Agitated depression in bipolar disorder.

OBJECTIVES: It has been suggested that agitated depression (AD) is a common, severe feature in bipolar disorder. We aimed to estimate the prevalence of AD and investigate whether presence of AD was associated with episodic and lifetime clinical features in a large well-characterized bipolar disorder sample. METHOD: The prevalence of agitation, based on semi-structured interview and medical case-notes, in the most severe depressive episode was estimated in 2925 individuals with DSM-IV bipolar disorder recruited into the UK Bipolar Disorder Research Network. Predictors of agitation were ascertained using symptoms within the same episode and lifetime clinical features using multivariate models. RESULTS: 32.3% (n = 946) experienced agitation during the worst depressive episode. Within the same episode, significant predictors of presence of agitation were: insomnia (OR 2.119, P < 0.001), poor concentration (OR 1.966, P = 0.027), decreased libido (OR 1.960, P < 0.001), suicidal ideation (OR 1.861, P < 0.001), slowed activity (OR 1.504, P = 0.001), and poor appetite (OR 1.297, P = 0.029). Over the lifetime illness course, co-morbid panic disorder (OR 2.000, P < 0.001), suicide attempt (OR 1.399, P = 0.007), and dysphoric mania (OR 1.354, P = 0.017) were significantly associated with AD. CONCLUSIONS: Agitation accompanied bipolar depression in at least one-third of cases in our sample and was associated with concurrent somatic depressive symptoms, which are also common features of mixed manic states. Furthermore, AD in our sample was associated with lifetime experience of mixed mania, in addition to severe lifetime illness course including comorbid panic disorder and suicidal behavior. Our results have implications for the diagnosis and treatment of agitated features in bipolar depression.

Stratification of the risk of bipolar disorder recurrences in pregnancy and postpartum.

BACKGROUND: Pregnancy and childbirth are a period of high risk for women with bipolar disorder and involve difficult decisions particularly about continuing or stopping medications.AimsTo explore what clinical predictors may help to individualise the risk of perinatal recurrence in women with bipolar disorder. METHOD: Information was gathered retrospectively by semi-structured interview, questionnaires and case-note review from 887 women with bipolar disorder who have had children. Clinical predictors were selected using backwards stepwise logistic regression, conditional permutation random forests and reinforcement learning trees. RESULTS: Previous perinatal history of affective psychosis or depression was the most significant predictor of a perinatal recurrence (odds ratio (OR) = 8.5, 95% CI 5.04-14.82 and OR = 3.6, 95% CI 2.55-5.07 respectively) but even parous women with bipolar disorder without a previous perinatal mood episode were at risk following a subsequent pregnancy, with 7% developing postpartum psychosis. CONCLUSIONS: Previous perinatal history of affective psychosis or depression is the most important predictor of perinatal recurrence in women with bipolar disorder and can be used to individualise risk assessments.Declaration of interestNone.

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type.

Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10-5 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10-8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder.

Comorbid medical illness in bipolar disorder.

BACKGROUND: Individuals with a mental health disorder appear to be at increased risk of medical illness. AIMS: To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden. METHOD: Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria. RESULTS: We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset. CONCLUSIONS: Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.

In moderate-to-severe asthma patients monitoring exhaled nitric oxide during exacerbation is not a good predictor of spirometric response to oral corticosteroid.

