Wendy Fergusson

Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial

BACKGROUND Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulatory properties. We tested the hypothesis that azithromycin would decrease the frequency of exacerbations, increase lung function, and improve health-related quality of life in patients with non-cystic fibrosis bronchiectasis. METHODS We undertook a randomised, double-blind, placebo-controlled trial at three centres in New Zealand. Between Feb 12, 2008, and Oct 15, 2009, we enrolled patients who were 18 years or older, had had at least one pulmonary exacerbation requiring antibiotic treatment in the past year, and had a diagnosis of bronchiectasis defined by high-resolution CT scan. We randomly assigned patients to receive 500 mg azithromycin or placebo three times a week for 6 months in a 1:1 ratio, with a permuted block size of six and sequential assignment stratified by centre. Participants, research assistants, and investigators were masked to treatment allocation. The coprimary endpoints were rate of event-based exacerbations in the 6-month treatment period, change in forced expiratory volume in 1 s (FEV(1)) before bronchodilation, and change in total score on St Georges respiratory questionnaire (SGRQ). Analyses were by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000641493. FINDINGS 71 patients were in the azithromycin group and 70 in the placebo group. The rate of event-based exacerbations was 0·59 per patient in the azithromycin group and 1·57 per patient in the placebo group in the 6-month treatment period (rate ratio 0·38, 95% CI 0·26-0·54; p<0·0001). Prebronchodilator FEV(1) did not change from baseline in the azithromycin group and decreased by 0·04 L in the placebo group, but the difference was not significant (0·04 L, 95% CI -0·03 to 0·12; p=0·251). Additionally, change in SGRQ total score did not differ between the azithromycin (-5·17 units) and placebo groups (-1·92 units; difference -3·25, 95% CI -7·21 to 0·72; p=0·108). INTERPRETATION Azithromycin is a new option for prevention of exacerbations in patients with non-cystic fibrosis bronchiectasis with a history of at least one exacerbation in the past year. FUNDING Health Research Council of New Zealand and Auckland District Health Board Charitable Trust.

Ambulatory oxygen improves quality of life of COPD patients: a randomised controlled study

It is unknown whether acute response to ambulatory oxygen (O2) predicts longer term improvement in health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients. The aims of this study were 1) to assess the short-term clinical impact, as determined by HRQL, of ambulatory O2 in a 12-week, double-blind, randomised crossover study of O2 (versus cylinder compressed air) of dyspnoeic but not chronically hypoxic COPD patients with exertional desaturation ≤88% (n=41), and 2) to determine whether either baseline characteristics or acute response to O2 predicts short-term (12 weeks) response. Primary outcome measures were Chronic Respiratory Questionnaire (CRQ), Hospital Anxiety and Depression scale and the short form (SF)-36. Improvements were seen in all domains of the CRQ for cylinder O2 compared with cylinder air. Significant improvements were also noted in anxiety and depression and in certain domains of the SF-36. There were 28 (68%) acute responders to cylinder O2 (defined as increase in 6‐min walk ≥54 m or decrease in post-Borg dyspnoea ≥1) and 23 (56%) short-term responders (defined as clinically significant improvement in CRQ). However, acute and short-term responses were not correlated with no predictors of short-term response identified. At study completion, 14 (41%) of acute or short-term responders did not want to continue therapy, with 11 citing poor acceptability or tolerability. Short-term ambulatory oxygen is associated with significant improvements in health-related quality of life. These benefits cannot be predicted by baseline characteristics or acute response. Despite acute or short-term response, a substantial proportion of patients declined ambulatory oxygen.

