Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge‐induced cough

Background and Aims: Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge‐induced cough in assessing the efficacy of inhaled corticosteroid treatment. Methods: A total of 16 steroid‐naïve asthmatics and 10 non‐asthmatic, symptomatic controls received 800‐µg beclomethasone (Beclomet Easyhaler®, Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV₁(PC₂₀). Results: CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209–1168) to 73.6 (29.8–182) coughs per mg/mL (P = 0.002). Their PC₂₀ levels were 1.31 (1.07–1.60) and 1.91 (1.33–2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC₂₀ level, in CCR level or in symptom frequency in non‐asthmatic subjects during the treatment. Conclusions: Hypertonic histamine challenge‐induced cough and PC₂₀ are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably. Please cite this paper as: Purokivi M, Koskela H, Koistinen T, Peuhkurinen K and Kontra KM. Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge‐induced cough. The Clinical Respiratory Journal 2010; 4: 67–73.     

Challenges in managing difficult‐to‐treat asthma in children: Stop,look, and listen

It is recognized that asthma places a significant economic burden on the United States, with a total cost of $81.9 billion total costs including costs incurred by absenteeism and mortality. Severe asthma places a large burden of morbidity on children and their caregivers, including severe exacerbations, medication side effects, increased missed school days leading to impaired school performance, and lower caregiver quality of life. Therefore, we need to take a careful look at how we can make asthma care more efficient and cost effective, especially for those children with severe asthma. The 2019 American Thoracic Society symposium reported in this theme issue presented four aspects of managing severe asthma in children that merit attention including patient variables that affect severe asthma, understanding patient behaviors around medications, the appropriate use of bronchoscopy in diagnosis and management of severe asthma, and also the rational use of biologic therapy. This editorial will summarize key points in each of these reviews and prompt a more careful reading of each contribution.     

Utility of cough response during hypertonic histamine challenge in diagnosing asthma

Airway responses to bronchial provocation tests are traditionally assessed with spirometry which necessitates considerable patient co-operation. It has been shown that coughing during bronchial provocation tests is related to the degree of bronchoconstriction which, in turn, is independent of patient co-operation. The aim of the present study was to evaluate the utility of coughing induced by the hypertonic histamine challenge in the differential diagnosis of asthma in a clinically relevant patient population. The study population consisted of 25 healthy volunteers, 30 asthmatics, and 82 non-asthmatic subjects with respiratory symptoms due to other diseases. Hypertonic histamine solution was administered with ultrasonic nebuliser with the challenges being videotaped. The cough response was expressed as the cumulative number of coughs divided by the final histamine concentration administered (CCR). The geometric mean (95% CI) of CCR for asthmatics was 302 (166-562) coughs per mg/ml, for the symptomatic controls 29.5 (20.0-43.7) coughs per mg/ml (p<0.001) and for the healthy controls 6.61 (3.02-14.5) (p<0.001) coughs per mg/ml. According to the ROC curve, the optimal cut-off point for logCCR was 2.22, with the specificity and sensitivity to detect asthma among symptomatic subjects being 86% and 70%. Cough response to hyperosmolar challenge may be useful in the differential diagnosis of airway diseases.     

高渗盐水与组胺支气管激发试验在咳嗽变异性哮喘相关性的研究

目的研究探讨高渗盐水与组织胺支气管激发试验在咳嗽变异性哮喘患者中相关性。方法将12名咳嗽变异性哮喘患者分别行组织胺和高渗盐水支气管激发试验,两次试验间隔一周,记录组胺和高渗盐水的累计激发量（PD20）,对其行相关性分析研究。结果两者之间相关系数为0．794,有显著性统计学意义（P〈0．05）。结论两者在咳嗽变异性哮喘中有较强的相关性。     

Determination of airway hyper-reactivity in asthmatic children: a comparison among exercise, nebulized water, and histamine challenge

An easy and accurate method of assessing bronchial hyper-reactivity could be of great value in identifying and classifying the degree of severity of asthma in children. The sensitivity and specificity of three methods of provocation, ie, histamine, nebulized water, and exercise, were compared in 20 asthmatic and 20 control children between ages 5 and 13 years. Three clinical categories of severity ranging from slight (Group 1) through moderate (Group 2) to severe asthma (Group 3) were identified. The three methods were compared in each subgroup for detecting a tendency to bronchospasm. An inverse correlation (-0.57) was found between the histamine dose and clinical degree of severity, whereas distilled water and exercise proved to be too insensitive for identifying Group 1 asthmatics. Histamine challenge in children is a safe and sensitive technique for identifying asthma and for monitoring the severity of the disease during follow-up.     

