Long-term corticosteroid use, adrenal insufficiency and the need for steroid-sparing treatment in adult severe asthma.

Secondary adrenal insufficiency (AI) occurs as the result of any process that disrupts normal hypothalamic and/or anterior pituitary function and causes a decrease in the secretion of steroid hormones from the adrenal cortex. The most common cause of secondary AI is exogenous corticosteroid therapy administered at supraphysiologic dosages for ≥ 1 month. AI caused by oral corticosteroids (OCS) is not well-recognized or commonly diagnosed but is often associated with reduced well-being and can be life-threatening in the event of an adrenal crisis. Corticosteroid use is common in respiratory diseases, and asthma is a representative condition that illustrates the potential challenges and opportunities related to corticosteroid-sparing therapies. For individuals with severe asthma (approximately 5%-10% of all cases), reduction or elimination of maintenance OCS without loss of control can now be accomplished with biologic therapies targeting inflammatory mediators. However, the optimal strategy to ensure early identification and treatment of AI and safe OCS withdrawal in routine clinical practice remains to be defined. Many studies with biologics have involved short evaluation periods and small sample sizes; in addition, cautious approaches to OCS tapering in studies with a placebo arm, coupled with inconsistent monitoring for AI, have contributed to the lack of clarity. If the goal is to greatly reduce and, where possible, eliminate long-term OCS use in severe asthma through the increasing adoption of biologic treatments, there is an urgent need for clinical trials that address both the speed of OCS withdrawal and how to monitor for AI.

The current and future role of biomarkers in type 2 cytokine-mediated asthma management.

Assessment and management of asthma is complicated by the heterogeneous pathophysiological mechanisms that underlie its clinical presentation, which are not necessarily reflected in standardized management paradigms and which necessitate an individualized approach to treatment. This is particularly important with the emerging availability of a variety of targeted forms of therapy that may only be appropriate for use in particular patient subgroups. The identification of biomarkers can potentially aid diagnosis and inform prognosis, help guide treatment decisions and allow clinicians to predict and monitor response to treatment. Biomarkers for asthma have been identified from a variety of sources, including airway, exhaled breath and blood. Biomarkers from exhaled breath include fractional exhaled nitric oxide, measurement of which can help identify patients most likely to benefit from inhaled corticosteroids and targeted anti-immunoglobulin E therapy. Biomarkers measured in blood are relatively non-invasive and technically more straightforward than those measured from exhaled breath or directly from the airway. The most well established of these are the blood eosinophil count and serum periostin, both of which have demonstrated utility in identifying patients most likely to benefit from targeted anti-interleukin and anti-immunoglobulin E therapies, and in monitoring subsequent treatment response. For example, serum periostin appears to be a biomarker for responsiveness to inhaled corticosteroid therapy and may help identify patients as suitable candidates for anti-IL-13 treatment. The use of biomarkers can therefore potentially help avoid unnecessary morbidity from high-dose corticosteroid therapy and allow the most appropriate and cost-effective use of targeted therapies. Ongoing clinical trials are helping to further elucidate the role of established biomarkers in routine clinical practice, and a range of other circulating novel potential biomarkers are currently being investigated in the research setting.

The cost of systemic corticosteroid-induced morbidity in severe asthma: a health economic analysis.