Case-control study of severe life threatening asthma (SLTA) in adults: psychological factors

Background: Severe life threatening asthma (SLTA) is important in its own right and as a proxy for asthma death. In order to target hospital based intervention strategies to those most likely to benefit, risk factors for SLTA among those admitted to hospital need to be identified. Adverse psychological factors are purported risk factors for asthma death and SLTA /near fatal asthma. A study was undertaken to determine whether, in comparison with patients admitted to hospital with acute asthma, those with SLTA have specific adverse psychological factors. Methods: A case-control study was undertaken. Cases (n=77) were admitted to the intensive care unit with SLTA (mean (SD) pH 7.17 (0.15), Paco2 10.7 (5.0) kPa). Controls (n=239) were admitted to general wards with acute asthma and were matched only by date of index attack. An interviewer administered questionnaire was undertaken 24–48 hours after admission. A random sample of community based asthmatics was recruited to provide normative data on asthmatics for comparison with cases and hospital controls. Results: The risk of SLTA increased with age (OR 1.04/year, 95% CI 1.01 to 1.07) and was less for women (OR 0.36, 95% CI 0.20 to 0.68). These variables were controlled for in all further analyses. There was a high prevalence of psychological disorder in both cases and matched controls, but there was no difference in prevalence of caseness for anxiety or depression, total (or individual) life events in last 12 months, availability of general or disease specific social support, nor in any of the domains of the Attitudes and Beliefs about Asthma Questionnaire (emotional (mal) adjustment, doctor-patient relationship, stigma, self-efficacy). Cases (SLTA) were less likely to have had previous emotional counselling (25% v 35%, p<0.05). However, when comparison was made with a community based group of asthmatic patients, those admitted to hospital with acute asthma (SLTA and hospital controls) had a higher prevalence of anxiety and depression, higher total life events, and higher prevalence of certain specific life events. Conclusions: There was considerable psychological morbidity generally (and anxiety specifically) in those admitted with acute asthma. Specific adverse psychological factors were not risk factors for SLTA, when comparison was made with those admitted to hospital with acute asthma, but adverse psychological factors were a risk factor for hospitalisation for acute asthma (including SLTA). Psychological risk factors for adverse events in asthma are dependent both on the type of event under study and the comparison group used.

Isolated nocturnal desaturation in COPD: prevalence and impact on quality of life and sleep

Background and aims: The clinical impact of nocturnal desaturation on health related quality of life (HRQL) and sleep in chronic obstructive pulmonary disease (COPD) has been little studied. The aim of this study was to evaluate the prevalence and clinical impact of nocturnal desaturation in a typical outpatient population with COPD. Patients and methods: Between 2002 and 2005, consecutive patients with COPD attending outpatient services at the study centre underwent resting oximetry if they were not on domiciliary oxygen therapy. If their resting saturations were less than 95%, overnight pulse oximetry was performed. Significant nocturnal desaturation was defined as spending more than 30% of at least one of two nights with a saturation of less than 90%. The Chronic Respiratory Questionnaire (CRQ) and Short Form 36 (SF36) were used to assess HRQL, and the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Score (ESS) and Functional Outcomes of Sleep (FOSQ) questionnaires were used to assess sleep quality and daytime function. Results: Of 1104 patients, 803 underwent resting oximetry and 79 had resting oxygen saturations of less than 95%. Of these, 59 agreed to undergo overnight oximetry (mean age 70 years, forced expiratory volume in 1 s 37.2% predicted, resting Po2 on air 8.9 kPa). Significant nocturnal desaturation was seen in 29 (49.2%) of the 59 subjects. Assuming the less hypoxic patients do not have nocturnal desaturation, the prevalence of nocturnal desaturation in the whole clinic population could be estimated at 4.8%. There were no significant differences in CRQ, SF36, PSQI, ESS or FOSQ scores for desaturators compared with non-desaturators. Conclusion: Significant nocturnal desaturation was common in patients with COPD with resting saturations of less than 95%, but was estimated to have a prevalence of less than 5% in the whole outpatient population. Nocturnal desaturation was not associated with impairment of HRQL, sleep quality or daytime function.

Does early pulmonary rehabilitation reduce acute health-care utilization in COPD patients admitted with an exacerbation? A randomized controlled study

Background and objective:  In COPD, hospital admissions and readmissions account for the majority of health‐care costs. The aim of this prospective randomized controlled study was to determine if early pulmonary rehabilitation, commenced as an inpatient and continued after discharge, reduced acute health‐care utilization.