Cold air challenge in children with asthma

A study was designed to determine the sensitivity and specificity of a cold air bronchial provocation test. A total of 18 children with asthma (mean age 12 years) and 18 normal children (mean age 14 years) were studied. The cold air challenge consisted of a 4 min period of isocapnic hyperventilation of subfreezing air (mean temperature -15 degrees C). In-Induced response in forced expiratory volume in 1 sec (FEV1) expressed as a percentage of predicted normal values was obtained at 4, 6, and 8 min post-challenge. The average response to the cold air was a 27% decrease of FEV1 in asthmatics, which was significantly different from that of the normal children, who showed no statistically significant drop. In both the asthmatic and normal groups, the maximal drop in FEV1 had occurred by the time measurements 4 min post-challenge had been made. At that time, the smallest overlap was observed between normal and asthmatic children. This suggests that the fourth minute post-challenge can be chosen as a cut-off time to distinguish normal from asthmatic children. Considering a decrease of FEV1 greater than 10% as a positive test, the sensitivity of the cold air challenge was 95% and the specificity was 89%.     

Exercise-induced asthma and the use of hypertonic saline aerosol as a ronchial challenge

Abstract Exercise induced asthma is a common complaint and the prevalence appears to be increasing worldwide. Once confined to the research domain of university teaching hospitals, the study of EIA has extended into the school playground, defence force establishments and sports institutions. Standardized protocols have been developed to study EIA in the laboratory and in the field. A surrogate challenge using eucapnic or isocapnic hyperventilation with dry air is becoming popular because it has advantages over exercise, at least for adults. The stimulus that leads the airways to narrow is caused by the inhalation of dry air during hyperventilation and exercise, during which water is evaporated from the airways in order to condition the inspired air. The mechanism whereby the airways narrow is thought to be due to the dehydrating effects of water loss, particularly in relation to its potential to cause the airways to become hyperosmolar. Mast cell mediators such as histamine and the leucotrienes are probably involved in EIA because specific antagonists reduce severity. As a result of the osmotic theory of EIA, studies were carried out to determine whether subjects with EIA were sensitive to the effects of increasing airway osmolarity by inhalation of hyperosmolar aerosols of sodium chloride. A challenge protocol using an aerosol of 4.5% sodium chloride, generated from an ultrasonic nebulizer, has been used to identify persons with asthma and to assess response to drug therapy. There are many similarities between responses to exercise, hyperventilation and hypertonic saline in the physiological and biochemical responses and the responses to drugs. Challenge with hypertonic saline is easier and cheaper to use because expensive equipment and a source of dry air is not required as with exercise or hyperventilation. The ability to obtain a dose-response curve rather than a single response and the ability to collect inflammatory cells at the same time make challenge with hypertonic saline an attractive technique to study patients suspected of having asthma.     

The challenge of asthma in adolescence

The adolescents with asthma are a distinct group of patients with different problems and needs compared to children and adults. Specific issues of asthma in adolescence are the variability of the clinical spectrum, the presence of particular risk factors for the persistence of symptoms, underdiagnosis and undertreatment of the disease. Refusal of the sick role, denial of symptoms, carelessness about dangerous inhalation exposure, erratic self-medication, overexertion without taking precautions against exercise-induced asthma, and a poor relationship between patients, their families, and often doctors are the main obstacles to successful management of asthma in this critical age. There are also major problems of compliance for these patients. The goal of optimal quality of life will be achieved only if the physician thoroughly understands the adolescent's needs and provides optimal care.     

The efficacy and safety of mannitol challenge in a workplace setting for assessing asthma prevalence

Objective: There is no standard definition of asthma for epidemiological purposes; most surveys use symptoms and bronchial hyperresponsiveness. Few studies tested mannitol challenge test (MCT) in occupational settings. We sought to determine efficacy and safety of MCT in detecting subjects with asthma symptoms in the workplace. Methods: In this cross-sectional study we recruited 908 workers in 2 universities; they underwent a respiratory questionnaire, spirometry, skin prick tests, and MCT. Results: Eight hundred and eleven subjects completed the study; 11.1% had a positive MCT; 8.14% had asthma. MCT had low sensitivity (35.4–61.9%) but high specificity (90.2–94.9%) to detect symptomatic individuals. The most prevalent symptom was wheezing in the last 12 months. Twenty-four of those with a positive MCT (26.7%) had no positive replies to the questions on asthma symptoms. Among subjects with a positive MCT, 71.9% achieved 95% of baseline FEV₁ after 15 minutes of salbutamol recovery treatment. Nine subjects (1.1%) had adverse events that prevented the test from being completed. Conclusions: MCT has high specificity but low sensitivity to detect symptomatic subjects in the workplace. It may detect subjects with hyperresponsiveness but no symptoms, who could be at risk of developing airway diseases. The test is safe and well tolerated.     

