eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.

BACKGROUND: Genome-wide association studies (GWASs) have identified various genes associated with asthma, yet, causal genes or single nucleotide polymorphisms (SNPs) remain elusive. We sought to dissect functional genes/SNPs for asthma by combining expression quantitative trait loci (eQTLs) and GWASs. METHODS: Cis-eQTL analyses of 34 asthma genes were performed in cells from human bronchial epithelial biopsy (BEC, n = 107) and from bronchial alveolar lavage (BAL, n = 94). RESULTS: For TSLP-WDR36 region, rs3806932 (G allele protective against eosinophilic esophagitis) and rs2416257 (A allele associated with lower eosinophil counts and protective against asthma) were correlated with decreased expression of TSLP in BAL (P = 7.9 × 10(-11) and 5.4 × 10(-4) , respectively) and BEC, but not WDR36. Surprisingly, rs1837253 (consistently associated with asthma) showed no correlation with TSLP expression levels. For ORMDL3-GSDMB region, rs8067378 (G allele protective against asthma) was correlated with decreased expression of GSDMB in BEC and BAL (P = 1.3 × 10(-4) and 0.04) but not ORMDL3. rs992969 in the promoter region of IL33 (A allele associated with higher eosinophil counts and risk for asthma) was correlated with increased expression of IL33 in BEC (P = 1.3 × 10(-6) ) but not in BAL. CONCLUSIONS: Our study illustrates cell-type-specific regulation of the expression of asthma-related genes documenting SNPs in TSLP, GSDMB, IL33, HLA-DQB1, C11orf30, DEXI, CDHR3, and ZBTB10 affect asthma risk through cis-regulation of its gene expression. Whenever possible, disease-relevant tissues should be used for transcription analysis. SNPs in TSLP may affect asthma risk through up-regulating TSLP mRNA expression or protein secretion. Further functional studies are warranted.

Roflumilast for asthma: Efficacy findings in placebo-controlled studies.

BACKGROUND: The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. AIM: To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12-70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV1) of 45-90%. Roflumilast was investigated at doses of 125, 250 and 500 µg versus placebo. In two studies, 500 µg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 µg fluticasone propionate, or 400 µg beclomethasone dipropionate (BDP). Improvement in FEV1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. RESULTS: Roflumilast consistently improved FEV1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV1 which was statistically significant for 500 µg roflumilast/400 µg BDP versus placebo/400 µg BDP. CONCLUSION: Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Roflumilast for asthma: Safety findings from a pooled analysis of ten clinical studies.

BACKGROUND: The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. AIM: To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. SUBJECTS AND METHODS: The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 µg, were analyzed. At randomization patients had a forced expiratory flow of 45-100%. RESULTS: Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 µg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. CONCLUSIONS: The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177, NCT00076076, NCT00163527.

Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trial.

BACKGROUND: Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. METHODS: A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1 ) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. RESULTS: Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: -55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. CONCLUSIONS: FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.

Severe chronic allergic (and related) diseases: a uniform approach--a MeDALL--GA2LEN--ARIA position paper.

Concepts of disease severity, activity, control and responsiveness to treatment are linked but different. Severity refers to the loss of function of the organs induced by the disease process or to the occurrence of severe acute exacerbations. Severity may vary over time and needs regular follow-up. Control is the degree to which therapy goals are currently met. These concepts have evolved over time for asthma in guidelines, task forces or consensus meetings. The aim of this paper is to generalize the approach of the uniform definition of severe asthma presented to WHO for chronic allergic and associated diseases (rhinitis, chronic rhinosinusitis, chronic urticaria and atopic dermatitis) in order to have a uniform definition of severity, control and risk, usable in most situations. It is based on the appropriate diagnosis, availability and accessibility of treatments, treatment responsiveness and associated factors such as comorbidities and risk factors. This uniform definition will allow a better definition of the phenotypes of severe allergic (and related) diseases for clinical practice, research (including epidemiology), public health purposes, education and the discovery of novel therapies.

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial.

Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma. In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n=132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1)% predicted. Secondary end-points included morning peak expiratory flow, FEV1% pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire. No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study. Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

Is intrinsic asthma synonymous with infection?

Rackemann described the 'intrinsic asthma' population over 50 years ago as a unique subgroup that was characterized by onset of progressive loss of lung function beginning later in life, possibly after a respiratory infection. It has also been associated with a female predominance, aspirin-sensitive bronchospasm, and nasal polyposis. While the aetiology is not understood, we propose that persistent respiratory infections play a central role in the development of intrinsic asthma.