Rapid onset asthma: a severe but uncommon manifestation

BACKGROUND Studies of asthma death and severe life threatening asthma (SLTA) include reports of patients who had rapid onset asthma. A study was undertaken to determine the relative frequency of rapid (<6 hours duration) and slow (⩾6 hours) onset attacks in patients admitted to hospital with acute severe asthma, and to establish whether those with rapid onset asthma differ in terms of risk factors for asthma morbidity and mortality such as indices of asthma severity/control, socioeconomic factors, health care, and psychological factors. METHODS A cross sectional study was performed on 316 patients aged 15–49 years admitted with acute severe asthma and interviewed within 24–48 hours of admission. RESULTS Patients underestimated the duration of the index attack. Only 27 (8.5%) were classified as rapid onset. There were more men in the rapid onset group than in the slow onset group (52% versus 26%), and there was evidence of socioeconomic advantage in the patients with rapid onset attacks. The rapid onset group had more previous episodes of SLTA and were more likely to present with SLTA, but there was no difference in length of stay in hospital. The rapid onset group were less likely to have presented to a GP during the index attack and were more likely to have used ambulance services. There was no difference between the groups in any psychological or health care measure. CONCLUSIONS Rapid onset attacks are an important but uncommon manifestation of asthma that are more likely to present with SLTA in patients who are more likely to have had previous SLTA. Male subjects are at increased risk of rapid onset attacks, and socioeconomic disadvantage, deficiencies in health care (ongoing and acute), and psychological factors are no more common in these patients than in those with attacks of slow onset. These data are consistent with the hypothesis that there is a small proportion of patients with rapid onset severe asthma who do not have the usual risk factors associated with asthma morbidity or mortality, and thus require different management strategies.

Case-control study of severe life threatening asthma (SLTA) in adults: demographics, health care, and management of the acute attack

BACKGROUND Severe life threatening asthma (SLTA) is important in its own right and as a proxy for asthma death. In order to target hospital based intervention strategies to those most likely to benefit, risk factors for SLTA among those admitted to hospital need to be identified. A case-control study was undertaken to determine whether, in comparison with patients admitted to hospital with acute asthma, those with SLTA have different sociodemographic and clinical characteristics, evidence of inadequate ongoing medical care, barriers to health care, or deficiencies in management of the acute attack. METHODS Seventy seven patients with SLTA were admitted to an intensive care unit (pH 7.17 (0.15), Paco 2 10.7 (5.0) kPa) and 239 matched controls (by date of index attack) with acute asthma were admitted to general medical wards. A questionnaire was administered 24–48 hours after admission. RESULTS The risk of SLTA in comparison with other patients admitted with acute asthma increased with age (odds ratio (OR) 1.04/year, 95% CI 1.01 to 1.07) and was less for women (OR 0.36, 95% CI 0.20 to 0.68). These variables were controlled for in all subsequent analyses. There were no differences in other sociodemographic features. Cases were more likely to have experienced a previous SLTA (OR 2.04, 95% CI 1.20 to 3.45) and to have had a hospital admission in the last year (OR 1.86, 95% CI 1.09 to 3.18). There were no differences between cases and controls in terms of indicators of quality of ongoing asthma specific medical care, nor was there evidence of disproportionate barriers to health care. During the index attack cases had more severe asthma at the time of presentation, were less likely to have presented to general practitioners, and were more likely to have called an ambulance or presented to an emergency department. In terms of pharmacological management, those with SLTA were more likely to have been using oral theophylline (OR 2.14, 95% CI 1.35 to 3.68) and less likely to have been using inhaled corticosteroids in the two weeks before the index attack (OR 0.69, 95% CI 0.47 to 0.99). While there was no difference in self-management knowledge or behaviour scores, those with SLTA were more likely to have inappropriately used oral corticosteroids during the acute attack (OR 2.09, 95% CI 1.02 to 4.47). CONCLUSIONS In comparison with those admitted to hospital with acute severe asthma, patients with SLTA were indistinguishable on sociodemographic criteria (apart from male predominance), were more likely to have had a previous SLTA or hospital admission in the previous year, had similar quality ongoing asthma care, had no evidence of increased physical, economic or other barriers to health care, but had demonstrable deficiencies in the management of the acute index attack. Educational interventions, while not losing sight of the need for good quality ongoing care, should focus on providing individual patients with better advice on self-management of acute exacerbations.

