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Atopic dermatitis and delayed hypersensitivity.

Studies of patients with atopic dermatitis show both clinical and laboratory evidence of a depression of cellular immunity. In order to study one aspect of this disease in vivo we studied 40 patients with atopic dermatitis of both sexes, aged 2-30 years and 40 supposedly healthy subjects with similar characteristics in regard to age and sex who served as the control group. Both groups were subjected to tests of delayed hypersensitivity with Candidin, Trycophytin and Tuberculin. Candidin response was negative in 72.5% and 85% at 48 and 72 hours respectively. Trycophytin response was negative in 77.5% and 87.5% of the readings at the same time intervals, and Tuberculin response was negative in 85.5% of the patients with atopic dermatitis studied. The results are shown to be statistically significant. It is concluded that, cellular immunity should be evaluated in patients with atopic dermatitis.

Adolescent↗

Immunology of atopic dermatitis.

Thirty-two adult patients with atopic dermatitis were studied at the Allergology Service of the "Hnos. Ameijeiras" Clinical Surgical Hospital. The diagnosis was established following the criteria of Hanifin and Lobitz. A detailed medical history was written for the patients; the study of some immunological parameters, such as the serum immunoglobulin quantification, delayed skin tests with a battery of antigens, and the spontaneous rosette-test, was also carried out. Almost all the patients showed serum IgE values above 150 UI, by means of the ELISA test modified by C.E.N.I.C. The mean values of the spontaneous rosette-test were low; this was more noticeable during the exacerbation period of the lesions. Candida sp, Mantoux and Streptokinase-Streptodornase antigens showed negative results in a high proportion of patients with atopic dermatitis, in relation with the control group. In atopic dermatitis, there are humoral disorders of immunity; this was demonstrated in our group by increased values of IgE and cellular disorders due to skin anergy, and to a low percentage of rosette forming cells; this does not allow to state that these phenomena have an active participation in the etiopathogenesis of this entity.

Adult↗

Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis.

Approximately 10-20% of infants in industrialized countries experience atopic dermatitis. In recent decades topical corticosteroids have been the first-choice therapy for treatment of flares. However, this form of therapy may induce skin atrophy, especially after application to facial lesions or with long-term use. Thus, development of new anti-inflammatory topical agents for the treatment of childhood atopic dermatitis was needed. The topical calcineurin inhibitors tacrolimus and pimecrolimus have an effect on various cells of the cutaneous immune system, specifically on T cells, by inhibiting the phosphatase calcineurin and preventing the transcription of proinflammatory cytokines. In several clinical studies of children and adults with atopic dermatitis, topical calcineurin inhibitors were found to be effective both on the face and the trunk and extremities, in both short- and long-term treatment regimens. Tachyphylaxis or rebound were not observed. In most patients an improvement of their eczema occurred during the first week of treatment, as measured by subjective and objective clinical signs of atopic dermatitis. Treatment significantly reduced the incidence of flares and the need for corticosteroids in children and adults. Treatment success, commonly defined as 'excellent improvement' or 'clearing of all lesions', was observed in more than one-third of all children treated with 0.03% or 0.1% tacrolimus or 1% pimecrolimus. Topical application of pimecrolimus and tacrolimus does not lead to significant blood concentrations of these agents in the majority of children with atopic dermatitis, and any increase in blood concentrations decreases after a few days of therapy. No changes in laboratory parameters were observed in short- and long-term studies in patients with atopic dermatitis. The most common adverse effect following the application of topical calcineurin inhibitors is mild to moderate symptoms of irritation such as burning, erythema and pruritus, which occurred in up to 20% of all children treated with tacrolimus and 10% of children treated with pimecrolimus, and usually faded after a few days. In contrast to topical corticosteroids, calcineurin inhibitors do not induce skin atrophy, even after long-term use. Topical calcineurin inhibitors have been proven to be effective and have a good safety profile during short-term and long-term use for up to 1 year with pimecrolimus and up to 4 years with tacrolimus. Given the lack of extensive experience with use of topical calcineurin inhibitors over longer periods, regular use of these agents, particularly in children, should be undertaken only after careful consideration of individual cases. Sun protection should also be advised.