Histamine inhibition of neutrophil lysosomal enzyme release: an H2 histamine receptor response.

Human polymorphonuclear leukocytes treated with cytochalasin B release the lysosomal enzyme beta glucuronidase during contact with serum-activated zymosan particles. Histamine increases intracellular cyclic adenosine monophosphate and inhibits release of this enzyme. The H2 antihistamine metiamide blocks the histamine inhibition of lysosomal enzyme release and the increase in the intracellular adenoisine 3,5'-monophosphate of granulocytes. Chlorpheniramine, an H1 antihistamine, did not block the histamine inhibition of granulocyte lysosomal enzyme release.

A new perspective on concepts of asthma severity and control.

Concepts of asthma severity and control are important in the evaluation of patients and their response to treatment but the terminology is not standardised and the terms are often used interchangeably. This review, arising from the work of an American Thoracic Society/European Respiratory Society Task Force, identifies the need for separate concepts of control and severity, describes their evolution in asthma guidelines and provides a framework for understanding the relationship between current concepts of asthma phenotype, severity and control. "Asthma control" refers to the extent to which the manifestations of asthma have been reduced or removed by treatment. Its assessment should incorporate the dual components of current clinical control (e.g. symptoms, reliever use and lung function) and future risk (e.g. exacerbations and lung function decline). The most clinically useful concept of asthma severity is based on the intensity of treatment required to achieve good asthma control, i.e. severity is assessed during treatment. Severe asthma is defined as the requirement for (not necessarily just prescription or use of) high-intensity treatment. Asthma severity may be influenced by the underlying disease activity and by the patient's phenotype, both of which may be further described using pathological and physiological markers. These markers can also act as surrogate measures for future risk.

Stability of asthma control with regular treatment: an analysis of the Gaining Optimal Asthma controL (GOAL) study.

BACKGROUND: Uncontrolled asthma is characterized by variability. Current asthma guidelines recommend focussing on the achievement and maintenance of control but few studies have examined in detail, using composite measures of control, the stability and potential duration of control once achieved. In this post-hoc analysis of the results of the Gaining Optimal Asthma controL (GOAL) study, we examine the association between the level of asthma control achieved during the step-up phase of the study and the stability of control experienced during the maintenance phase. METHODS: GOAL was a 1-year, randomized, stratified, double-blind study of 3421 patients with uncontrolled asthma, which compared salmeterol/fluticasone propionate combination with fluticasone propionate in achieving two composite, guideline-based measures of control: totally controlled and well-controlled asthma. We analysed the proportion and duration of time spent in control, the effect of treatment on asthma stability, and the impact of asthma control stability on unscheduled use of healthcare resources. RESULTS: In patients achieving well-controlled or totally controlled asthma, at least well-controlled asthma was maintained for a median of almost 3 and 6 months, and for more than 85% and 95% of weeks of follow-up, respectively. A high level of stability was confirmed in a Markov analysis investigating transitional probability of change in control status. Variability in control was associated with increased probability of an unscheduled healthcare resource use (odds ratio: 1.06, P < 0.001). CONCLUSIONS: Most patients achieving guideline-defined control can maintain at least a similar level of control with regular, stable dosing, with little likelihood of losing control.

Decreased H2 histamine response of granulocytes of asthmatic patients.

Increased bronchial sensitivity to inhaled histamine in asthma is well known. The mechanism of this increased bronchial sensitivity is not known nor has it been demonstrated that isolated cells respond abnormally to histamine. Polymorpho-nuclear leukocytes (PMNs) provide a homogeneous cell population to study agonist response. Release of granulocyte lysosomal enzymes is inhibited by agonists increasing the PMN cyclic AMP concentration. The release of the lysosomal enzyme beta glucuronidase by serum-activated particles of zymosan was similar in PMNs isolated from normal and asthma subjects. Histamine (100-0.01 muM) inhibited enzyme release. Except at the maximal concentration of histamine (100 muM), the response to histamine was decreased in asthma. The inhibition of enzyme release paralleled an increase in intracellular PMN cyclic AMP. In asthma, the cyclic AMP response to histamine was reduced. The H2 antihistamine metiamide blocked histamine inhibition of lysosomal enzyme release and the increase in cyclic AMP. The effect was maximal at concentrations equimolar to those of histamine. The H1 antihistamine chlorpheniramine had no effect on histamine inhibition of granulocyte lysosomal enzyme release. A decrease in the inhibition of the release of the inflammatory lysosomal enzymes from granulocytes in asthma may contribute to an enhanced bronchial inflammatory reaction.