BACKGROUND: The importance of monitoring exhaled nitric oxide (NO) in asthma remains controversial. OBJECTIVE: To measure exhaled NO, postnebulized albuterol/ipratropium spirometry, and Asthma Control Test (ACT) during asthma exacerbation requiring 8- to 10-day tapering oral corticosteroid in nonsmoking patients with moderate-to-severe asthma on moderate-dose inhaled corticosteroid and long-acting ß(2)-agonist but not maintenance oral corticosteroid. METHODS: After measuring the fraction of exhaled NO (Feno [ppb]) at 50, 100, 150, and 200 mL/s, the total Feno at 50 mL/s (ppb), large central airway NO flux (J'(awNO) [nL/s]), and peripheral small airway/alveolar NO concentration (C(ANO) [ppb]) were calculated and corrected for NO axial back-diffusion. Outpatient exacerbation required the patient with asthma to be afebrile with normal chest x-ray and white blood cell count. RESULTS: Group 1 included 17 patients (6 men) with asthma, age 52 ± 12 years, studied at baseline, during 18 exacerbations with abnormal Feno at 50 mL/s, J'(awNO), and/or C(ANO), and post 8- to 10-day tapering 40 mg prednisone (recovery). Baseline: IgE, 332 ± 243 Kµ; total blood eosinophils, 304 ± 266 cells/µL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV(1), 2.5 ± 0.7 L (86% ± 20% predicted); exacerbation: FEV(1), 1.7 ± 0.4 L (60% ± 17%) (P < .001); recovery: FEV(1), 2.5 ± 0.7 L (85% ± 13%) (P < .001). Group 2 included 11 (7 men) similarly treated patients with asthma, age 49 ± 14 years, studied at baseline, during 15 exacerbations with normal Feno at 50 mL/s, J'(awNO), and C(ANO). Baseline: IgE, 307 ± 133 Kµ; total blood eosinophils, 296 ± 149 cells/µL; body mass index, 28 ± 6; ACT, 16 to 19; and FEV(1), 2.7 ± 0.9 L (71% ± 12% predicted); exacerbation: FEV(1), 1.7 ± 0.6 L (54% ± 19%) (P< .006); recovery: FEV(1), 2.7 ± 0.9 L (70% ± 14%) (P= .002). On comparing group 1 versus group 2, there was no significant difference for baseline IgE, eosinophils, body mass index, and ACT and similar significant (≤.006) decrease from baseline in FEV(1) (L) during exacerbation and similar increase (≤.006) at recovery. CONCLUSIONS: Increased versus normal exhaled NO during outpatient exacerbation in patients with moderate-to-severe asthma on inhaled corticosteroid and long-acting ß(2)-agonist but not maintenance oral corticosteroid does not preclude a robust clinical and spirometric response to tapering oral prednisone.

Toward Shared Decision-Making in Degenerative Cervical Myelopathy: Protocol for a Mixed Methods Study.

BACKGROUND: Health care decisions are a critical determinant in the evolution of chronic illness. In shared decision-making (SDM), patients and clinicians work collaboratively to reach evidence-based health decisions that align with individual circumstances, values, and preferences. This personalized approach to clinical care likely has substantial benefits in the oversight of degenerative cervical myelopathy (DCM), a type of nontraumatic spinal cord injury. Its chronicity, heterogeneous clinical presentation, complex management, and variable disease course engenders an imperative for a patient-centric approach that accounts for each patient's unique needs and priorities. Inadequate patient knowledge about the condition and an incomplete understanding of the critical decision points that arise during the course of care currently hinder the fruitful participation of health care providers and patients in SDM. This study protocol presents the rationale for deploying SDM for DCM and delineates the groundwork required to achieve this. OBJECTIVE: The study's primary outcome is the development of a comprehensive checklist to be implemented upon diagnosis that provides patients with essential information necessary to support their informed decision-making. This is known as a core information set (CIS). The secondary outcome is the creation of a detailed process map that provides a diagrammatic representation of the global care workflows and cognitive processes involved in DCM care. Characterizing the critical decision points along a patient's journey will allow for an effective exploration of SDM tools for routine clinical practice to enhance patient-centered care and improve clinical outcomes. METHODS: Both CISs and process maps are coproduced iteratively through a collaborative process involving the input and consensus of key stakeholders. This will be facilitated by Myelopathy.org, a global DCM charity, through its Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy community. To develop the CIS, a 3-round, web-based Delphi process will be used, starting with a baseline list of information items derived from a recent scoping review of educational materials in DCM, patient interviews, and a qualitative survey of professionals. A priori criteria for achieving consensus are specified. The process map will be developed iteratively using semistructured interviews with patients and professionals and validated by key stakeholders. RESULTS: Recruitment for the Delphi consensus study began in April 2023. The pilot-testing of process map interview participants started simultaneously, with the formulation of an initial baseline map underway. CONCLUSIONS: This protocol marks the first attempt to provide a starting point for investigating SDM in DCM. The primary work centers on developing an educational tool for use in diagnosis to enable enhanced onward decision-making. The wider objective is to aid stakeholders in developing SDM tools by identifying critical decision junctures in DCM care. Through these approaches, we aim to provide an exhaustive launchpad for formulating SDM tools in the wider DCM community. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46809.

Normal Routine Spirometry Can Mask COPD/Emphysema in Symptomatic Smokers.