Administration, Topical↗

Feline atopic dermatitis. A model for Langerhans cell participation in disease pathogenesis.

Atopic dermatitis is a disorder characterized by cutaneous exanthemata as a consequence of exaggerated eczematous reactions to topical and systemic allergens. Langerhans cells, expressing CD1a and HLA-DR, and dermal dendritic cells, expressing HLA-DR, are known to be potent antigen-presenting cells and are thought to play an important role in the pathogenesis of atopic dermatitis. The immunophenotype of lesional skin in atopic dermatitis in humans involves increased numbers of CD1a+/MHC class II+ dendritic cells in addition to activated T cells, mast cells, and macrophages. To establish feline skin as a model for the study of human atopic dermatitis, and to elucidate the role of dendritic cells in feline atopic dermatitis, we investigated the presence of CD1a+ cells and MHC class II+ cells in the epidermis and dermis of lesional feline skin and in skin of healthy control animals. Immunohistochemistry revealed that MHC class II+ epidermal dendritic cells were CD1a+ in normal feline skin and significantly increased numbers of CD1a+ cells and MHC class II+ cells were present in the epidermis and dermis of lesional skin. These data provide the first correlative documentation of CD1a expression by feline dendritic cells containing Birbeck granules, and indicate the utility of feline skin in the study of human cutaneous atopy.

Animals↗

Selective enhancement of production of IgE, IgG4, and Th2-cell cytokine during the rebound phenomenon in atopic dermatitis and prevention by suplatast tosilate.

BACKGROUND: Atopic dermatitis is a chronic inflammatory skin disease, which is commonly treated with topical steroids. It is, however, associated with rebound after therapy has been discontinued. OBJECTIVE: This study was designed to elucidate the mechanisms of the rebound phenomenon, and to test the effect of an oral anti-allergic medication, suplatast tosilate, on atopic dermatitis. METHODS: This is a randomized, placebo controlled study. Patients with atopic dermatitis who had been treated with strong steroid ointment (dexamethasone valerate) for several years were divided into two groups. One group (the control group, n = 15) was treated with a non-steroid anti-inflammatory ointment (bufexamac ointment), while the other group (the suplatast tosilate group, n = 17) was treated with the anti-allergic medications, suplatast tosilate and bufexamac ointment. In each group, in vitro production of immunoglobulins and cytokines before and after 2 weeks of treatment was measured. RESULTS: In the control group, 15 of the 15 patients experienced rebound and mean production of IgE, IgG4, IL-4, IL-5, IL-10, and IL-13 was enhanced after 2 weeks. In contrast, only 2 of the 17 patients in the suplatast tosilate group experienced rebound. There was no enhancement of production of immunoglobulins and cytokines after 2 weeks of treatment. CONCLUSION: Enhanced production of the Th2-cell cytokines, which selectively induces IgE and IgG4 production, may be involved in the pathogenesis of the rebound phenomenon, and that suplatast tosilate may prevent the rebound phenomenon by down-regulating the production of these cytokines.

Administration, Oral↗

Enhanced basal and stimulated PMN chemiluminescence activity in children with atopic dermatitis: stimulatory role of colonizing staphylococci?