BACKGROUND: Treatment of severe asthma may include high dose systemic-steroid therapy which is associated with substantial additional morbidity. This study estimates the additional healthcare costs associated with steroid-induced morbidity by comparing three patients groups: those with severe asthma, moderate asthma and no asthma. METHODS: Patients with severe asthma (n = 808, GINA step 5 treatment) were matched by age and gender with patients with mild/moderate asthma (n = 3,975, GINA step 2 and 3 treatment) and a non-asthma control cohort (with a diagnosis of rhinitis; n = 2,412) from the Optimum Patient Care Research Database (OPCRD), a nationally representative primary care database. Prescribed drugs and publicly funded healthcare activity were monetised and annual costs per patient estimated. Regression analyses were used to estimate the additional healthcare cost associated with steroid-induced morbidity. RESULTS: Average healthcare costs per person per year range from £2603 - £4533 for the severe asthma cohort, to £978 - £2072 for the mild/moderate asthma cohort, to £560 - £1324 for the non-asthma control cohort, depending on the costing scenario. Differences in induced morbidity costs were evident between patients with asthma differentiated by steroid exposure. In relation to prescription drugs used to treat steroid-induced co-morbidities, females with severe asthma and high steroid exposure cost approximately £789 more per year than a corresponding female with no asthma, while males cost approximately £744 more than their counterparts with no asthma. Estimates were extrapolated to all healthcare costs. CONCLUSIONS: This study provides the first robust estimates of the additional cost of healthcare related to steroid-induced morbidity relative to patients with no steroid exposure. The study will help inform use of steroid-sparing strategies in this patient group.

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity.

BACKGROUND: The mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Upregulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility, and the transient receptor potential (TRP) channel family are potential candidates. We have used an in vitro model of sensory neurons and human rhinovirus (HRV-16) to study the effect of virus infection on TRP expression. METHODS: IMR-32 neuroblastoma cells were differentiated in culture to express three TRP channels: TRPV1, TRPA1 and TRPM8. Flow cytometry and qRT-PCR were used to measure TRP channel protein and mRNA levels following inoculation with live virus, inactivated virus, virus-induced soluble factors or pelleted virus particles. Multiplex bioassay was used to determine nerve growth factor (NGF), interleukin (IL)-1ß, IL-6 and IL-8 levels in response to infection. RESULTS: Early upregulation of TRPA1 and TRPV1 expression occurred 2-4 h post infection. This was independent of replicating virus as virus-induced soluble factors alone were sufficient to increase channel expression 50-fold and 15-fold, respectively. NGF, IL-6 and IL-8 levels, increased in infected cell supernatants, represent possible candidates. In contrast, TRPM8 expression was maximal at 48 h (9.6-fold) and required virus replication rather than soluble factors. CONCLUSIONS: We show for the first time that rhinovirus can infect neuronal cells. Furthermore, infection causes upregulation of TRP channels by channel-specific mechanisms. The increase in TRPA1 and TRPV1 levels can be mediated by soluble factors induced by infection whereas TRPM8 requires replicating virus. TRP channels may be novel therapeutic targets for controlling virus-induced cough.

EUFOREA summit in Brussels 2023: inspiring the future of allergy & respiratory care.

In March 2023, the European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual Summit in Brussels with expert panel members of EUFOREA, representatives of the EUFOREA patient advisory board, and the EUFOREA board and management teams. Its aim was to define the research, educational and advocacy initiatives to be developed by EUFOREA over the next 2 years until the 10th anniversary in 2025. EUFOREA is an international non-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic allergic and respiratory diseases via research, education, and advocacy. Based on its medical scientific core competency, EUFOREA offers an evidence-supported platform to introduce innovation and education in healthcare leading to optimal patient care, bridging the gap between latest scientific evidence and daily practice. Aligned with the mission of improving health care, the expert panels of asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS) & European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), allergen immunotherapy (AIT) and paediatrics have proposed and elaborated a variety of activities that correspond to major unmet needs in the allergy and respiratory field. The current report provides a concise overview of the achievements, ambitions, and action plan of EUFOREA for the future, allowing all stakeholders in the allergy and respiratory field to be up-dated and inspired to join forces in Europe and beyond.

Stress-related health depreciation: Using allostatic load to predict self-rated health.

