A case-controlled study of relatives' complaints concerning patients who died in hospital: The role of treatment escalation/limitation planning.

OBJECTIVES: To independently assess quality of care among patients who died in hospital and whose next-of-kin submitted a letter of complaint and make comparisons with matched controls. To identify whether use of a treatment escalation limitation plan (TELP) during the terminal illness was a relevant background factor. DESIGN: The study was an investigator-blinded retrospective case-note review of 42 complaints cases and 72 controls matched for age, sex, ward location and time of death. SETTING: The acute medical and surgical wards of three District General Hospitals administered by NHS Lanarkshire, Scotland. PARTICIPANTS: None. INTERVENTION: None. OUTCOME MEASURES: Quality of care: clinical 'problems', non-beneficial interventions (NBIs) and harms were evaluated using the Structured Judgment Review Method. Complaints were categorized using the Healthcare Complaints Analysis Tool. RESULTS: The event frequencies and rate ratios for clinical 'problems', NBIs and harms were consistently higher in complaint cases compared to controls. The difference was only significant for NBIs (P = 0.05). TELPs were used less frequently in complaint cases compared to controls (23.8 versus 47.2%, P = 0.013). The relationship between TELP use and the three key clinical outcomes was nonsignificant. CONCLUSIONS: Care delivered to patients at end-of-life whose next-of-kin submitted a complaint was poorer overall than among control patients when assessed independently by blinded reviewers. Regular use of a TELP in acute clinical settings has the potential to influence complaints relating to end-of-life care, but this requires further prospective study.

Futility and appropriateness: challenging words, important concepts.

The provision of healthcare is being challenged by a 'perfect storm' of forces including an increasing population with multiple comorbidities, high expectations and resource limitations, and in the background, the pre-eminence of the 'curative medical model'. Non-beneficial (futile) treatments are wasteful and costly. They have a negative impact on quality of life especially in the last year of life. Among professionals, frequent encounters with futility cause moral distress and demoralisation. The factors that drive non-beneficial treatments include personal biases, patient-related pressures and institutional imperatives. Breaking loose from the perceived necessity to deliver non-beneficial treatment is a major challenge. Curative intent should give way to appropriateness such that curative and palliative interventions are valued equally. Goals of treatment should be shaped by illness trajectory, the risk of harms as well as potential benefits and patient preferences. This strategy should be reflected in professional training and the design of acute services.

Improving quality of care for end-stage respiratory disease: Changes in attitude, changes in service.

The illness trajectory for many patients with severe respiratory disease is characterized by steady decline. Yet most healthcare resources are poured into managing acute exacerbations that are only temporarily effective. Further, 'bad deaths' can result from inappropriate medical interventions at times of crisis. In this article, we describe a range of changes in attitudes, behaviour and service provision that together focus on improving quality of care for respiratory patients with frequent crises. These changes include prognostic conversations, developing and implementing anticipatory care plans both in hospital and in the outpatient settings, and establishing a supportive care clinic devoted to complex disease and optimizing palliative care. The underpinning philosophy is that common sense and compassion should motivate broader and more flexible care much more than adherence to the 'curative-restorative' guidelines-based model.

Sputum mast cell subtypes relate to eosinophilia and corticosteroid response in asthma.

Mast cells are a resident inflammatory cell of the airways, involved in both the innate and adaptive immune response. The relationship between mast cells and inflammatory phenotypes and treatment response of asthma is not clear.Clinical characteristics of subjects with stable asthma (n=55), inflammatory cell counts and gene expression microarrays in induced sputum were analysed. Sputum mast cell subtypes were determined by molecular phenotyping based on expression of mast cell biomarkers (tryptase (TPSAB1), chymase (CMA1) and carboxypeptidase A3 (CPA3)). Effects of mast cell subtypes on steroid response were observed in a prospective cohort study (n=50).MCT(n=18) and MCT/CPA3(mRNA expression of TPSAB1 and CPA3; n=29) subtypes were identified, as well as a group without mast cell gene expression (n=8). The MCT/CPA3 subtype had elevated exhaled nitric oxide fraction, sputum eosinophils, bronchial sensitivity and reactivity, and poorer asthma control. This was accompanied by upregulation of 13 genes. Multivariable logistic regression identified CPA3(OR 1.21, p=0.004) rather than TPSAB1(OR 0.92, p=0.502) as a determinant of eosinophilic asthma. The MCT/CPA3 subtype had a better clinical response and reduced signature gene expression with corticosteroid treatment.Sputum mast cell subtypes of asthma can be defined by a molecular phenotyping approach. The MCT/CPA3 subtype demonstrated increased bronchial sensitivity and reactivity, and signature gene expression, which was associated with airway eosinophilia and greater corticosteroid responsiveness.