In adults, intense staphylococcal skin colonization and hyperactivity of polymorphonuclear leukocyte (PMN) oxidative metabolism are characteristic features of atopic dermatitis. Precise data on childhood atopic dermatitis are lacking. In a prospective study we analysed the PMN chemiluminescence activity with special reference to staphylococcal stimuli in 19 children (mean age 6.2 years) with mild to moderate atopic dermatitis. Staphylococcus aureus was isolated from 17/19 (90%) of children with atopic dermatitis and 13/45 (29%) of healthy age-matched controls (p less than 0.001). The mean (SEM) chemiluminescence activity of unstimulated atopic dermatitis-PMN was 0.34 (0.009) (controls: 0.092 (0.003) x 10(6) cpm/10(6) PMN/min (p less than 0.02). Staphylococcal antigens (S. aureus, S. epidermidis, S. haemolyticus) induced a 1.9-3.1-fold higher peak chemiluminescence response in children with atopic dermatitis than in controls (p less than 0.05). The time interval until peak chemiluminescence activity was considerably shorter for all stimuli in atopic dermatitis. We conclude that PMN of children with atopic dermatitis are "primed", showing enhanced release of reactive oxygen metabolites even in the "resting" state, and are easily stimulated by staphylococcal antigens present on the skin of patients with atopic dermatitis from early childhood on. We speculate that PMN hyperreactivity may contribute to chronic skin damage in atopic dermatitis.

Adolescent↗

Atopic dermatitis is associated with a decrement in health-related quality of life.

BACKGROUND: Although atopic dermatitis is a chronic skin disease that can have a major impact on a patient's life, the burden of illness associated with this condition has not been well characterized. OBJECTIVE: To determine the health-related quality of life (HRQL) of patients with atopic dermatitis by disease severity and to compare it with that of the general public and of patients suffering from other chronic illnesses or skin disorders. METHODS: Two hundred and thirty-nine atopic dermatitis patients aged 4-70 years completed the Medical Outcomes Study Short Form-36 Health Survey (SF-36) and the Dermatology Life Quality Index (DLQI) or the Children's Dermatology Life Quality Index. These HRQL scores were compared by self-reported patient disease severity ratings. Health-related quality of life scores were compared with those of the general population and those of patients with other chronic conditions (clinical depression, hypertension, type 2 diabetes) or skin disease (psoriasis). Dermatology Life Quality Index scores were also compared with those of other skin diseases (such as psoriasis, Darier's disease, and Hailey-Hailey disease). RESULTS: Patients with atopic dermatitis had inferior scores on the SF-36 vitality, social functioning, and mental health subscales compared with individuals in the general population. In seven of eight subscales, individuals reporting more severe disease had inferior DLQI and SF-36 scores. Patients with atopic dermatitis had inferior mental health scores compared with those with diabetes or hypertension, and inferior social functioning scores compared with patients with hypertension. When compared with a psoriasis cohort, patients with atopic dermatitis had inferior scores in the role-physical, vitality, social functioning, role-emotional, and mental health SF-36 domains. Patients with atopic dermatitis had similar DLQI scores to patients with other chronic dermatologic diseases. CONCLUSIONS: These results demonstrate that atopic dermatitis has an impact on HRQL, particularly in social functioning and psychological wellbeing. Patient-assessed severity of atopic dermatitis correlates with HRQL decrements, indicating greater HRQL impact with greater disease severity. Atopic dermatitis has as large an impact on HRQL as several chronic conditions and other dermatologic conditions.

Adolescent↗

Cell-mediated immunity in vitro in atopic dermatitis.

The function of T cells in atopic dermatitis was studied by leukocyte migration agarose and lymphocyte transformation tests. We found that phytohemagglutinin (PHA)- and PPD-induced release of leukocyte migration inhibition factor (LIF) from lymphocytes is significantly decreased (P less than .001) in patients with atopic dermatitis as compared with healthy controls. Blastogenic response of lymphocytes induced by PPD was also decreased in atopic patients as compared with controls (P less than .01). No differences were found in spontaneous blastogenesis or in blastogenic response of lymphocytes in vitro to PHA, concanavalin A (ConA), or streptokinase-streptodornase (SK-SD) between patients with atopic dermatitis and controls.

Adolescent↗

A variety of skin responses to ultraviolet irradiation in patients with atopic dermatitis.