BACKGROUND: Recent studies have emphasized the difficulty of early detection of chronic obstructive pulmonary disease (COPD) in symptomatic smokers with normal routine spirometry. This includes post-bronchodilator normal forced expiratory volume in 1 second (FEV1)(L)≥80% predicted, forced vital capacity (FVC)(L)≥80% predicted, and FEV1/FVC ≥70% or greater than age corrected lower limit of normal (LLN). However, in COPD the pathologic site of small airway obstruction and emphysema begins in the small peripheral airways ≤2 mm id which normally contribute <20% of total airway resistance. METHODS: Expiratory airflow at high and low lung volumes post-bronchodilator were measured and correlated with lung computed tomography (CT) and lung pathology (6 patients) in 16 symptomatic, treated smokers, and all with normal routine spirometry. RESULTS: Despite normal routine spirometry, all16 patients had isolated, abnormal forced expiratory flow at 75% of FVC (FEF75) using data from Knudson et al, Hankinson et al NHAMES III, and Quanjer et al and the Global Lung Function Initiative. This reflects isolated detection of small airways obstruction and/or emphysema. Measuring airflow at FEF50 detected only 8 of 16 patients, maximal expiratory flow at 25%-75% of FVC (MEF25-75) only 4 of 16, residual volume (RV) 4 of 16, and RV to total lung capacity ratio only 2 of 16. There was excellent correlation between limited lung pathology and lung CT for absence of emphysema. CONCLUSION: This study confirms our earlier observations that detection of small airways obstruction and/or emphysema, in symptomatic smokers with normal routine spirometry, requires analysis of expiratory airflow at low lung volumes, including FEF75. Dependence upon normal routine spirometry may result in clinical and physiologic delay in the diagnosis and treatment in symptomatic smokers with emphysema and small airways obstruction.

Central and peripheral airway/alveolar sites of exhaled nitric oxide in acute asthma.

INTRODUCTION: Central airway nitric oxide flux (J'(awNO)) and peripheral airway/alveolar nitric oxide concentration (C(ANO)) during asthma exacerbation has not been investigated after correction for axial NO back-diffusion. METHODS: After measuring exhaled NO (fraction of exhaled nitric oxide (F(E)NO); ppb) at 50, 100, 150 and 200 ml/s, J'(awNO) (nl/s) and C(ANO) (ppb) were calculated using the two-compartment model and corrected for axial NO back-diffusion. Fifteen (8 males), non-smoking, patients with moderate-to-severe treated (inhaled corticosteroid (ICS) and inhaled long-acting beta(2)-agonist (LABA)) asthma, age 57+/-13 years (mean+/-SD), were studied at baseline, during exacerbation prior to oral corticosteroid, and during recovery after an 8 day tapering prednisone course. Based on earlier asthma studies without correction, it was hypothesised that with correction for NO axial back-diffusion, the incidence of abnormal J'(awNO) and C(ANO) at baseline and after exacerbation would be > or = 30% in 15 patients with asthma with 80% power. RESULTS: At baseline when clinically stable, after 180 microg of albuterol, forced expiratory volume in 1 s (FEV(1); litres) was 78+/-26% predicted (p=0.009) with increased F(E)NO at 50 ml/s (p=0.01) and J'(awNO) (p=0.02), but C(ANO) was normal compared with the controls. During exacerbation FEV(1) (litres) was 57+/-20% predicted (p=0.02), with increased F(E)NO at 50 ml/s (p=0.01) and J'(awNO) (p=0.004), but C(ANO) was normal. Recovery results were similar to baseline. Two of 15 patients with asthma always had normal exhaled NO gas exchange. CONCLUSIONS: The central airways were the major site of abnormal NO flux in 13 of 15 patients with moderate-severe asthma when stable and during exacerbation and could be easily detected with abnormal F(E)NO at 50 ml/s. C(ANO) was normal.

Electrical stimulation therapy increases rate of healing of pressure ulcers in community-dwelling people with spinal cord injury.

OBJECTIVE: To investigate whether electric stimulation therapy (EST) administered as part of a community-based, interdisciplinary wound care program accelerates healing of pressure ulcers in people with spinal cord injury (SCI). DESIGN: Single-blind, parallel-group, randomized, controlled, clinical trial. SETTING: Community-based home care setting, Ontario, Canada. PARTICIPANTS: Adults (N=34; mean age +/- SD, 51+/-14y) with SCI and stage II to IV pressure ulcers. INTERVENTIONS: Subjects were stratified based on wound severity and duration and randomly assigned to receive either a customized, community-based standard wound care (SWC) program that included pressure management or the wound care program plus high-voltage pulsed current applied to the wound bed (EST+SWC). MAIN OUTCOME MEASURES: Wound healing measured by reduction in wound size and improvement in wound appearance at 3 months of treatment with EST+SWC or SWC. RESULTS: The percentage decrease in wound surface area (WSA) at the end of the intervention period was significantly greater in the EST+SWC group (mean +/- SD, 70+/-25%) than in the SWC group (36+/-61%; P=.048). The proportion of stage III, IV, or X pressure ulcers improving by at least 50% WSA was significantly greater in the EST+SWC group than in the SWC group (P=.02). Wound appearance assessed using the photographic wound assessment tool was improved in wounds treated with EST+SWC but not SWC alone. CONCLUSIONS: These results demonstrate that EST can stimulate healing of pressure ulcers of people with SCI. EST can be incorporated successfully into an interdisciplinary wound care program in the community.