Biomarker-based asthma phenotypes of corticosteroid response.

BACKGROUND: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable. OBJECTIVE: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness. METHODS: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients. RESULTS: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy. CONCLUSION: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes.

BACKGROUND: Airway inflammation is associated with asthma exacerbation risk, treatment response, and disease mechanisms. OBJECTIVE: This study aimed to identify and validate a sputum gene expression signature that discriminates asthma inflammatory phenotypes. METHODS: An asthma phenotype biomarker discovery study generated gene expression profiles from induced sputum of 47 asthmatic patients. A clinical validation study (n = 59 asthmatic patients) confirmed differential expression of key genes. A 6-gene signature was identified and evaluated for reproducibility (n = 30 asthmatic patients and n = 20 control subjects) and prediction of inhaled corticosteroid (ICS) response (n = 71 asthmatic patients). Receiver operating characteristic curves were calculated, and area under the curve (AUC) values were reported. RESULTS: From 277 differentially expressed genes between asthma inflammatory phenotypes, we identified 23 genes that showed highly significant differential expression in both the discovery and validation populations. A signature of 6 genes, including Charcot-Leydon crystal protein (CLC); carboxypeptidase A3 (CPA3); deoxyribonuclease I-like 3 (DNASE1L3); IL-1ß (IL1B); alkaline phosphatase, tissue-nonspecific isozyme (ALPL); and chemokine (C-X-C motif) receptor 2 (CXCR2), was reproducible and could significantly (P < .0001) discriminate eosinophilic asthma from other phenotypes, including patients with noneosinophilic asthma (AUC, 89.6%), paucigranulocytic asthma (AUC, 92.6%), or neutrophilic asthma (AUC, 91.4%) and healthy control subjects (AUC, 97.6%), as well as discriminating patients with neutrophilic asthma from those with paucigranulocytic asthma (AUC, 85.7%) and healthy control subjects (AUC, 90.8). The 6-gene signature predicted ICS response (>12% change in FEV1; AUC, 91.5%). ICS treatment reduced the expression of CLC, CPA3, and DNASE1L3 in patients with eosinophilic asthma. CONCLUSIONS: A sputum gene expression signature of 6 biomarkers reproducibly and significantly discriminates inflammatory phenotypes of asthma and predicts ICS treatment response. This signature has the potential to become a useful diagnostic tool to assist in the clinical diagnosis and management of asthma.

Early detection of asthma exacerbations by using action points in self-management plans.

Our aim was to validate optimal action points in written action plans for early detection of asthma exacerbations. We analysed daily symptoms and morning peak expiratory flows (PEFs) from two previous studies. Potential action points were based on analysis of symptom scores (standard deviations) percentage of personal best PEF, PEF variability in relation to a run-in period or combinations of these measures. Sensitivity and specificity for predicting exacerbations were obtained for each action point. The numbers needed to treat to prevent one exacerbation and the time interval between reaching action point criteria and the start of the exacerbation were calculated. Based on these parameters, the optimal action points for symptoms, PEF and PEF plus symptoms were determined, and their performance compared with published guidelines' action points. The optimal action points were, for symptoms, statistical variability (standard deviations) and, for PEF, <70% of personal best. The combination of PEF plus symptoms performed best, with improved specificity and earlier detection. The main benefits associated with using these action points was to reduce false positive rates for detecting exacerbations. Early detection of asthma exacerbations can be improved using a composite action point comprising symptoms and PEF measurements over 1 week.

Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial.

