impairment instrument, had additional utility in identifying patients at risk for COPD in whom spirometry testing is appropriate. This study was part of the Canadian Obstructive Lung Disease prevalence study. Consenting participants ≥ 40 years of age were identified by random digit dialing. Smoking history, 8-item CAT scores, and post-bronchodilator spirometry were recorded for each. Stepwise logistic regression analysis was used to identify variables related to the presence of airway obstruction and a final logistic model was developed which best predicted COPD in this sample. Of the 801 individuals approached, 532 were included: 51 (9.6%) had COPD, the majority (92%) of whom fit GOLD I or II severity criteria. Items that correlated significantly with a COPD diagnosis included the CAT total score (p = 0.01) and its breathlessness (p < 0.0001) and phlegm (p = 0.001) components. The final logistic model included: age (<55 or ≥55 years), smoking status (current, former, never) and the CAT breathlessness score (ordinal scale 0-5). The area under the receiver-operating characteristic curve for this model was 0.77, sensitivity was 77.6%, specificity was 64.9% and the positive likelihood ratio was 2.21. In summary, the triad of smoking history, age at least 55 years and the presence of exertional breathlessness were key elements of a simple model which had reliable measurement properties when tested in a random population. This may help identify patients at risk for COPD for whom spirometry testing is recommended.

Effects of BMI on static lung volumes in patients with airway obstruction.

BACKGROUND: Both chronic airway obstruction and obesity are increasing in prevalence but the effect of their combination on pulmonary function parameters across the range of airway obstruction is unknown. METHODS: We studied the impact of increasing BMI on static lung volumes and airway function in a cohort of 2,265 subjects from a large pulmonary function laboratory database who were 40 to 80 years of age and met GOLD (Global Initiative for Chronic Obstructive Lung Disease) spirometric criteria for COPD (postbronchodilator FEV1/FVC < 0.7). We also evaluated the influence of severity of airway obstruction (by GOLD criteria) on these relationships. RESULTS: With increasing BMI in the group as a whole, functional residual capacity, residual volume, expiratory reserve volume, and specific airway resistance (sRaw) decreased exponentially (all P < .001); total lung capacity (TLC) decreased linearly (P < .001); and inspiratory capacity (IC) and IC/TLC increased linearly (P < .001). However, vital capacity was not influenced significantly. The effects of increasing BMI on FEV1/FVC and sRaw were greatest in GOLD stage III/IV (P < .05), whereas increasing BMI had greater effects on IC in GOLD stage I (P < .001). CONCLUSIONS: With increasing BMI, subjects with airway obstruction had consistent reductions in lung hyperinflation, with significant improvements in IC and the FEV1/FVC ratio; this effect was greatest in patients with the most severe airway obstruction. These results have important implications for the clinical assessment of patients with combined obesity and airway obstruction.

Lung hyperinflation and its reversibility in patients with airway obstruction of varying severity.

The natural history of lung hyperinflation in patients with airway obstruction is unknown. In particular, little information exists about the extent of air trapping and its reversibility to bronchodilator therapy in those with mild airway obstruction. We completed a retrospective analysis of data from individuals with airway obstruction who attended our pulmonary function laboratory and had plethysmographic lung volume measurements pre- and post-bronchodilator (salbutamol). COPD was likely the predominant diagnosis but patients with asthma may have been included. We studied 2,265 subjects (61% male), age 65 ± 9 years (mean ± SD) with a post-bronchodilator FEV(1)/FVC <0.70. We examined relationships between indices of airway obstruction and lung hyperinflation, and measured responses to bronchodilation across subgroups stratified by GOLD criteria. In GOLD stage I, vital capacity (VC) and inspiratory capacity (IC) were in the normal range; pre-bronchodilator residual volume (RV), functional residual capacity (FRC) and specific airway resistance were increased to 135%, 119% and 250% of predicted, respectively. For the group as a whole, RV and FRC increased exponentially as FEV(1) decreased, while VC and IC decreased linearly. Regardless of baseline FEV(1), the most consistent improvement following bronchodilation was RV reduction, in terms of magnitude and responder rate. In conclusion, increases (above normal) in airway resistance and plethysmographic lung volumes were found in those with only minor airway obstruction. Indices of lung hyperinflation increased exponentially as airway obstruction worsened. Those with the greatest resting lung hyperinflation showed the largest bronchodilator-induced volume deflation effects. Reduced air trapping was the predominant response to acute bronchodilation across severity subgroups.