Variation at the GABAA receptor gene, Rho 1 (GABRR1) associated with susceptibility to bipolar schizoaffective disorder.

We have previously reported evidence that variation at GABA(A) receptor genes is associated with susceptibility to bipolar disorder with schizophrenia-like psychotic features (Research Diagnostic Criteria (RDC) schizoaffective disorder, bipolar type) with gene-wide significance at GABRB1, GABRA4, GABRB3, GABRA5, and GABRR3. Here we provide suggestive evidence implicating a sixth member of the gene family, GABRR1 (gene-wide P = 0.0058; experiment-wide corrected significance P = 0.052).

Adverse childhood experiences and postpartum depression in bipolar disorder.

BACKGROUND: Women are particularly vulnerable to recurrence of bipolar disorder (BD) following childbirth. Risk of postpartum psychosis (PP) is especially high, but postpartum depression (PPD) is also common. Adverse childhood experiences (ACEs) have not been associated with PP, but have been associated with PPD in non-bipolar samples. The relationship between ACEs and PPD within BD remains to be investigated. Here, we examined this association in a large, well-defined sample of women with BD. METHODS: Participants were 575 parous women with DSM-IV BD. Lifetime psychopathology, including perinatal, was assessed via semi-structured interview and case-notes. ACEs, assessed via self-report and case-notes, were compared between women with lifetime PPD (n = 368) and those without a lifetime history of perinatal mood episodes (n = 207). RESULTS: In univariate analysis exposure to 3 or more ACEs, and to childhood abuse specifically, was significantly associated with PPD (p = 0.026 and 0.041 respectively), but this did not remain significant after adjusting for lifetime number of episodes of depression and parity. Post-hoc analysis revealed more frequent episodes of depression to be associated with both a history of 3 or more ACEs and of childhood abuse. LIMITATIONS: Limited range of ACEs assessed and potential recall bias. CONCLUSIONS: Increased frequency of ACEs and particularly childhood abuse was associated with more frequent lifetime episodes of depression, but not specifically episodes with postpartum onset. Understanding factors that mediate the pathway between ACEs and PPD in BD has implications for risk prediction of PPD.

Symptom profile of postpartum and non-postpartum manic episodes in bipolar I disorder: a within-subjects study.

The relationship of postpartum mania to episodes of mania occurring outside the perinatal period among women with bipolar disorder remains controversial. Previous studies have used between-subjects designs to compare the clinical presentations of these episodes meaning the differences, in part, may reflect between-group differences. To overcome this we have undertaken within-subject comparisons of the symptom profile of postpartum and non-postpartum manic episodes in 50 women with DSM-IV bipolar I disorder. For each woman detailed symptom information on a postpartum episode of mania and a comparison non-postpartum manic episode was collected. The occurrence of manic, psychotic and depressive symptoms in these episodes were compared. Postpartum manic episodes had a significantly higher incidence of perplexity and excessive self-reproach. Classic manic symptoms, specifically pressured speech and increased sociability, were significantly less frequent in postpartum manic episodes. Overall there were significantly fewer manic symptoms and significantly more depressive symptoms in the postpartum episodes than in the non-postpartum episodes. The mixed presentation of postpartum manic episodes suggests childbirth may act as a pathoplastic trigger in women with bipolar disorder. The differences in symptom profiles suggests further research is warranted into whether differences in treatment response exist among women experiencing postpartum and non-postpartum manic episodes.

Polarity at illness onset in bipolar I disorder and clinical course of illness.