Approximately one quarter of UK adults are currently diagnosed with two or more chronic conditions, often referred to as multimorbidity. Chronic stress has been implicated in the development of many diseases common to multimorbidity. Policymakers and clinicians have acknowledged the need for more preventative approaches to deal with the rise of multimorbidity and "early ageing". However divergence may occur between an individual's self-rated health and objectively measured health that may preclude preventative action. The use of biomarkers which look 'under the skin' provide crucial information on an individual's underlying health to facilitate lifestyle change or healthcare utilisation. The UK's Understanding Society dataset, was used to examine whether baseline variation in biomarkers measuring stress-related "wear and tear" - Allostatic Load (AL) - predict changes in future self-rated health (SRH) while adjusting for baseline SRH, socioeconomic and lifestyle factors, and healthcare inputs. An interaction between baseline AL and baseline SRH was included to test for differential rates of SRH change. We examined SRH using the SF6D instrument, measuring health-related-quality of life (HRQoL), as well as its physical and mental health components separately. We found that HRQoL and physical health decline faster for those with higher baseline AL (indicating greater "wear and tear") however the same pattern was not observed for mental health. These findings provide novel insights for clinicians and policymakers on the usefulness of AL in capturing health trajectories of which individual's may not be aware and its importance in targeting resilience enhancing measures earlier in the lifecourse to delay physical health decline.

Respiratory viral infection in lower airways of asymptomatic children.

AIM: The aim of this study was to determine if asthmatic children have viruses more commonly detected in lower airways during asymptomatic periods than normal children. METHODS: Fifty-five asymptomatic children attending elective surgical procedures (14 with stable asthma, 41 normal controls) underwent non-bronchoscopic bronchoalveolar lavage. Differential cell count and PCR for 13 common viruses were performed. RESULTS: Nineteen (35%) children were positive for at least one virus, with adenovirus being most common. No differences in the proportion of viruses detected were seen between asthmatic and normal 'control' children. Viruses other than adenovirus were associated with higher neutrophil counts, suggesting that they caused an inflammatory response in both asthmatics and controls (median BAL neutrophil count, 6.9% for virus detected vs. 1.5% for virus not detected, p = 0.03). CONCLUSIONS: Over one-third of asymptomatic children have a detectable virus (most commonly adenovirus) in the lower airway; however, this was not more common in asthmatics. Viruses other than adenovirus were associated with elevated neutrophils suggesting that viral infection can be present during relatively asymptomatic periods in asthmatic children.

Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

BACKGROUND: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough. MATERIALS AND METHODS: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay. RESULTS: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels. CONCLUSION: Susceptibility to develop chronic cough is not associated with ACE genotype.

Cost minimisation analysis of provision of oxygen at home: are the drug tariff guidelines cost effective?

OBJECTIVES: To determine the level of oxygen cylinder use at which it becomes more cost effective to provide oxygen by concentrator at home in Northern Ireland, and to examine potential cost savings if cylinder use above this level had been replaced by concentrator in 1996. DESIGN: Cost minimisation analysis. SETTING: Area health boards in Northern Ireland. MAIN OUTCOME MEASURES: Cost effective cut off point for switch to provision of oxygen from cylinder to concentrator. Potential maximum and minimum savings in Northern Ireland (sensitivity analysis) owing to switch to more cost effective strategy on the basis of provision of cylinders in 1996. RESULTS: In Northern Ireland it is currently cost effective to provide oxygen by concentrator when the patient is using three or more cylinders per month independent of the duration of the prescription. More widespread use of concentrators at this level of provision is likely to lead to a cost saving. CONCLUSIONS: The Drug Tariff prescribing guidelines, advocating that provision of oxygen by concentrator becomes cheaper when 21 cylinders are being used per month-are currently inaccurate in Northern Ireland. Regional health authorities should review their current arrangements for provision of oxygen at home and perform a cost analysis to determine at what level it becomes more cost effective to provide oxygen by concentrator.

Prescription of oxygen concentrators and survival in Northern Ireland.