BACKGROUND: Asthma exacerbations during pregnancy are common and can be associated with substantial maternal and fetal morbidity. Treatment decisions based on sputum eosinophil counts reduce exacerbations in non-pregnant women with asthma, but results with the fraction of exhaled nitric oxide (F(E)NO) to guide management are equivocal. We tested the hypothesis that a management algorithm for asthma in pregnancy based on F(E)NO and symptoms would reduce asthma exacerbations. METHODS: We undertook a double-blind, parallel-group, controlled trial in two antenatal clinics in Australia. 220 pregnant, non-smoking women with asthma were randomly assigned, by a computer-generated random number list, before 22 weeks' gestation to treatment adjustment at monthly visits by an algorithm using clinical symptoms (control group) or F(E)NO concentrations (active intervention group) used to uptitrate (F(E)NO >29 ppb) or downtitrate (F(E)NO <16 ppb) inhaled corticosteroid dose. Participants, caregivers, and outcome assessors were masked to group assignment. Longacting ß2 agonist and minimum dose inhaled corticosteroid were used to treat symptoms when F(E)NO was not increased. The primary outcome was total asthma exacerbations (moderate and severe). Analysis was by intention to treat. This study is registered with the Australian and New Zealand Clinical Trials Registry, number 12607000561482. FINDINGS: 111 women were randomly assigned to the F(E)NO group (100 completed) and 109 to the control group (103 completed). The exacerbation rate was lower in the F(E)NO group than in the control group (0·288 vs 0·615 exacerbations per pregnancy; incidence rate ratio 0·496, 95% CI 0·325-0·755; p=0·001). The number needed to treat was 6. In the F(E)NO group, quality of life was improved (score on short form 12 mental summary was 56·9 [95% CI 50·2-59·3] in F(E)NO group vs 54·2 [46·1-57·6] in control group; p=0·037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p=0·046). INTERPRETATION: Asthma exacerbations during pregnancy can be significantly reduced with a validated F(E)NO-based treatment algorithm. FUNDING: National Health and Medical Research Council of Australia.

Biomarkers of inflammation in asthma: a clinical perspective.

Asthma is a heterogeneous disease, with wide variability in pathology, natural history, and response to therapy. Historically, treatment of asthma relied almost exclusively on clinical judgment and pulmonary function tests (spirometry or peak flows), despite the limitations of both. Physiological tests are one step removed from what the clinician needs to know, namely, the underlying activity and whether it is amenable to additional or alternative treatment. Within the past decade, categorization of different pathological phenotypes and the treatment-response phenotypes have been used to guide therapy. Additionally, biomarkers (particular induced sputum analysis and exhaled nitric acid) have been tests to assess disease "activity" and predict potential response (or lack of response) to therapy. Currently, the value of biomarkers from exhaled air or airway fluids remains controversial. Clinical utility is dependent on the performance characteristics in relation to specific clinical questions. Financial constraints applied by health providers and funding agencies have limited the use of induced sputum analysis and exhaled nitric oxide to date. However, evaluation of candidate biomarkers has provided important insights in clinical practice and in research settings. At the very least, existing techniques should have a regular place in severe asthma clinics, if not more widely, where heterogeneity is the norm and not all asthma is what it seems.

Asthma phenotypes: consistency of classification using induced sputum.

BACKGROUND AND OBJECTIVE: Asthma can be classified as eosinophilic or non-eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens. METHODS: Clinically stable, non-smoking, asthmatic adults were enrolled in one of two studies. In study one, induced sputum cell counts from 28 subjects were analysed after 4 weeks without corticosteroid treatment and after 6 week treatments with placebo, regular inhaled beta-agonist, inhaled corticosteroid, and combined beta-agonist and corticosteroid. In study two, sputum from 26 subjects with non-eosinophilic asthma was analysed after 12 weeks of placebo and after four 2-week corticosteroid washouts. Sputum with <2% eosinophils was classified as non-eosinophilic. RESULTS: Sputum classification changed frequently in both studies. In study one, only one of eight participants with non-eosinophilic sputum after placebo treatment remained non-eosinophilic throughout. In study two, all of participants had at least one eosinophilic sputum sample, despite the fact that all had been non-eosinophilic at recruitment. Neutrophilic asthma was uncommon in both studies and was also inconsistent. CONCLUSIONS: The phenotypic classification of asthma changes frequently. A diagnosis of non-eosinophilic asthma should not be based on a single sputum sample.

An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications.