Skin responses to ultraviolet irradiation in patients with atopic dermatitis were studied to evaluate the role of sunlight in the exacerbation of atopic dermatitis. A total of 15 patients, seven males and eight females, with atopic dermatitis who complained of exacerbation of their dermatitis after sun exposure were examined by photo testing with UVB and UVA irradiation and photopatch tests. Nine out of 15 patients showed abnormal skin reactions. Lowered minimal erythema doses (MEDs) to a single exposure of UVB, papular or erythematous responses after single or repeated exposures to UVB or UVA and positive photopatch test reactions to sunscreen ingredients and fragrances were found. There are apparently multiple mechanisms of photoexacerbation in patients with atopic dermatitis.

Adult↗

Staphylococcal infections in patients with atopic dermatitis.

Cutaneous staphylococcal infections appear to be relatively infrequent in atopic dermatitis even though patients have broken skin heavily colonized with staphylococcal organsism. We found superficial staphylococcal pustules on the skin of 22 patients with atopic dermatitis. Such lesions were more commonly found with severe exacerbations of atopic dermatitis. They appeared on unbroken skin independent of hair follicles and were associated with considerable pruritus. Such lesions were rapidly removed by excoriation and frequently were overlooked by patients and physicians. Most lesions appeared when polymorphonuclear leukocyte chemotaxis was depressed. Ineffective chemotaxis combined with high-colonization density and inadequate stratum corneum barrier during exacerbations of atopic dermatitis may lead to mild staphylococcal infections. These infections appear to have no systemic effects but possibly the considerable associated pruritus could worsen the atopic dermatitis. Occasional patients may require intermittent or continuous antibiotic therapy.

Adult↗

The role of microorganisms in atopic dermatitis.

The course of atopic dermatitis is widely determined by environmental factors such as physical or psychogenic stress and reactions to allergens or microorganisms. The latter include bacteria, viruses and fungi, especially Staphylococcus auerus, Herpes simplex virus (HSV), and Pityrosporum orbiculare. In childhood, Impetigo around the big joints is frequently seen, while the characteristic reaction to S. auerus in the young adults is pruritic pustules on the extremities or an exacerbation of the eczema to an exudative dermatitis. Similarily, P. orbiculare may induce a flare-up of the eczema of the head and neck, while HSV may cause a true wide-spread infection known as eczema herpeticum. An immunological disorder, a fragile skin, and special properties of the microorganism may account for the altered response to infection or severe colonization in the patient with atopic eczema. During exacerbations of the eczema, supplementary treatment with proper antimicrobial agents has been shown to be of great value.

Bacterial Physiological Phenomena↗

Dysregulated activation of activator protein 1 in keratinocytes of atopic dermatitis patients with enhanced expression of granulocyte/macrophage-colony stimulating factor.

Keratinocytes of patients with atopic dermatitis produce high amounts of granulocyte/macrophage colony-stimulating factor, a factor essential for dendritic cell function and thus for the development of skin immune responses. In contrast to keratinocytes cultured from nonatopic, healthy individuals, granulocyte/macrophage colony-stimulating factor mRNA could be detected in unstimulated cultures of atopic dermatitis keratinocytes, and phorbol myristate acetate induced much greater granulocyte/macrophage colony-stimulating factor mRNA levels in these cells, although the decay kinetics were not altered. Using reporter gene (chloramphenicol acetyl transferase) analysis, a minimal granulocyte/macrophage colony-stimulating factor promoter was shown to confer constitutive and phorbol-myristate-acetate-induced regulation of transcriptional activity in keratinocytes, and significantly higher levels of chloramphenicol acetyl transferase activity were measured in lysates of unstimulated and phorbol-myristate-acetate-treated atopic dermatitis keratinocytes than in control keratinocyte cultures. Electrophoretic mobility shift assays showed that low levels of NF-kappa B binding activity could be induced by phorbol myristate acetate in both normal and atopic dermatitis keratinocytes. By contrast, activator protein 1 complexes were efficiently induced, and they were invariably present at higher levels in nuclear lysates of atopic dermatitis keratinocytes. Atopic dermatitis keratinocyte nuclear lysates had higher constitutive levels of c-Jun, and phorbol myristate acetate promoted an earlier and stronger expression of c-Jun, JunB, and of the phosphorylated forms of c-Fos. A dysregulated activation of activator protein 1 may be implicated in the molecular mechanisms leading to increased granulocyte/macrophage colony-stimulating factor expression in atopic dermatitis keratinocytes. J Invest Dermatol 115:1134-1143 2000

Adolescent↗

Atopic dermatitis in adults: does it disappear with age?