Effects of obesity on perceptual and mechanical responses to bronchoconstriction in asthma.

RATIONALE: The influence of obesity on the perception of respiratory discomfort during acute bronchoconstriction in asthma is unknown. OBJECTIVES: We hypothesized that the respiratory impairment associated with an increased body mass index (BMI) would predispose to greater perceived symptom intensity during acute airway narrowing. We therefore compared relationships between induced changes in dyspnea intensity and lung function during methacholine (MCh) bronchoprovocation in obese (OBA) and normal-weight (NWA) individuals with asthma of mild to moderate severity. METHODS: High-dose MCh challenge tests to a maximum 50% decrease in FEV(1) were conducted in 51 NWA (BMI, 18.5-24.9 kg/m(2); 29% male) and 45 OBA (BMI, 30.1-51.4 kg/m(2); 33% male) between 20 and 60 years of age. Serial spirometry, inspiratory capacity (IC), plethysmographic end-expiratory lung volume (EELV) and dyspnea intensity using the Borg scale were measured throughout bronchoprovocation. MEASUREMENTS AND MAIN RESULTS: Spirometry and airway sensitivity were similar in both groups; baseline EELV was lower (P < 0.0005) and IC was higher (P = 0.007) in OBA compared with NWA. From baseline to PC(20), EELV increased more in OBA (20% predicted) than NWA (13% predicted) (P = 0.008) with concomitant greater reductions in IC (P < 0.0005). Dyspnea ratings were not different for a given FEV(1) or IC across groups. By mixed effects regression analysis, relationships between induced dyspnea and changes in lung function parameters were not influenced by BMI, sex, or their interaction. CONCLUSIONS: Perceptual responses to MCh-induced bronchoconstriction and lung hyperinflation were similar in obese and normal-weight individuals with asthma despite significant group differences in baseline lung volumes.

Sex differences in the perceived intensity of breathlessness during exercise with advancing age.

The prevalence of activity-related breathlessness increases with age, particularly in women, but the specific underlying mechanisms have not been studied. This novel cross-sectional study was undertaken to examine the effects of age and sex, and their interaction, on the perceptual and ventilatory responses to incremental treadmill exercise in 73 healthy participants (age range 40-80 yr old) with normal pulmonary function. Age-related changes at a standardized oxygen uptake (Vo(2)) during exercise included significant increases in breathlessness ratings (Borg scale), ventilation (Ve), ventilatory equivalent for carbon dioxide, and the ratio of tidal volume (Vt) to dynamic inspiratory capacity (IC) (all P < 0.05). These changes were quantitatively similar in women (n = 39) and in men (n = 34). For the group as a whole, exertional breathlessness ratings increased as resting static inspiratory muscle strength diminished (P = 0.05), as exercise ventilation increased relative to capacity (P = 0.013) and as the Vt/IC ratio increased (P = 0.003) during exercise. Older women (60-80 yr old, n = 23) reported greater (P < 0.05) intensity of exertional breathlessness at a standardized Vo(2) and Ve than age-matched men (n = 16), despite similar age-related changes in ventilatory demand and dynamic ventilatory mechanics. These increases in breathlessness ratings in older women disappeared when sex differences in baseline maximal ventilatory capacity were accounted for. In conclusion, although increased exertional breathlessness with advancing age is multifactorial, contributory factors included higher ventilatory requirements during exercise, progressive inspiratory muscle weakness, and restrictive mechanical constraints on Vt expansion related to reduced IC. The sensory consequences of this age-related respiratory impairment were more pronounced in women, who, by nature, have relatively reduced maximal ventilatory reserve.