BACKGROUND: Measurement of fractional nitric oxide (NO) concentration in exhaled breath (Fe(NO)) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. While Fe(NO) measurement has been standardized, there is currently no reference guideline for practicing health care providers to guide them in the appropriate use and interpretation of Fe(NO) in clinical practice. PURPOSE: To develop evidence-based guidelines for the interpretation of Fe(NO) measurements that incorporate evidence that has accumulated over the past decade. METHODS: We created a multidisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway disease and/or NO. The committee identified important clinical questions, synthesized the evidence, and formulated recommendations. Recommendations were developed using pragmatic systematic reviews of the literature and the GRADE approach. RESULTS: The evidence related to the use of Fe(NO) measurements is reviewed and clinical practice recommendations are provided. CONCLUSIONS: In the setting of chronic inflammatory airway disease including asthma, conventional tests such as FEV(1) reversibility or provocation tests are only indirectly associated with airway inflammation. Fe(NO) offers added advantages for patient care including, but not limited to (1) detecting of eosinophilic airway inflammation, (2) determining the likelihood of corticosteroid responsiveness, (3) monitoring of airway inflammation to determine the potential need for corticosteroid, and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy.

Using biomarkers in the assessment of airways disease.

A biomarker provides a window on underlying disease activity. This is helpful when the pathology, treatment response, or both are heterogeneous or when trying to interpret nonspecific respiratory symptoms in patients with comorbidities. The successful application of a biomarker result is critically dependent on the specific question being addressed and the performance characteristics of the biomarker in relation to that question in the context of pretest probabilities. Negative prediction might be the best way to use a biomarker, such as a D-dimer, pro-brain natriuretic peptide, and exhaled nitric oxide. In this review the role of biomarkers in airways disease (notably induced sputum eosinophils and exhaled nitric oxide) is considered in relation to risk stratification, identification of treatment responders, identification of a clinical phenotype, monitoring of disease, and new drug development.

Responding to the deteriorating patient: The rationale for treatment escalation plans.

A Treatment Escalation Plan (TEP) is a communication tool designed to improve quality of care in hospital, particularly if patients deteriorate. The aims are to reduce variation caused by discontinuity of care; avoid harms caused by inappropriate treatment and promote patients' priorities and preferences. The TEP is based on the goals of treatment - 'What are we trying to achieve?' The goals take account of the context of acute illness, the consequences of interventions and discussion with the patient. They should reflect a shift away from 'fix-it' medicine to what is realistic and pragmatic. A TEP has three escalation categories: full escalation, selected appropriate treatments and palliative/supportive care. Other appropriate/inappropriate treatments are also recorded. Treatment Escalation Plans are associated with significant reductions in intensive care unit (ICU) admissions, non-beneficial interventions, harms and complaints. Treatment Escalation Plans contribute to staff well-being by reducing uncertainty. Successful implementation requires training and education in medical decision-making and communication skills.

Associations between fluctuations in lung function and asthma control in two populations with differing asthma severity.

BACKGROUND: Lung function is a major criterion used to assess asthma control. Fluctuation analyses can account for lung function history over time, and may provide an additional dimension to characterise control. The relationships between mean and fluctuations in lung function with asthma control, exacerbation and quality of life were studied in two independent data sets. METHODS: Data from 132 adults with mild to moderate asthma and 159 adults with severe asthma were analysed separately. Fluctuations in twice-daily peak expiratory flow (PEF) over 6 months were measured by α, representing the strength of correlation with past lung function and potentially asthma stability. α and mean percentage predicted PEF (%predPEF) were plotted with and compared between patients grouped by asthma control defined by recent GINA (Global Initiative for Asthma) guidelines, the Asthma Control Questionnaire score, exacerbations and Asthma Quality of Life Questionnaire score. Associations of α and %predPEF with these outcomes were examined using multiple regression analyses. RESULTS: Both α and %predPEF differed with and were significantly associated with GINA-defined asthma control in both the mild to moderate and severe asthma groups. Only α was related to whether or not exacerbations occurred in mild to moderate asthma, while %predPEF was more significantly related than α in severe asthma. In those with severe asthma, only %predPEF was significantly related to Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. CONCLUSION: Lung function history quantified by fluctuation analysis provides additional information to mean lung function, and may help characterise the current state of asthma control. It may also potentially aid in phenotyping clinical asthma.

Risk of severe asthma episodes predicted from fluctuation analysis of airway function.