OBJECTIVES: Studies have suggested that episode polarity at illness onset in bipolar disorder may be predictive of some aspects of lifetime clinical characteristics. We here examine this possibility in a large, well-characterized sample of patients with bipolar I disorder. METHODS: We assessed polarity at onset in patients with bipolar I disorder (N = 553) recruited as part of our ongoing studies of affective disorders. Lifetime clinical characteristics of illness were compared in patients who had a depressive episode at first illness onset (n = 343) and patients who had a manic episode at first illness onset (n = 210). RESULTS: Several lifetime clinical features differed between patients according to the polarity of their onset episode of illness. A logistic regression analysis showed that the lifetime clinical features significantly associated with a depressive episode at illness onset in our sample were: an earlier age at illness onset; a predominantly depressive polarity during the lifetime; more frequent and more severe depressive episodes; and less prominent lifetime psychotic features. CONCLUSIONS: Knowledge of pole of onset may help the clinician in providing prognostic information and management advice to an individual with bipolar disorder.

Clinical characteristics of unipolar disorder and bipolar disorder according to the lifetime presence of recurrent panic attacks.

OBJECTIVES: The frequent comorbidity of panic and affective disorders has been described in previous studies. However, it is not clear how panic disorder comorbidity in unipolar disorder and bipolar disorder is related to illness course. METHODS: We compared lifetime clinical characteristics of illness and items of symptomatology in samples of individuals with bipolar I disorder (n = 290) and unipolar disorder (n = 335) according to the lifetime presence of recurrent panic attacks. RESULTS: We found significant differences in clinical course of illness characteristics that were shared across the unipolar and bipolar samples according to the lifetime presence of panic attacks. We also found a number of differences according to the presence of panic attacks that may be specific to the diagnostic group. CONCLUSIONS: Distinguishing patients who have mood disorder diagnoses, especially bipolar I disorder, according to the lifetime presence of panic attacks may not only be of use in clinical practice, but may also be informative for aetiological research, such as molecular genetic studies.

The unfolded protein response transducer Ire1p contains a nuclear localization sequence recognized by multiple beta importins.

The Ire1p transmembrane receptor kinase/endonuclease transduces the unfolded protein response (UPR) from the endoplasmic reticulum (ER) to the nucleus in Saccharomyces cerevisiae. In this study, we analyzed the capacity of a highly basic sequence in the linker region of Ire1p to function as a nuclear localization sequence (NLS) both in vivo and in vitro. This 18-residue sequence is capable of targeting green fluorescent protein to the nucleus of yeast cells in a process requiring proteins involved in the Ran GTPase cycle that facilitates nuclear import. Mutagenic analysis and importin binding studies demonstrate that the Ire1p linker region contains overlapping potential NLSs: at least one classical NLS (within sequences 642KKKRKR647 and/or 653KKGR656) that is recognized by yeast importin alpha (Kap60p) and a novel betaNLS (646KRGSRGGKKGRK657) that is recognized by several yeast importin beta homologues. Kinetic binding data suggest that binding to importin beta proteins would predominate in vivo. The UPR, and in particular ER stress-induced HAC1 mRNA splicing, is inhibited by point mutations in the Ire1p NLS that inhibit nuclear localization and also requires functional RanGAP and Ran GEF proteins. The NLS-dependent nuclear localization of Ire1p would thus seem to be central to its role in UPR signaling.

Predictive value of the quantitative fetal fibronectin levels for the management of women presenting with threatened preterm labour - A revised cut off level: A retrospective cohort study.

OBJECTIVE: To evaluate a new a cut off level of fetal fibronectin as a predictor of birth in women with threatened preterm labour. DESIGN: A retrospective cohort study performed at Ipswich hospital, Ipswich, Queensland, Australia, in women with threatened preterm labour with intact membranes between 23 weeks to 34 + 6 week gestation. STUDY DESIGN: A quantitative fetal fibronectin (fFN) was performed. Maternal demographics and birth outcome data were extracted from the routinely collected perinatal data held by the hospital. The odds of preterm birth were estimated for each cut off value of fFN (10, 50 and 200 ng ml-1) using logistic regression and accounting for multiple presentations by the same woman. RESULTS: Among the 447 presentations and 376 pregnancies, rates of preterm birth <34 weeks were 2.9%, 9.2%, 3.3%, 19.6%, 4.2% and 35.3% for each category of values respectively (fFN <10, ≥10, <50, ≥50, <200 and ≥200 ng ml-1). Birth rates within 7 d of testing were 1.1%, 7.5%, 1.8%, 16.1%, 2.1% and 41.2% respectively. Comparing fFN level of <10 to a level of 10-199 ng ml-1 there was no significant increase in odds of preterm birth < 34 weeks or birth within the next 7 d (OR 2.28, 95% CI 0.84-6.17 and OR 3.61, 95% CI 0.89-14.7 respectively. CONCLUSION: In women presenting with TPL, those with levels of <200 ng ml-1 have a low risk of birthing within 7 d or before 34 weeks gestation. This allows a personalised decision making and probable discharge home without need for steroid loading.