A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects.

Many patients with asthma have increased wheezing with colds. We hypothesized that rhinovirus colds might increase asthma by augmenting airway allergic responses (histamine release and eosinophil influx) after antigen challenge. Seven allergic rhinitis patients and five normal volunteers were infected with rhinovirus type 16 (RV16) and evaluated by segmental bronchoprovocation and bronchoalveolar lavage. Segmental challenge with saline and antigen was performed 1 mo before infection, during the acute infection, and 1 mo after infection. Lavage was performed immediately and 48 h after antigen challenge. Data were analyzed by two-way analysis of variance, and a P value of < or = 0.05 was considered to be significant. All volunteers inoculated with RV16 developed an acute respiratory infection. BAL fluid obtained from allergic rhinitis subjects during the acute viral infection, and 1 mo after infection, showed the following significant RV16-associated changes after antigen challenge: (a) an enhanced release of histamine immediately after local antigen challenge; (b) persistent histamine leak 48 h afterwards; and (c) a greater recruitment of eosinophils to the airway 48 h after challenge. These changes were not seen in non-allergic volunteers infected with RV16 and challenged with antigen, nor in allergic volunteers repetitively challenged with antigen but not infected with RV16, nor in RV16 infected allergic volunteers sham challenged with saline. We conclude that rhinovirus upper respiratory infection significantly augments immediate and late allergic responses in the airways of allergic individuals after local antigen challenge. These data suggest that one mechanism of increased asthma during a cold is an accentuation of allergic responses in the airway which may then contribute to bronchial inflammation.

Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions.

Although viral upper respiratory infections (URIs) provoke wheezing in many asthma patients, the effect of these illnesses on the airway response to inhaled antigen is not established. The following study evaluated the effect of an experimental rhinovirus (RV) illness on airway reactivity and response to antigen in 10 adult ragweed allergic rhinitis patients. Preinfection studies included measurements of airway reactivity to histamine and ragweed antigen. Furthermore, the patients were also evaluated for late asthmatic reactions (LARs) to antigen (a 15% decrease in forced expiratory volume of the first second approximately 6 h after antigen challenge). 1 mo after baseline studies, the patients were intranasally inoculated with live RV16. All 10 patients were infected as evidenced by rhinovirus recovery in nasal washings and respiratory symptoms. Baseline FEV1 values were stable throughout the study. During the acute RV illness, there was a significant increase in airway reactivity to both histamine and ragweed antigen (P = 0.019 and 0.014, respectively). Before RV inoculation, only 1 of the 10 subjects had an LAR after antigen challenge. However, during the acute RV illness, 8 of 10 patients had an LAR (P less than 0.0085 compared with baseline); the development of LARs was independent of changes in airway reactivity and the intensity of the immediate response to antigen. Therefore, we found that not only does a RV respiratory tract illness enhance airway reactivity, but it also predisposes the allergic patient to develop LARs, which may be an important factor in virus-induced bronchial hyperresponsiveness.

Parainfluenza 3 infection blocks the ability of a beta adrenergic receptor agonist to inhibit antigen-induced contraction of guinea pig isolated airway smooth muscle.

Guinea pigs, actively sensitized to ovalbumin, were inoculated by nasal insufflation with parainfluenza 3 or virus growth medium 4 d before performing in vitro pharmacological studies on tracheal and bronchial smooth muscle. In each airway segment, cumulative dose-response effects of ovalbumin were obtained in the absence and presence of a maximally effective concentration of a beta adrenergic receptor agonist, sulfonterol. Sulfonterol shifted the dose-response curve to the right and reduced the maximum smooth muscle contractile response to ovalbumin. Virus infection did not alter the dose-response effects of ovalbumin. However, the magnitude of the inhibitory effects of sulfonterol was smaller in segments taken from animals inoculated with virus. Blockade by virus infection of the inhibitory effect of sulfonterol was reversed when the concentrations of beta agonist were increased. Sulfonterol did not alter the dose-response effects of histamine at any of the concentrations that markedly antagonized the effects of ovalbumin. Virus infection did not alter the sensitivities to sulfonterol or papaverine in producing relaxation in either airway segment. The magnitude of relaxation produced by papaverine was significantly larger in bronchial rings taken from animals infected with virus for 4 d, but there was no alteration by virus of the dose-response effects of histamine or carbachol. In experiments measuring antigen-induced release of slow reacting substance of anaphylaxis and histamine from minced lung, virus infection did not alter the sensitivity or the maximum effects of ovalbumin. Also, the ability of sulfonterol to inhibit the release of slow reacting substance of anaphylaxis and histamine was not affected by virus infection.These results demonstrate that infection of guinea pigs with respiratory virus results in a selective blockade of the beta adrenergic-mediated inhibition of antigen-induced contraction of airway smooth muscle. The guinea pig may serve as a useful model in physiological studies of virus-induced asthma.

Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.

Endotypes of difficult-to-control asthma in inner-city African American children.

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

Long-and short-acting beta 2-adrenergic agonists. Effects on airway function in patients with asthma.

Inhaled beta-adrenergic agonist bronchodilators are integral components of effective asthma treatment. However, the risk of asthma morbidity and mortality associated with the regular use of certain inhaled beta-agonists was first noted in the United Kingdom during the 1960s and in New Zealand during the 1970s. There are also concerns that long-term use of both long-acting and short-acting inhaled beta-agonists may cause a loss of asthma control in some patients. These experiences have caused some investigators to question the safety of inhaled beta-agonists in patients with asthma. This review attempts to address these issues, which are of concern to both physicians and patients alike, and aims to increase the clinician's understanding and awareness of the problems and treatment options.

Response to corticosteroids in the hypereosinophilic syndrome. Association with increased serum IgE levels.

Severe blood eosinophilia (16,500/cu mm and 6,500/cu mm) accompanied by involvement of the lungs, pleura, heart, pericardium, liver, gastrointestinal tract, peripheral nerves, or skin developed in two patients with bronchial asthma. Associated with the eosinophilia were elevated serum IgE levels (1,400 IU/ml and 10,500 IU/ml), depressed serum C4 complement levels (13 mg/100 ml and 6 mg/100 ml), and high titers of rheumatoid factor (1:2560 and 1:640). Symptoms improved after treatment with prednisone and the eosinophil counts and serum IgE and C4 complement levels returned to normal.

Impaired H2 histamine granulocyte response in active atopic eczema.

Many clinical abnormalities in atopic eczema have been attributed to an imbalance in autonomic nervous system control, specifically a partial blockade of beta-adrenergic responsiveness. The lysosomal enzyme beta-glucuronidase is released from granulocytes during in vitro incubation with complement-activated zymosan particles. Isoproterenol will inhibit the release of this lysosomal enzyme from the granulocyte and the isoproterenol effect is associated with increased granulocyte cyclic AMP formation. In atopic eczema and asthma, this granulocyte response to isoproterenol is impaired. Histamine also inhibits in vitro zymosan induced release of beta-glucuronidase and this is an H2 histamine effect. In asthma, this H2 histamine response is diminished. In the following study, we found a similar impairment in histamine inhibition of beta-glucuronidase release and formation of granulocyte cAMP in atopic eczema. This defect was found only in granulocytes from patients with active eczema. Thus in active atopic eczema, defects in the pharmacological response of the granulocyte are not limited to beta-adrenergic agonists but include H2 histamine activity.

Adrenergic mechanisms and the adenyl cyclase system in atopic dermatitis.

Patients with atopic dermatitis have abnormal autonomic responses of the arterioles, pilomotor smooth muscle, and sweat glands. Their lesions have been reported to contain increased amounts of the neurohumors, acetylcholine and norepinephrine, as well as increased activity of acetylcholinesterase and catechol-O-methyltransferase. In vitro studies of epidermis show that beta adrenergic agonists fail to evoke the normal inhibition of mitosis of basal cells of patients with atopic dermatitis. Epidermis removed not only from the lesions, but also from normal-appearing skin, responded abnormally. The increase in intracellular levels of cAMP after exposure to catecholamines was similar in normal and atopic epidermis. Lymphocytes and PMN leukocytes isolated from patients with atopic dermatitis show both a decreased physiologic response (glycogenolysis and inhibition of lysosome enzyme release) and a decreased rise in intracellular levels of cAMP upon incubation with beta agonists, but a normal response to PGE1. Cortisol increases the response of lymphocyte adenyl cyclase to both agonists and, in the case of the patients with atopic disease, more than overcomes the depressed response to beta agonists. Because the leukocytes respond normally to PGE1 and because others have reported normal activities of skin and adenyl cyclase, phosphodiesterase, and protein kinases, we conclude that the step responsible for the diminished beta adrenergic response lies antecedent to the catalytic site of adenyl cyclase.