Long-term oxygen therapy (LTOT) has been shown to prolong survival and to improve quality of life in patients with chronic obstructive pulmonary disease (COPD) and in respiratory failure. In Northern Ireland oxygen concentrators have been available on prescription since August 1986, initially on a restricted basis from hospital physicians only. This was followed by open prescribing from April 1989, when concentrators could be prescribed by general practitioners. This study examined prescribing habits of LTOT during both periods, and patient survival. Case notes of all prescriptions of oxygen concentrators in Northern Ireland (to April 1991) were reviewed. Prescription criteria and advice regarding usage during both periods were analysed. A questionnaire survey of subjects during open prescribing documented the advice given at the time of prescription and current usage. 164 charts of 178 total installations were available for review. During both periods many concentrators were installed without adherence to the prescribing criteria at the time (75% restricted, 48% open). The majority of these were on the advice of a consultant respiratory physician and only 14 were prescribed directly by GPs. 89 of 91 subjects receiving current LTOT during the study period completed questionnaires. Of the subjects prescribed LTOT during the restricted period, 2 subjects are still alive (median survival 19 m, range 0-104). From the open period, survival data was available on 107 of 129 subjects with 17 still alive (median survival 22 m, range 0-94). This study documents an inadequate rate of prescribing and a lack of conformity to guidelines in the provision of LTOT in Northern Ireland. We would suggest that familiarisation with the prescribing criteria, formal written advice at the time of prescription, appropriate follow up to ensure adequate supplementation and regular patient education on the use of LTOT would address these problems to a substantial degree.

A cross-sectional study evaluating the relationship between cortisol suppression and asthma control in patients with difficult asthma.

AIM: To examine the relationship between cortisol suppression and asthma symptoms in patients with difficult asthma. METHODS: Patients, referred to a specialist difficult asthma service and who fulfilled the criteria for difficult asthma, were recruited to the study in a sequential, unselected manner. At each clinic visit, all patients completed a validated asthma control questionnaire. For measuring cortisol suppression, early morning urinary cortisol [corrected for creatinine to give urinary cortisol creatinine ratio (UCC ratio)] was used. The urine samples were collected and stored at -70 degrees C until ready for analysis. Urinary cortisol was extracted (solid-phase extraction) and analysed using high-performance liquid chromatography. The Pearson correlation coefficient was used for correlation analysis while t-tests were used for between-group differences for normally distributed data. If the data were not normally distributed, nonparametric statistics were used. A P-value < 0.05 was considered statistically significant. RESULTS: During the study period all the patients who attended the difficult asthma clinic and fulfilled the criteria for difficult asthma (n = 66) agreed to take part in the study. There were moderate to strong and significant associations between several measures of asthma control and UCC ratio. The correlation coefficient with five indicators of asthma control ranged between 0.3 and 0.5 (P < 0.05). CONCLUSIONS: We have demonstrated a relationship between cortisol suppression and asthma control in difficult asthmatics on high-dose steroid therapy. We have proposed a model based on the relationship between symptom control and cortisol suppression, whereby both adherence and therapeutic adjustments could potentially be made. A properly controlled prospective clinical trial should examine the utility of this approach in clinical practice.

Airway expression of calcitonin gene-related peptide in T-cell peptide-induced late asthmatic reactions in atopics.

BACKGROUND: The mechanisms of late asthmatic reactions provoked in atopic asthmatics by allergen-derived T-cell peptide epitopes remain unclear. Previous studies showed no changes in airway eosinophils or mast cell products after peptide challenge. In the present study our aim was to measure calcitonin gene-related peptide (CGRP), neurokinin (NK)-A, and substance P (SP) in bronchoalveolar lavage fluid and bronchial biopsies (BB) after inhalation of allergen-derived T-cell peptide epitopes since these neuropeptides (NP) had not previously been evaluated in this chronic asthma model. METHODS: Bronchoscopy, with BB and bronchoalveolar lavage (BAL), was performed in 24 cat-allergic subjects 6 h after inhalation of Fel d 1-derived peptides. Neuropeptides were measured in BAL by enzyme-linked immunosorbent assay and CGRP expression in the airways was assessed by immunohistochemistry and confocal microscopy. RESULTS: Twelve subjects (termed 'responders') developed isolated late reactions. Calcitonin gene-related peptide, but not NK-A or SP, was significantly elevated in BAL in responders only. Biopsy studies showed that in virtually all responders peptide challenge induced marked increases in CGRP immunoreactivity in bronchial epithelial cells, infiltrating submucosal cells and in association with airway smooth muscle. Double immunostaining indicated that CGRP colocalized predominantly to CD3+/CD4+ and CD68+ submucosal inflammatory cells. CONCLUSION: Calcitonin gene-related peptide, a potent vasodilator, is markedly up-regulated in the airways of atopic asthmatics during late-phase reactions provoked by inhalation of allergen-derived T-cell peptides.