Further Studies of Unsuspected Emphysema in Nonsmoking Patients With Asthma With Persistent Expiratory Airflow Obstruction.

BACKGROUND: Previously, we and other investigators have described reversible loss of lung elastic recoil in patients with acute and persistent, moderate-to-severe, chronic, treated asthma who never smoked, and its adverse effect on maximal expiratory airflow. In four consecutive autopsies, we reported the pathophysiologic mechanism(s) has been unsuspected mild, diffuse, middle and upper lobe centrilobular emphysema. METHODS: We performed prospective studies (5 to 22 years) in 25 patients (12 female) with chronic asthma, age 55 ± 15 years, who never smoked, with persistent moderate-to-severe expiratory obstruction. Studies included measuring blood eosinophils, IgE, total exhaled nitric oxide (NO), central airway NO flux, peripheral airway/alveolar NO concentration, impulse oscillometry, heliox curves, lung elastic recoil, and high-resolution thin-section (1 mm) lung CT imaging at full inspiration with voxel quantification. RESULTS: In 25 patients with stable asthma with varying type 2 phenotype, after 270 µg of aerosolized albuterol sulfate had been administered with a metered dose inhaler with space chamber, FVC was 3.1 ± 1.0 L (83% ± 13% predicted) (mean ± SD), FEV1 was 1.8 ± 0.6 L (59% ± 11%), the FEV1/FVC ratio was 59% ± 10%, and the ratio of single-breath diffusing capacity of the lung for carbon monoxide to alveolar volume was 4.8 ± 1.1 mL/min/mm Hg/L (120% ± 26%). All 25 patients with asthma had loss of static lung elastic recoil pressure, which contributed equally to decreased intrinsic airway conductance in limiting expiratory airflow. Lung CT scanning detected none or mild emphysema. In all four autopsied asthmatic lungs previously reported and one unreported explanted lung, microscopy revealed unsuspected mild, diffuse centrilobular emphysema in the upper and middle lung fields, and asthma-related remodeling in airways. In eight cases, during asthma remission, there were increases in measured static lung elastic recoil pressure-calculated intrinsic airway conductance, and measured maximal expiratory airflow at effort-independent lung volumes. CONCLUSIONS: As documented now in five cases, unsuspected microscopic mild centrilobular emphysema is the sentinel cause of loss of lung elastic recoil. This contributes significantly to expiratory airflow obstruction in never-smoking patients with asthma, with normal diffusing capacity and near-normal lung CT scan results. TRIAL REGISTRY: Protocol No. 20070934 and Study No. 1090472, Western Institutional Review Board, Olympia, WA; ClinicalTrials.gov; No. NCT00576069; URL: www.clinicaltrials.gov.

Lack of protective effect of tiotropium vs induced dynamic hyperinflation in moderate COPD.

STUDY OBJECTIVE: Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation (DH) during metronome paced hyperventilation (MPH) in moderate COPD. METHODS: Prospective, randomized, double-blind, placebo control, crossover study. Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 (18 M) COPD patients (GOLD Stage 2) age 70±9 yr (mean ± SD) before and after 30 days of 18 µg tiotropium bromide vs placebo. Lung CT scored for emphysema (ES). RESULTS: At baseline post 180 µg aerosolized albuterol sulfate, FEV(1): 1.8±0.6 L (69±6% pred) and ≥60% predicted in all, and 14 of 29 had FEV(1) (L) ≥70% predicted with FEV(1)/FVC 58±8%. After 29 days + 23 h post tiotropium (trough) there was significant decrease only in FRC/TLC% (p=0.04); after 30 days + 2 h post tiotropium (peak) significant increase only in FEV(1) (L) (p=0.03) compared to placebo. Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L (p<0.001). Correlation between ES and increased FEV(1) (L) at peak tiotropium: r=0.19, p=0.96 and decreased FRC/TLC% at trough tiotropium: r=-0.26, p=0.36. CONCLUSION: In moderate COPD, tiotropium did not reduce MPH induced DH and reduction in IC. However, at peak tiotropium, there was significant bronchodilation in FEV(1) (L) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema.