Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants, but without bronchial obstruction, has been found among subjects referred for suspected asthma. They have no well-defined diagnosis, and no objective diagnostic method has previously been available. These patients are more sensitive to inhaled capsaicin than are patients with asthma or healthy controls. The aim was to study cough and other capsaicin-induced symptoms and to test the effect of a drug (lidocaine) that inhibits nerve transmission in sensory nerves. METHODS: Twelve patients were provoked with three different concentrations of inhaled capsaicin solutions in a randomized, double-blind order. They all had asthma-like symptoms and were sensitive to chemical irritants, but had no IgE-mediated allergy or demonstrable bronchial obstruction. Before the provocations, the patients inhaled lidocaine or placebo (saline), also in a double-blind, randomized order. The results were expressed as the number of coughs and scores of various symptoms. RESULTS: The patients reacted in a dose-dependent way with cough, airway, and eye symptoms, which were significantly reduced after preinhalation of lidocaine. CONCLUSIONS: A drug that inhibits transmission in sensory nerves successfully blocked the number of coughs and other symptoms provoked by inhalation of capsaicin. This indicates that the mechanisms underlying chemical sensitivity in these patients may originate in the sensory nervous system, and we call this condition "sensory hyperreactivity".     

Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms

BACKGROUND: Capsaicin, the pungent ingredient in red pepper, is known to stimulate coughing via the sensory nervous system. Earlier studies showed that patients with airway symptoms induced by chemicals and strong scents cough more after inhalation of capsaicin than healthy control subjects and this has been interpreted as a hyperreactivity of airway sensory nerves. Our aim was to study airway sensitivity to inhaled capsaicin and the occurrence of airway symptoms induced by strong scents in patients who underwent a bronchial methacholine test, primarily because of suspected asthma. METHODS: Fifty-two consecutive patients referred for testing with methacholine were also provoked with inhaled capsaicin in increasing concentrations. Cough sensitivity to capsaicin was compared with that in 40 healthy control subjects. RESULTS: The patients coughed significantly more compared with the healthy control subjects with each dose of capsaicin (P < 0.0001). Twelve patients (23%) had a positive methacholine test, and of these, nine were diagnosed with asthma. There was no difference in capsaicin sensitivity between patients sensitive or insensitive to methacholine. CONCLUSIONS: The majority of the patients had no increased sensitivity to methacholine but did demonstrate sensory hyperreactivity (SHR). SHR appears to be a common diagnosis in investigations of patients with obscure airway symptoms.     

Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms

Background Investigations of patients referred for suspected asthma have revealed a little-known group with symptoms suggesting hyperreactive airways in whom provocation with methacholine does not lead to bronchial obstruction. The underlying mechanisms are not known, and no objective diagnostic method has been available.
Methods Provocations by inhalation of capsaicin solutions in stepwise increasing concentrations were used. Ten patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were compared to 10 patients with verified bronchial asthma and 28 healthy controls. Results The patients with asthma-like symptoms reacted with cough in a dose-dependent way. The number of coughs was significantly greater than in asthmatic patients and healthy controls. The latter two groups did not differ significantly.
Conclusions The capsaicin provocation test may be a valuable method for showing not only a greater cough sensitivity, but also asthma-like symptoms. The pathophysiology underlying the symptoms may be related to increased sensitivity of free, overactive nerve endings in the respiratory mucosa. Therefore, we suggest that this overreaction in the lower airways be called "sensory hyperreactivity".     

Provocations with perfume in the eyes induce airway symptoms in patients with sensory hyperreactivity

BACKGROUND: In earlier studies, we have shown that patients with a history of sensory hyperreactivity develop asthma-like symptoms when exposed to strong scents, even if they cannot smell any scent. METHODS: For study of possible pathophysiologic mechanisms behind sensory hyperreactivity, the patients' airways and eyes were separately exposed to a common inducing factor, perfume. Eleven patients with a history of hyperreactivity to chemical trigger factors, such as perfume, were provoked single-blindly in a placebo-controlled, randomized study. During airway exposure, the eyes were covered and, during the eye exposure, the patients inhaled fresh air. A special face mask or a nose clip was used to avoid any smell. RESULTS: During the 30-min exposure to perfume, there was a gradual increase in three main symptoms; i.e., eye irritation, cough, and dyspnea, after both the airway and eye exposures. The increases were significant compared with placebo. CONCLUSIONS: Asthma-like and other symptoms, such as irritation of the eyes, may be induced by exposure of both the airways and the eyes in patients with sensory hyperreactivity. This points to the importance of studying the sensory nervous system, not only in the airways, but also in other organs.     