Children with stable asthma have reduced airway matrix metalloproteinase-9 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio.

BACKGROUND: Childhood asthma is characterized by inflammation of the airways. Structural changes of the airway wall may also be seen in some children early in the course of the disease. Matrix metalloproteinases (MMPs) are key mediators in the metabolism of the extracellular matrix (ECM). OBJECTIVE: To investigate the balance of MMP-8, MMP-9 and tissue inhibitor of metalloproteinases (TIMP)-1 in the airways of children with asthma. METHODS: One hundred and twenty-four children undergoing elective surgical procedures also underwent non-bronchoscopic bronchoalveolar lavage (BAL). MMP-8, MMP-9 and TIMP-1 were measured by ELISA. RESULTS: There was a significant reduction in MMP-9 in atopic asthmatic children (n=31) compared with normal children (n=30) [median difference: 0.57 ng/mL (95% confidence interval: 0.18-1.1 ng/mL)]. The ratio of MMP-9 to TIMP-1 was also reduced in asthmatic children. Levels of all three proteins were significantly correlated to each other and to the relative proportions of particular inflammatory cells in BAL fluid (BALF). Both MMP-8 and MMP-9 were moderately strongly correlated to the percentage neutrophil count (r=0.40 and 0.47, respectively, P<0.001). CONCLUSIONS: An imbalance of MMPs and their inhibitors occurs in children with well-controlled asthma, which may indicate early derangement of the metabolism of the ECM.

Adenosine, inflammation and asthma--a review.

Adenosine is a ubiquitous molecule present in every cell of the human body. It has a wide range of physiological functions mediated predominantly through specific cell surface adenosine receptors. Adenosine has both pro- and anti-inflammatory effects and acts on inflammatory and resident immune cells and antioxidant enzymes. The elevation of adenosine in the bronchoalveolar lavage (BAL) fluid of asthmatics combined with its bronchoconstrictor effect on the airways in asthmatics has led to increased research into the contribution of adenosine in the pathophysiology of inflammation and asthma. This review looks at the airway response to adenosine and at the interaction of adenosine with mast cells and basophils.

Brewer's asthma due to malt contamination.

We describe a case of a 28 year old brewery worker who developed asthma whilst grinding malt. Lung function measurements demonstrated deterioration and improvement in lung function associated with work and absence from work. Inhalation challenge with ground malt from the brewery was positive but with ground malt from another source was negative suggesting a contaminant of the malt was responsible. Culture of the brewery malt showed heavy contamination with Aspergillus niger, but A. niger skin test was negative and aspergillus-specific IgG was not detected in the patients serum. Removal of the subject from the grinding room resulted in resolution of symptoms and normal lung function. We discuss the role of A. niger as an aetiological agent for occupational asthma with reference to the above case.

Histamine release from human bronchoalveolar lavage mast cells by neurokinin A and bradykinin.