Asthma is an increasing health problem worldwide, but the long-term temporal pattern of clinical symptoms is not understood and predicting asthma episodes is not generally possible. We analyse the time series of peak expiratory flows, a standard measurement of airway function that has been assessed twice daily in a large asthmatic population during a long-term crossover clinical trial. Here we introduce an approach to predict the risk of worsening airflow obstruction by calculating the conditional probability that, given the current airway condition, a severe obstruction will occur within 30 days. We find that, compared with a placebo, a regular long-acting bronchodilator (salmeterol) that is widely used to improve asthma control decreases the risk of airway obstruction. Unexpectedly, however, a regular short-acting beta2-agonist bronchodilator (albuterol) increases this risk. Furthermore, we find that the time series of peak expiratory flows show long-range correlations that change significantly with disease severity, approaching a random process with increased variability in the most severe cases. Using a nonlinear stochastic model, we show that both the increased variability and the loss of correlations augment the risk of unstable airway function. The characterization of fluctuations in airway function provides a quantitative basis for objective risk prediction of asthma episodes and for evaluating the effectiveness of therapy.

Variability of lung function predicts loss of asthma control following withdrawal of inhaled corticosteroid treatment.

BACKGROUND One aspect of a multidimensional approach to understanding asthma as a complex dynamic disease is to study how lung function varies with time. Variability measures of lung function have been shown to predict response to beta(2)-agonist treatment. An investigation was conducted to determine whether mean, coefficient of variation (CV) or autocorrelation, a measure of short-term memory, of peak expiratory flow (PEF) could predict loss of asthma control following withdrawal of regular inhaled corticosteroid (ICS) treatment, using data from a previous study. METHODS 87 adult patients with mild to moderate asthma who had been taking ICS at a constant dose for at least 6 months were monitored for 2-4 weeks. ICS was then withdrawn and monitoring continued until loss of control occurred as per predefined criteria. Twice-daily PEF was recorded during monitoring. Associations between loss of control and mean, CV and autocorrelation of morning PEF within 2 weeks pre- and post-ICS withdrawal were assessed using Cox regression analysis. Predictive utility was assessed using receiver operator characteristics. RESULTS 53 out of 87 patients had sufficient PEF data over the required analysis period. The mean (389 vs 370 l/min, p<0.0001) and CV (4.5% vs 5.6%, p=0.007) but not autocorrelation of PEF changed significantly from prewithdrawal to postwithdrawal in subjects who subsequently lost control, and were unaltered in those who did not. These changes were related to time to loss of control. CV was the most consistent predictor, with similar sensitivity and sensitivity to exhaled nitric oxide. CONCLUSION A simple, easy to obtain variability measure of daily lung function such as the CV may predict loss of asthma control within the first 2 weeks of ICS withdrawal.

Simvastatin in the treatment of asthma: lack of steroid-sparing effect.

BACKGROUND: Statins have anti-inflammatory actions which in theory are potentially beneficial in asthma. Small trials have failed to show a significant benefit, but a systematic study to evaluate the steroid-sparing effect of statin treatment has not been carried out. METHODS: A randomised, placebo-controlled, crossover trial was conducted of simvastatin 40 mg at night with simultaneous stepwise reduction of fluticasone propionate dose until loss of control occurred, followed by an increase until regain of control ('minimum' dose required) in 51 patients with asthma and sputum eosinophils (steroid-free) ≥ 2%. RESULTS: 43 patients completed the study. There was no significant difference in 'minimum' inhaled corticosteroid (ICS) dose requirement between simvastatin and placebo: (median (IQR) 50 µg daily (0-250) vs 100 µg daily (0-250), p=0.931). 'Minimum' dose distribution was similar (p=0.269). The fluticasone dose at which loss of control occurred did not differ significantly between simvastatin and placebo (p=0.404). In patients with loss of control in both treatment arms, fluticasone dose at loss of control was similar with simvastatin and placebo (median (IQR) 50 µg daily (0-100) for both, p=0.620). In those patients who reached 0 µg/day (n=18), Astma Control Questionnaire (ACQ) was lower (p=0.037), forced expiratory volume in 1 s (FEV(1)) higher (p<0.01) and sputum eosinophils lower with simvastatin compared with placebo (9.5% compared with 25.4%, p=0.033). CONCLUSIONS: Simvastatin does not have clinically important steroid-sparing effects in patients with eosinophilic asthma. In the absence of steroid, simvastatin is associated with minor improvements in symptoms and lung function, and a reduction in sputum eosinophils. Clinical trial number ACTRN12606000531516.