Enhanced cough response to hyperpnea with cold air challenge in chronic cough patients showing increased cough sensitivity to inhaled capsaicin

BACKGROUND: Although many chronic cough patients have complained of an induced cough by cold air contact, the clinical relevance of cold air to inducing a cough and the diagnostic value of a hyperpnea with cold air (HCA) challenge to detect a hyperreactive cough reflex have not yet been investigated. METHODS: Recordings of cough counts after a 2-min HCA challenge were performed in 49 chronic cough patients and 15 healthy controls. Capsaicin cough provocation tests, which determine the threshold concentration of capsaicin that induces five or more consecutive coughs (C5), were also administered. RESULTS: After comparing the results from the capsaicin cough provocation tests of the patients and the controls, the chronic cough patients were divided into two groups: an increased cough sensitivity (ICS) group (n = 28) (C5 < 32 micromol/l) and a normal cough sensitivity (NCS) group (n = 21) (C5 >or= 32 micromol/l). The median value of induced cough counts after a HCA challenge was 11 coughs in patients with ICS and was a significantly enhanced cough response compared to that of the patients with NCS and healthy controls (four coughs, respectively). CONCLUSIONS: A simple cough provocation test using a HCA challenge may be useful for detecting ICS. It also suggests that hyperreactive cough reflexes may be one of the mechanisms of inducing chronic cough.     

Relationship of airway symptoms from chemicals to capsaicin cough sensitivity in atopic subjects

BACKGROUND: It is well known that some patients with allergy complain of airway symptoms from chemicals (ASCs) and strong odours. However, the importance of such information for the treatment of allergic disease is not known. Such symptoms in non-allergic patients have previously been shown to be related to increased sensory nerve reactivity, which is expressed as increased cough sensitivity to inhaled capsaicin. OBJECTIVE: The aim of this study was to examine ASC in atopic patients and relate it to cough reaction to capsaicin inhalation. MATERIALS AND METHODS: Fifty-seven consecutively chosen, skin prick-positive patients with symptoms of the upper and/or lower airways completed a questionnaire concerning ASC. The patients were then divided into two groups, those with and those without such symptoms. Both groups were provoked with inhaled capsaicin in three increments and compared with 73 healthy control subjects. RESULTS: Out of 57 atopic patients, 34 reported ASC agents and 23 did not. The patients with ASC were older (P<0.01) and coughed significantly more on capsaicin provocation (P<0.001), but did not differ from them with respect to the allergic disease or its treatment or to smoking habits. Patients with atopy but without ASC did not differ from healthy controls with regard to sensitivity to capsaicin inhalation. The scored degree of ASC was directly related to the number of coughs during the capsaicin provocation. CONCLUSION: ASC in atopic patients are related to increased airway sensory nerve reactivity. There is still no explanation for this in certain patients with atopy, but age may be a confounding factor.     

Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study

BACKGROUND: In a recent study, we showed that intranasal capsaicin spray gives a significant and long-term reduction of symptoms in nonallergic noninfectious perennial rhinitis patients. However, in daily practice, the studied application regimen proved to be impractical because of the large number of visits required in a short period of time. In the present study, we conducted a double-blind double-dummy parallel groups trial to determine whether a more practical capsaicin application schedule is equally effective. METHODS: Thirty patients were randomized into two different treatment regimens: one group received capsaicin five times on the first day at 1-h intervals. This was followed by a placebo dummy once every second or third day for a total of five treatments 2 weeks after the capsaicin application (group A). The other group (B) received the placebo dummy five times on the first day followed by capsaicin once every second or third day for a total of five treatments 2 weeks after the placebo application. RESULTS: The visual analogue scale scores for overall nasal symptoms, rhinorrhea and nasal blockage showed significant decrease after the start of treatment in both groups, with a significantly steeper decrease in group A. A significant reduction in cold dry air dose responsiveness was also found up to 9 months after therapy in both groups, reflecting a decrease in nasal hyperreactivity. No significant changes in safety data (smell, blood pressure, heart rate) were found. CONCLUSIONS: We conclude that intranasal capsaicin seems safe to use and that five treatments of capsaicin on a single day is at least as effective as five treatments of capsaicin in 2 weeks.     

Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma

The prevalence of allergic diseases has increased dramatically during the last four decades and is paralleled by a striking increase in iron intake by infants in affluent societies. Several studies have suggested a link between increased iron intake and the marked increase in prevalence of allergic diseases. We hypothesized that the increased iron intake by infants offers an explanation for the increased prevalence of allergic disease in industrialized societies during the past four decades. A well-established mouse model of ovalbumin (OVA)-driven allergic asthma was used to test the effects of differences in iron intake and systemic iron levels on the manifestations of allergic asthma. Surprisingly, iron supplementation resulted in a significant decrease in airway eosinophilia, while systemic iron injections lead to a significant suppression of both allergen-induced airway eosinophilia and hyperreactivity compared to placebo. In contrast, mice fed on an iron-deprived diet did not show any difference in developing experimentally induced allergic asthma when compared to those fed on an iron-sufficient control diet. In contrast to our hypothesis, airway manifestations of allergic asthma are suppressed by both increased levels of iron intake and systemic iron administrations in the mouse model.     

Placebo-controlled challenges with perfume in patients with asthma-like symptoms

A group of nine patients with respiratory symptoms after nonspecific irritating stimuli, but without any IgE-mediated allergy or demonstrable bronchial obstruction, were referred to the asthma/allergy outpatient department for evaluation of suspected asthma. In order to find a provocation model and objectively assess these patients' symptoms in controlled studies, provocation with perfume or placebo was performed. The same patients were also subjected to perfume provocation with or without a carbon filter mask to ascertain whether breathing through a filter with active carbon could prevent the symptoms. The patients breathed through the mouth during the provocations, as they used a nasal clamp to prevent any smell of perfume. We found that the patients' earlier symptoms could be verified by perfume provocation. Breathing through the carbon filter had no protective effect. The conclusion is that symptoms suggesting hyperreactivity of the respiratory tract and asthma can be provoked by perfume without the presence of bronchial obstruction, and that using a carbon filter mask has no preventive effect. The symptoms are not transmitted via the olfactory nerve, since the patients could not smell the perfume, but they may have been induced by a trigeminal reflex via the respiratory tract or by the eyes.     

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.     

Physical capacity and dyspnea in patients with asthma-like symptoms but negative asthma tests

Ringsberg KC, Wetterqvist H, Löwhagen O, Sivik T. Physical capacity and dyspnea in patients with asthma-like symptoms but negative asthma tests.
Ten female patients with asthma-like symptoms but negative asthma tests 'study group' were compared with 10 female asthmatics in an exercise test with and without pretreatment with β₂-stimulants. The aim was to determine whether the asthma-like symptoms in the patients of the study group could be explained by bronchoconstriction, circulatory abnormalities, or physical unfitness when provoked physically, and whether the exercise test could be used to distinguish these patients from asthmatics. Without pretreatment, the asthma group reacted with bronchoconstriction, as indicated by postexercise systematic changes in PEFR, FEV₁, FVC, and S a_o2, which were not seen in the study group. The groups differed in the ratings of "difficulty in getting air", as only the asthma group had significantly lower ratings when pretreated. The study group's mean test performance was 94 W; the asthma group's was 106 W. The low performance was not explained by disturbances in heart rate, electrocardiogram, or blood pressure or physical unfitness. The exercise test was found to distinguish between the groups, especially for bronchoconstriction, oxygen saturation, and ratings of dyspnea. It could be used complementary to lung function tests to eliminate bronchoconstriction, circulatory abnormalities, and physical unfitness as a cause of the asthma-like symptoms.     

Clinical health education for patients with asthma-like symptoms but negative asthma tests

BACKGROUND: Patients with asthma-like symptoms but negative asthma tests often state that they lack strategies to cope with their symptoms. The aim of the study was to determine whether a problem-based health education program had a beneficial effect on the participants' experience of symptoms and subjective health. METHODS: Thirty-eight patients, consecutively drawn from an outpatient clinic for asthma and allergy, were randomly allocated to an intervention group (I group, n=18) and a control group (C group, n=20). The I group, divided into three subgroups, met on seven occasions over 5 months. The program had a multidisciplinary approach, used exercises inspired by cognitive behavioral therapy, and was performed according to the principles of problem-based learning. All patients answered the Nijmegen Symptom Questionnaire (NQ) and the SF-36 health survey before and 2 months after the training was terminated. RESULTS: Before the program, there were no significant differences between the groups in their earlier experience of symptoms. After it, the I group scored significantly lower on shortness of breath (P=0.001) and central tetany (P=0.05) than the C group. On both test occasions, the asthma-like patients scored lower on all variables of the SF-36 than the reference groups of asthmatics and healthy subjects. No significant differences were seen between the I group and the C group except for vitality, in which the C group scored lower before the intervention. CONCLUSIONS: Patients with asthma-like symptoms but negative asthma tests benefit from taking part in a problem-based health education program. It mainly reduces the frequency of symptoms.     

CD4+ T cells from mice with intestinal immediate-type hypersensitivity induce airway hyperreactivity

BACKGROUND: A subset of food-allergic patients does not only respond clinically with symptoms in the gastro-intestinal tract but also with asthmatic reactions. OBJECTIVE: The aim of this study was to analyse whether CD4+ T cells from mice with intestinal immediate-hypersensitivity reactions to food allergen are involved in the development of experimental asthma. METHODS: BALB/c mice were intraperitoneally sensitized to ovalbumin (OVA), followed by repeated intra-gastric (i.g.) OVA challenges. Control animals were either sham-sensitized or sham-challenged with phosphate-buffered saline (PBS). Duodenum, jejunum, ileum and colon were histologically examined. CD4+ T cells from mesenteric lymph nodes were transferred from various donor groups into recipient mice that received either OVA or PBS aerosol challenges. Recipients were analysed by measurements of lung function using head-out body-plethysmography and examination of broncho-alveolar lavage and lung histology. RESULTS: The highest levels of OVA-specific IgE antibody levels were detected in OVA-sensitized and OVA-challenged mice. Throughout the lower intestinal tract, a marked infiltration with eosinophils was observed, and goblet cell numbers as well as goblet cell area were significantly increased. The villus/crypt ratio was decreased compared with controls. The transfer of CD4+ T cells from mesenteric lymph nodes of OVA-sensitized and OVA-challenged mice triggered airway hyperreactivity and eosinophilic airway inflammation in recipients aerosol challenged with OVA, but not with PBS. CONCLUSION: We conclude that CD4+ T cells from mesenteric lymph nodes of mice with allergen-induced immediate-type hypersensitivity reactions in the gut are able to transfer the phenotype of experimental asthma.     

Intracisternal capsaicin: Selective degeneration of chemosensitive primary sensory afferents in the adult rat

The present study reports that intracisternal administration of capsaicin induces the selective degeneration of chemosensitive primary sensory afferents and results in a practically complete abolition of chemical pain sensitivity in the adult rat. This treatment, however, failed to affect neurogenic inflammation in the corresponding skin areas. Accordingly, intracisternal capsaicin induces merely the degeneration of the centrally directed axons of chemosensitive primary sensory neurones (CPSNs). To indicate their particular dual function, CPSNs are proposed to be termed secreto-sensory nociceptive neurones. It is suggested that these neurones, through the release of neurogenic factor(s) at their peripheral end, may effectively modulate the afferent input related to pain sensation at the level of sensory receptors.     

Airway inflammation and cough sensitivity in cough-variant asthma

BACKGROUND: Mechanisms underlying cough and bronchoconstriction in patients with cough-variant asthma (CVA) are not well established. Differences in location or degree of activation of eosinophils and allergic cytokines have been suggested as the likely causes. To address this issue, we have carried out a comparative study of airway inflammatory markers between patients with CVA and classic asthma (CA). The relationship between these markers with airway hyperresponsiveness (AHR) and cough sensitivity has also been studied. METHODS: Twenty-seven non-smokers and steroid-naive patients with CVA (12) and CA (15) were examined. Capsaicin challenge, histamine bronchoprovocation test, nitric oxide levels in exhaled air and sputum induction were performed in all of them. Differential cell sputum recount and supernatant concentrations of eosinophil granule-derived cationic proteins (ECP), interleukin (IL)5, IL8 and tumour necrosis factor (TNF)-alpha were also measured. RESULTS: There were no significant differences in either the inflammatory pattern of soluble markers or differential cell counts between CA and CVA. Histamine PC20 was correlated with IL-5 in CVA, whereas it was associated with sputum eosinophilia in CA. Cough sensitivity (log C5) and histamine PC20 were inversely related in CA. CONCLUSIONS: Although the pattern of inflammatory sputum markers in patients with asthma and cough-variant asthma is similar, its relation with bronchial hyperreactivity and cough sensitivity is different in each group.     

Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge

Although nasal hyperreactivity (NHR) is a common feature in patients suffering from allergic and nonallergic rhinitis, it is widely neglected during history taking, underdiagnosed in the majority of patients with rhinitis and rhinosinusitis, not considered as an outcome parameter in clinical trials on novel treatments for rhinitis and rhinosinusitis, and no target for routine treatment. In contrast to the simple nature of diagnosing NHR by a history of nasal symptoms induced by nonspecific exogenous and/or endogenous triggers, quantification is hardly performed in routine clinic given the lack of a simple tool for its diagnosis. So far, limited efforts have been invested into gaining better insight in the underlying pathophysiology of NHR, helping us to explain why some patients with inflammation develop NHR and others not. Of note, environmental and microbial factors have been reported to influence NHR, contributing to the complex nature of understanding the development of NHR. As a consequence of the neglect of NHR as a key clinical feature of rhinitis and chronic rhinosinusitis (CRS), patients with NHR might be suboptimally controlled and/or dissatisfied with current treatment. We here aim to provide a comprehensive overview of current knowledge on the pathophysiology, and the available tools to diagnose and treat NHR.     

慢性咳嗽患者咳嗽敏感性的影响因素

目的探讨慢性咳嗽患者咳嗽敏感性的影响因素.方法按照慢性咳嗽病因诊断程序,人选并诊断慢性咳嗽患者.通过辣椒素咳嗽激发试验测定慢性咳嗽患者(治疗前)的气道咳嗽敏感性,以最先诱发5次或以上咳嗽的辣椒素溶液浓度(C5)的对数作为咳嗽阈值.分析咳嗽阈值与咳嗽积分、年龄、性别、病程、肺通气功能与诱导痰炎性细胞分类间的相关性.结果入选并获得明确诊断的不同病因慢性咳嗽患者共计150例.单因素相关分析显示,慢性咳嗽患者的咳嗽阈值与日间咳嗽积分、性别、年龄、咳嗽病程及诱导痰嗜酸细胞百分比有相关,r分别为-0.175、-0.305、-0.297、-0.238及0.173,P均<0.05;咳嗽阈值与夜间咳嗽积分、痰中性粒细胞百分比、痰巨噬细胞百分比、痰淋巴细胞百分比及肺通气功能[第1秒用力呼气容积占预计值的百分比(FEV1/pred%)、用力呼气中段流速占预计值的百分比(MMEF/pred%)]均不相关,P均>0.05.多元线性回归分析显示,咳嗽阈值仅与性别、咳嗽病程有关(P均<0.01).结论咳嗽敏感性与咳嗽症状积分反映咳嗽程度的不同特征,性别与咳嗽病程可能影响慢性咳嗽患者的咳嗽敏感性.     