OBJECTIVE AND DESIGN: This study examined whether bradykinin and neurokinin A activate human pulmonary mast cells retrieved by bronchoalveolar lavage (BAL). SUBJECTS: BAL samples were obtained at routine bronchoscopy from 14 unpreselected patients. METHODS: Histamine release experiments were performed using substance P, neurokinin A, bradykinin (peptides 25 and 50 microM), compound 48/80 (0.75-10 micrograms/ml) and A23187 (1 microM). Statistical analyses were performed using the paired Student's t-test and Pearson's linear correlation coefficient. RESULTS: Compound 48/80 induced release was significantly lower than that induced by the other secretagogues (p < 0.05). Neurokinin A and bradykinin induced release correlated significantly with substance P induced release (p < 0.01), suggesting similar mechanisms of action. No correlations were observed between neurokinin A or bradykinin-induced release and the non-peptide stimuli studied. CONCLUSIONS: The mechanism of neurokinin A- and bradykinin-induced bronchoconstriction is not yet clear but our data suggest an indirect effect mediated by mast cell degranulation.

A retrospective survey of diagnosis and management of patients presenting with chronic cough to a general chest clinic.

Respiratory physicians often encounter patients with chronic cough. The evaluation and outcome of such patients by centres with established diagnostic protocols has been well described. By contrast, little is known about patients referred to general respiratory clinics where no such protocol exists. We describe the findings of a retrospective survey of all new patient referrals with chronic cough to a general respiratory clinic over a 12-month period. A diagnosis of asthma or chronic airflow obstruction was made in 43% of patients. Gastro-oesophageal reflux and postnasal drip syndrome, together accounting for over 60% of diagnoses in specialist clinics, were infrequently identified in our study (4% and 2% respectively). At follow-up, 43% of patients reported persistent symptoms, contrasting the excellent treatment response reported by specialist clinics. In general respiratory clinics where a specific diagnostic protocol is not in place, these differences in diagnosis and outcome may be due to inadequate investigation or may reflect a different patient population.

Histamine release from bronchoalveolar lavage cells from asthmatic subjects after allergen challenge and relationship to the late asthmatic response.

BACKGROUND: Metachromatic cells obtained from asthmatic subjects demonstrate increased spontaneous and stimulated histamine release in vitro. Their ability to synthesize and store proinflammatory cytokines has focused renewed interest on their role in asthma. OBJECTIVE: The late asthmatic response provides a useful model of clinical asthma. The aim of the study was to examine metachromatic cell derived mediators and histamine releasability in vitro after in vivo allergen exposure in atopic subjects with and without asthma and relate them to the type of physiological response observed. METHODS: Bronchoalveolar lavage (BAL) cells were obtained 4 h after challenge from asthmatics exhibiting a single early response (EAR, n = 5), a dual response (LAR, n = 7), unchallenged (basal, n = 5), atopic non-asthmatic (ANA, n = 6) and non-atopic non-asthmatics (normal, n = 5). BAL histamine and tryptase concentrations and in vitro histamine release (HR) after stimulation with anti-IgE, allergen, A23187, conconavalin A and substance P were compared. RESULTS: Metachromatic cell numbers were lower in normal controls compared with all asthmatic groups and in LAR compared with EAR. Metachromatic cell derived mediators were higher in asthmatic compared with normal subjects. Spontaneous HR in LAR (20.5 +/- 5.0%) was lower than EAR (29.5 +/- 3.9%) and ANA (30.2 +/- 1.4%) (P < 0.05). No differences were seen in stimulated HR between EAR and LAR. HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). HR in ANA stimulated with anti-IgE was greater than LAR (P < 0.05). After stimulation with ionophore A23187 (1 microM), release was greater in LAR compared with basal (P < 0.05) and no different at 5 microM. All subject groups responded to substance P (SP) but was significantly more in the asthmatic subjects compared to normal controls (P < 0.05). Allergen challenge did not modify the response of asthmatic subjects to SP. CONCLUSION: Functional differences in metachromatic cell reactivity are present in atopic subjects 4h after in vivo allergen exposure which relate to the physiological response observed after this time and suggest that there is ongoing metachromatic cell degranulation subjects who subsequently develop LAR.