There is limited knowledge of the prognosis in adult atopic dermatitis. We previously published a long-term follow-up questionnaire study of adults with atopic dermatitis. This study is a clinical examination of 79 adults (mean age 57 years) recruited 3 years after that study. Most patients (68%) still reported that they had atopic dermatitis and 53% had ongoing eczema at examination, mainly located on the head and neck. Severity was mainly mild to moderate, but 12% had severe atopic dermatitis. IgE antibodies to Malassezia (m70) were more common in patients with ongoing atopic dermatitis, while positive Malassezia culture was seen mainly in patients with no ongoing atopic dermatitis. M. obtusa and M. globosa were the most commonly cultured Malassezia species. In conclusion, considering increased prevalence of atopic dermatitis in children in recent decades and the fact that atopic dermatitis in most adults continues for many years, we should expect to see more adults with atopic dermatitis in the future.

Aged↗

[Epicutaneous test with inhalers in the study of atopic dermatitis].

In some 80% of patients with atopic dermatitis, the presence of specific IgE is found when facing food or environmental allergens. It has also been demonstrated in a sub-group of patients with atopic dermatitis that the dermatitis lesions are exacerbated following the ingestion or inhalation of allergens, and that they improve with reduction of exposure to allergens. Although the prick method and the determination of specific IgE in serum are highly sensitive techniques, epicutaneous tests, applying the allergen directly to the skin, might be the ideal diagnostic method since they reproduce the characteristic inflammatory response of the disease on the affected organ itself, the skin. However, there is great variability in the results obtained through epicutaneous tests with aeroallergens, basically due to methodological differences, which are reviewed in this paper. Finally, we present the results of carrying out epicutaneous tests with inhalant allergens on our patients with atopic dermatitis and controls, where some 27% of positive patches were obtained, basically with acari, and in those patients with more severe dermatitis, without there being complete concordance with the prick technique. For this reason, the epicutaneous test appears to be a method of allergological diagnosis that might be useful and complementary to the routine techniques of the prick method and the determination of specific IgE in serum, but it is in need of suitable standardization.

Administration, Inhalation↗

Overexpression of IL-10 in atopic dermatitis. Contrasting cytokine patterns with delayed-type hypersensitivity reactions.

The skin lesions of patients with atopic dermatitis provide a model to study immunoregulation in human allergy. To determine the local cytokine pattern of cells present (both endogenous and recruited) at the site of disease, we extracted RNA from skin biopsy specimens from patients with atopic dermatitis, allergic contract dermatitis, and positive tuberculin reactions and used PCR to assay for cytokine mRNA. cDNAs were normalized to the intensity of the CD3 delta PCR product as a marker of T cell mRNA. We found overexpression of IL-10 mRNA in atopic dermatitis lesions, in comparison with allergic contact dermatitis lesions and tuberculin reactions. In contrast, IL-4 mRNA was most strongly expressed in allergic contact dermatitis lesions and IFN-gamma mRNA was the predominant cytokine in tuberculin reactions. Using an anti-IL-10 mAb with immunoperoxidase, we localized IL-10 protein to large mononuclear cells in the dermal infiltrate of atopic lesions. After immunomagnetic sorting of mononuclear cell populations from PBMC of atopic dermatitis subjects, IL-10 mRNA as measured by PCR was found to be strongly expressed in CD14+ cells. Spontaneous release of IL-10 from PBMC-derived adherent cells was greater in atopic dermatitis donors than normal controls. We therefore renormalized skin biopsy cDNA according to the level of beta-actin PCR product, as a marker of total cellular mRNA, and found by PCR that IL-10 was nevertheless greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis greatest in atopic dermatitis subjects. We conclude that the relative overexpression of IL-10 in atopic dermatitis may contribute to the up-regulation of humoral responses and the down-regulation of Th1 responses.