Pediatric obesity‐related asthma: A prototype of pediatric severe non‐T2 asthma

Childhood obesity contributes to many diseases, including asthma. There is literature to suggest that asthma developing as a consequence of obesity has a nonallergic or non‐T2 phenotype. In this review, obesity‐related asthma is utilized as a prototype of non‐T2 asthma in children to discuss several nonallergic mechanisms that underlie childhood asthma. Obesity‐related asthma is associated with systemic T helper (Th)1 polarization occurring with monocyte activation. These immune responses are mediated by insulin resistance and dyslipidemia, metabolic abnormalities associated with obesity, that are themselves associated with pulmonary function deficits in obese asthmatics. As in other multifactorial diseases, there is both a genetic and an environmental contribution to pediatric obesity‐related asthma. In addition to genetic susceptibility, differential DNA methylation is associated with non‐T2 immune responses in pediatric obesity‐related asthma. Initial investigations into the biology of non‐T2 immune responses have identified the upregulation of genes in the CDC42 pathway. CDC42 is a RhoGTPase that plays a key role in Th cell physiology, including preferential naïve Th cell differentiation to Th1 cells, and cytokine production and exocytosis. Although these novel pathways are promising findings to direct targeted therapy development for obesity‐related asthma to address the disease burden, there is evidence to suggest that dietary interventions, including diet modification, rather than caloric restriction alone, decrease disease burden. Adoption of a diet rich in micronutrients, including carotenoids and 25‐OH cholecalciferol, a vitamin D metabolite, may be beneficial since these are positively correlated with pulmonary function indices, while being protective against metabolic abnormalities associated with the obese asthma phenotype.     

咳嗽变异型哮喘患者11例咳嗽受体敏感性观察

目的　探讨咳嗽变异型哮喘（ＣＶＡ）的咳嗽机制。方法　对１１ 例咳嗽变异型哮喘患者、７ 例哮喘稳定期患者、１０ 例急性支气管炎迁延期患者和１０ 例健康成年人,以组胺吸入进行激发感应ＦＥＶ１ 下降２０ ％ 的浓度（ＰＣ２０ＦＥＶ１）和吸入酒石酸测定咳嗽受体敏感性（ＣＲＳ５）。结果　ＣＶＡ患者、哮喘稳定期患者、急性支气管炎迁延期患者和健康成年人的ＰＣ２０ＦＥＶ１ 分别为（３－７５ ±１－５８）ｇ／Ｌ、（２－０１ ±１－４６）ｇ／Ｌ、（１７－４ ±１－５２）ｇ／Ｌ 和（１８－０３ ±１－６９）ｇ／Ｌ,ＣＶＡ 患者显著降低（ Ｐ ＜ ０－０１）;ＣＲＳ５ 分别为（３８－０１ ±２－０４）ｇ／Ｌ、（８２－２８ ±１－４５）ｇ／Ｌ、（３５－８８ ±２－１８）ｇ／Ｌ、（１１４－８１±１－３３）ｇ／Ｌ,ＣＶＡ 患者显著降低（ Ｐ＜ ０－０１） 。结论　ＣＶＡ 患者咳嗽受体敏感性的阈值明显降低。     

Subject discomfort associated with the histamine challenge in a population study

BACKGROUND: Many review articles report the safety and lack of serious side-effects associated with the histamine challenge. Even though methacholine and hypertonic saline are more commonly used to measure airway responsiveness, histamine challenges are used in many countries around the world. Levels of subjects discomfort after a challenge have not been quantified.This study quantified the incidence, severity and duration of subject discomfort after histamine challenge. METHODS: Ninety-nine subjects were recruited in an Australian multi-centre population-based study of the genetic epidemiology of asthma. Subjects completed a histamine challenge with final cumulative dose 3.2 micromol. Immediately, and 10 min, after challenge subjects rated their discomfort for cough, headache, throat irritation, hoarse voice and flushed. Research personnel also reported their perception of subjectdiscomfort. RESULTS: Subjects and research personnel reported a small degree of subject discomfort for all symptoms immediately after the histamine challenge. Overall, median symptom scores were less than 1.5 out of 10. Discomfort scores improved 10 min after challenge and cough, throat irritation and flushed improved significantly CONCLUSIONS: This study confirms the tolerability of the histamine challenge.