Attenuating effect of H+K+ATPase inhibitors on airway cough hypersensitivity induced by allergic airway inflammation in guinea-pigs

BACKGROUND: Gastrooesophageal reflux (GER) is a frequent cause of chronic cough. Several investigators have indicated that inhibitors of H(+)K(+)ATPase (proton pump inhibitors; PPIs) could relieve coughing via inhibition of acid reflux. However, we considered that PPIs might directly inhibit increased cough reflex sensitivity. OBJECTIVE: The present study was designed to examine whether PPIs directly inhibit antigen-induced increase in cough reflex sensitivity and to elucidate the mechanism. METHODS: Actively sensitized guinea-pigs were challenged with aerosol antigen (ovalbumin, OVA) and cough reflex sensitivity to inhaled capsaicin was measured 24 h later. The PPIs (omeprazole and rabeprazole) or the histamine H(2) blocker cimetidine were administered intraperitoneally 1 h before OVA challenge and before measuring cough reflex sensitivity, then bronchoalveolar lavage fluid (BALF) was immediately collected. The pH of the fluid obtained by bronchial washing was determined after examining the effect of rabeprazole on the cough response to capsaicin. RESULTS: The number of coughs elicited by capsaicin was significantly increased 24 h after challenge with OVA compared with saline, indicating antigen-induced increase in cough reflex sensitivity. Both PPIs dose dependently and significantly inhibited antigen-induced cough hypersensitivity. Omeprazole did not influence the antigen-induced increase in the total number of cells or ratio (%) of eosinophils in BALF. Cimetidine did not affect the antigen-induced cough hypersensitivity or cellular components of BALF. The pH of the bronchial washing fluid was significantly decreased in antigen-challenged animals. Rabeprazole did not affect the antigen-induced decrease in the pH of bronchial washing fluid. CONCLUSION: These findings show that PPIs, but not histamine H(2) blockers, can directly decrease antigen-induced cough reflex hypersensitivity, while the mechanism remains unclear.     

大鼠气道炎症与支气管高反应性的关系及茶碱的抑制作用

目的：分析致敏大鼠在抗原攻击后嗜酸粒细胞炎性浸润为特征的气道炎症与支气管高反应性的相关性,并观察不同剂量茶碱的作用。方法：在卵白蛋白（OA）致敏的大鼠,用1% OA气雾攻击后,以计算机辅助技术测定气道管壁面积、支气管周围嗜酸粒细胞数量以及对乙酰甲胆碱（MCh）的反应性。结果：OA攻击可诱导气道炎症反应和支气管高反应性,两者间有显著正相关。口服7 d茶碱（1-12.5 mg/kg, bid）可减轻气道炎症（细支气管壁肿胀和肺嗜酸粒细胞浸润）,对支气管高反应性也有一定抑制作用。结论：提示支气管高反应性与气道炎症有正相关,小剂量茶碱有抗气道过敏性炎症的作用。     

Association between − 308 tumour necrosis factor promoter polymorphism and bronchial hyperreactivity in asthma

BACKGROUND: Tumour necrosis factor (TNF) is a pivotal cytokine in the inflammation underlying asthma. The TNF gene is located in the polymorphic HLA class 3 region on chromosome 6p. Several polymorphisms in this region have been described and associated with alteration of TNF secretion in vitro. OBJECTIVE: In this study we tested the hypothesis that two such polymorphisms, lymphotoxin alpha NcoI B*1 and -308 TNF2 may be components of the genetic predisposition to asthma. METHODS: Five hundred and fifty-six random individuals were studied, comprising approximately equal numbers of asthmatic subjects, with or without atopy, and a nonatopic nonasthmatic control group. In addition, 355 subjects (172 asthmatics) from 60 multiplex families were typed at the LTalpha NcoI locus. RESULTS: There was an association between allele two of the -308 TNF polymorphism and bronchial hyperreactivity (OR 2.12, 95% CI 1.04-4.32, P = 0.036). However, there was no association with LTalpha NcoI alleles. To determine whether this was influenced by linkage disequilibrium within the MHC, 91 subjects with bronchial hyperreactivity and 85 control subjects were typed for class 2 and 3 alleles. Following identification of the extended TNF2 haplotype, we found no independent association of these alleles with BHR. CONCLUSIONS: We conclude that the -308 TNF2 promoter polymorphism may form a component of the genetic predisposition to BHR in asthma.