Physiological mechanisms of hyperventilation during human pregnancy.

This study examined the role of pregnancy-induced changes in wakefulness (or non-chemoreflex) and central chemoreflex drives to breathe, acid-base balance and female sex hormones in the hyperventilation of human pregnancy. Thirty-five healthy women were studied in the third trimester (TM(3); 36.3+/-1.0 weeks gestation; mean+/-S.D.) and again 20.2+/-7.8 weeks post-partum (PP). An iso-oxic hyperoxic rebreathing procedure was used to evaluate wakefulness and central chemoreflex drives to breathe. At rest, arterialized venous blood was obtained for the estimation of arterial PCO(2) (PaCO(2)) and [H(+)]. Blood for the determination of plasma strong ion difference ([SID]), albumin ([Alb]), as well as serum progesterone ([P(4)]) and 17beta-estradiol ([E(2)]) concentrations was also obtained at rest. Wakefulness and central chemoreflex drives to breathe, [P(4)] and [E(2)], ventilation and V CO(2) increased, whereas PaCO(2) and the central chemoreflex ventilatory recruitment threshold for PCO(2) (VRTCO(2)) decreased from PP to TM(3) (all p<0.01). The reductions in PaCO(2) were not related to the increases in [P(4)] and [E(2)]. The alkalinizing effects of reductions in PaCO(2) and [Alb] were partly offset by the acidifying effects of a reduced [SID], such that arterial [H(+)] was still reduced in TM(3) vs. PP (all p<0.001). A mathematical model of ventilatory control demonstrated that pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, V CO(2) and cerebral blood flow account for the reductions in PaCO(2), [H(+)] and VRTCO(2). This is the first study to demonstrate that the hyperventilation and attendant hypocapnia/alkalosis of human pregnancy results from a complex interaction of pregnancy-induced changes in wakefulness and central chemoreflex drives to breathe, acid-base balance, metabolic rate and cerebral blood flow.

Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease.

RATIONALE: Smokers with a relatively preserved FEV(1) may experience dyspnea and activity limitation but little is known about underlying mechanisms. OBJECTIVES: To examine ventilatory constraints during exercise in symptomatic smokers with GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage I chronic obstructive lung disease (COPD) so as to uncover potential mechanisms of dyspnea and exercise curtailment. METHODS: We compared resting pulmonary function and ventilatory responses (breathing pattern, operating lung volumes, pulmonary gas exchange) with incremental cycle exercise as well as Borg scale ratings of dyspnea intensity in 21 patients (post-bronchodilator FEV(1), 91 +/- 7% predicted, and FEV(1)/FVC, 60 +/- 6%; mean +/- SD) with significant breathlessness and 21 healthy age- and sex-matched control subjects with normal spirometry. MEASUREMENTS AND MAIN RESULTS: In patients with COPD compared with control subjects, peak oxygen consumption and power output were significantly reduced by more than 20% and dyspnea ratings were higher for a given work rate and ventilation (P < 0.05). Compared with the control group, the COPD group had evidence of extensive small airway dysfunction with increased ventilatory requirements during exercise, likely on the basis of greater ventilation/perfusion abnormalities. Changes in end-expiratory lung volume during exercise were greater in COPD than in health (0.54 +/- 0.34 vs. 0.06 +/- 0.32 L, respectively; P < 0.05) and breathing pattern was correspondingly more shallow and rapid. Across groups, dyspnea intensity increased as ventilation expressed as a percentage of capacity increased (P < 0.0005) and as inspiratory reserve volume decreased (P < 0.0005). CONCLUSIONS: Exertional dyspnea in symptomatic patients with mild COPD is associated with the combined deleterious effects of higher ventilatory demand and abnormal dynamic ventilatory mechanics, both of which are potentially amenable to treatment.