Normal adult values, diurnal variation, and repeatability of nasal nitric oxide measurement.

Reports of elevated nasal nitric oxide (NO) levels in allergic rhinitis suggest that nasal NO levels could be a valuable marker of upper airway inflammation, provided that the reproducibility of nasal NO measurement is acceptable. The aims of this study were to evaluate the precision with which nasal NO levels can be measured at single point in time, and to quantify within-day and between-day variation. Nasal NO was measured using a modified chemiluminiscence analyzer. Population data were normally distributed, as judged by testing for skewness and kurtosis. NO levels were not related to age or gender, and there was no evidence of diurnal variation. Sampling rates of 250 mL/minute and 500 mL/minute at a single point in time had acceptable reproducibility (coefficients of variation 10.2% and 6.6%, respectively). However, within-day variation (coefficient of variation 13.4%) and between-day variation (coefficient of variation 11.8%), at a sampling rate of 500 L/minute, were substantially higher. These findings highlight the importance of taking measurement variation into account, in the interpretation of NO levels, in clinical research and, potentially, in routine practice. In individual patients, an alteration of 20–25% in NO levels is required, to ensure that change is genuine and not ascribable to the noise of measurement.

Exhaled nitric oxide in sarcoidosis.

Background: Increased production of nitric oxide (NO) by the lower respiratory tract is viewed as a marker of airway inflammation in asthma and bronchiectasis. NO is a potentially important immune modulator, inhibiting the release of several key pro-inflammatory cytokines. As sarcoidosis is characterised by granulomatous airway inflammation, we hypothesised that exhaled NO levels might be raised in sarcoidosis and correlate with the morphological extent and functional severity of disease. Methods: Fifty two patients with sarcoidosis (29 men) of mean age 42 years underwent thin section computed tomography (CT), pulmonary function tests, and measurement of exhaled NO. Results: Exhaled NO levels (median 6.8 ppb, range 2.4–21.8) did not differ significantly from values in 44 control subjects, and were not related to the extent of individual CT abnormalities or the level of pulmonary function impairment. Conclusion: Exhaled NO levels are not increased in pulmonary sarcoidosis.

Short-burst oxygen therapy for COPD patients: a 6-month randomised, controlled study

Short-burst oxygen therapy (SBOT) remains widely advocated for patients with chronic obstructive pulmonary disease (COPD), despite a lack of supporting evidence. The aim of this randomised, double-blind, placebo-controlled, parallel group study was to determine whether SBOT improves health-related quality of life (HRQL) or reduces acute healthcare utilisation in patients discharged following an acute exacerbation of COPD. Consecutive patients were screened; 78 of 331 were eligible for randomisation to cylinder oxygen, cylinder air or usual care following discharge. Patients were elderly with high acute healthcare utilisation, forced expiratory volume in one second of <1 L and had dyspnoea limiting daily activity but were not hypoxaemic at rest. Over the 6-month study period, there were no significant differences between patient groups in HRQL (Chronic Respiratory Questionnaire (CRQ), 36-item Short-Form Health Survey, Hospital Anxiety and Depression Scale) except for CRQ emotion domain. There were no significant differences in acute healthcare utilisation. Time to readmission was greatest in the usual care group. Cylinder use was high initially, but rapidly fell to very low levels within weeks in both cylinder oxygen and air groups. In conclusion, the availability of short-burst oxygen therapy for chronic obstructive pulmonary disease patients discharged from hospital following an acute exacerbation did not improve health-related quality of life or reduce acute healthcare utilisation. These results provide no support for the widespread use of short-burst oxygen therapy.