Adult↗

Adult height in patients with childhood onset atopic dermatitis.

Cross sectional studies have reported impaired growth in children with atopic dermatitis. If this growth impairment is irreversible, it would be expected to adversely influence final height attainment. The standing heights and other anthropometric parameters were assessed in 35 adults with onset of atopic dermatitis before 5 years of age and a control group of 35 adults with adult onset contact dermatitis or psoriasis. There was no significant difference in the standing height SD score, mid-parental height SD score, sitting height SD score, subischial leg length SD score, nor body mass index between the atopic dermatitis and control groups. The standing height SD score was not significantly different among: (a) patients with atopic dermatitis affecting less than 50% of their body surface area and those with greater than 50% affected; (b) patients using the four different potency topical corticosteroids; and (c) patients with atopic dermatitis without asthma and those with coexisting asthma. It is concluded that short stature is not a feature of our group of adult patients with onset of atopic dermatitis before 5 years of age, continuing into adulthood, and severe enough to require specialist care. This suggests that if growth impairment occurs in childhood, it is likely to be temporary and reversible.

Administration, Topical↗

Cyclosporin is safe and effective in severe atopic dermatitis of childhood. Report of three cases.

Severe atopic dermatitis causes major impairment in the life of both children and their parents. Generally, symptoms can be controlled with emollients, topical steroids, antibiotics, antihistaminic but some patients remain intensely ill and may require treatment with systemic steroids and so on. Cyclosporin has been found to be effective in a variety of inflammatory skin disorders since it reduces the number of activated T-cells expressing interleukin 2 (IL-2) receptors. In order to monitor the safety and clinical efficacy of therapy and days of remission we performed Cyclosporin on 3 children with severe atopic dermatitis, refractory to all traditional therapies. Cyclosporin suspension at dosage of 5 mg/kg daily, in 2 doses for 8 weeks has been used. Cyclosporin blood levels, liver and kidney function, blood pressure and some immunological parameters (eosinophils, IgE, IL-2 receptors) were monitored. All patients showed a marked clinical improvement with reduction of pruritus, erythema, papules, vesciculation, excoriation, scaly crusts and lichenification. No clinical or haematological side effects were demonstrated. The soluble IL-2 receptor concentration decreased even after 8 weeks of treatment in all 3 patients, regardless of IgE levels (case 1: low IgE level; case 2: very high IgE level) as in several others T-cell mediated non IgE-related skin disease. The authors suggest that courses of 8 weeks seem effective and safe as well as longer time in producing early remission with the advantage of a low cumulative exposure to the drug. The main question is whether a prolonged remission will permain as well as continuous therapy. This study underscores the potential value of systemic administration of this powerful immuno-suppressive agent in the treatment of many cases of severe atopic dermatitis working regardless of the IgE values. Although 3 cases report does not justify any definitive conclusion however it does a contribute to understand the heterogeneity of atopic dermatitis and it adds information to its current treatment guidelines.

Child, Preschool↗

Basophil histamine release and airway response to mite allergen in atopic dermatitis.

Twelve patients with atopic dermatitis (AD) were subjected to in vitro histamine release from peripheral blood leukocytes (basophils) and in vivo bronchial inhalation challenge using house dust mite (Dermatophagoides farinae) allergen. Not only seven patients with asthmatic history but also five patients without asthma responded to both the in vitro and the in vivo challenges. A significant correlation was observed between HR30 (a mite concentration producing a 30% release of total cellular histamine) and PC20 allergen (a mite concentration producing a 20% fall in FEV1). There was also a significant correlation between MHR (maximal histamine release) and the maximal fall in FEV1. The relationship held for both AD patients with asthma and without asthma. These results suggest that histamine release induced by the house dust mite allergen is a good in vitro test for predicting the bronchial response to this allergen. They also suggest that these tests are not disease specific, but are valuable in evaluating the degree of atopic state in a subject.

Allergens↗