Allergic hypersensitivity to topical and systemic corticosteroids: a review

 Corticosteroids, which are potent anti-inflammatory and immunomodulator agents used in the treatment of various inflammatory diseases including allergic diseases, can in some cases produce immediate or delayed hypersensitivity reactions. This review summarizes the epidemiological and clinical characteristics of such reactions, including related diagnostic issues. It also presents a detailed analysis of the proposed immunological mechanisms including underlying cross-reactions.     

Type-IV sensitization profile of individuals with atopic eczema: results from the Information Network of Departments of Dermatology (IVDK) and the German Contact Dermatitis Research Group (DKG)

The role of atopic eczema (AE) as risk factor for the development of allergic contact dermatitis is discussed controversially, as well as its influence on patch test results due to increased irritability. In this study, we analysed the pattern of positive patch test results to most frequent contact allergens in patients with AE (n = 9020) and age matched nonatopic (n = 15,263) individuals. The pattern and the frequencies of the observed sensitizations did not differ greatly from nonatopic individuals. Bufexamac is an exception: in AE patients sensitization is observed three times more often. For the other substances tested only minor differences were detected. Moreover, the frequencies of single, double or polyvalent sensitizations were nearly identical between the two groups. The analysis of the anatomical sites of dermatitis shows differences between the groups: in AE patients, the face (7.2%) and hand dermatitis (6.6%) was more common, and leg dermatitis (4.0%) less common. Analysis of occupation, suspected allergen source, and accompanying factors revealed no major differences between the both groups. CONCLUSION: The chronic and long-term exposure to external drugs and emollients presumably carries a risk for sensitization against specific contact allergens in AE patients. However, the sensitization of contact allergens differs surprisingly little between patients with or without AE.     

Contact sensitizer 2,4‐dinitrochlorobenzene is a highly potent human TRPA1 agonist

2,4‐Dinitrochlorobenzene (DNCB) is widely used in human clinical studies and in experimental animal studies to evoke allergic contact dermatitis. 2,4‐Dinitrochlorobenzene is a potent immunogen capable of inducing contact sensitization in all humans exposed. However, the mechanism by which DNCB evokes such symptoms is presently unknown. TRPA1 is a nonselective cation channel that is expressed in peptidergic sensory neurons and fibroblasts. TRPA1 activation was recently implicated in the pathophysiology of atopic dermatitis especially in transducing cutaneous itch signals. Here, we test the hypothesis that DNCB acts as a TRPA1 agonist and thereby evokes allergic symptoms. We found that DNCB activates human TRPA1 dose dependently in FLIPR experiments with an EC₅₀ of 167 nM, an effect that was fully blocked by selective TRPA1 antagonists Chembridge‐5861528 and A‐967079. Similarly, DNCB activated nonselective TRPA1 current in patch clamp studies. Neutralization of 3 critical cysteines in TRPA1 resulted in a loss of DNCB agonism.     

Allergic Contact Dermatitis to Condoms: Description of a Clinical Case and Analytical Review of Current Literature

We describe the case of a 42‐years‐old non‐atopic man who developed a severe eczematous reaction in the genital area some hours after the use of a condom (Settebello‐Hatù® Durex) containing a retarding cream. Patch test revealed a strong allergic reaction to the retarding cream and to benzocaine and paraben mix contained in the cream itself. Condoms with retarding cream should be avoided in man sensitized to local anestethetics.     

Contact allergy to budesonide contained in a nasal spray

We describe a case of contact allergic sensitization to budesonide in a nasal spray used in the treatment of allergic rhinitis. No cross-sensitivity to other topical corticosteroids was found.     

Natural killer T cells expressing IFN-γ and IL-4 in lesional skin of atopic eczema

Background:  The inflammation of atopic eczema (AE) is orchestrated not only by T cells predominantly but also B cells, eosinophils and dendritic cells. Recently, a role of invariant natural killer T (NKT) cells has been reported in bronchial asthma and allergy. Natural killer T cells express a restricted repertoire of T-cell receptor α/β and produce interferon (IFN)-γ and/or interleukin (IL)-4 upon activation.
Aim of the study:  To determine the presence of NKT cells in lesional AE skin in comparison with other eczematous disorders and to analyse their cytokine expression.
Methods:  Immunofluorescence stainings were carried out using antibodies recognizing NKT cells, CD3+ and CD4+ cells, IFN-γ and IL-4.
Results:  Natural killer T cells have been detected in small numbers in the majority of AE specimens as well as in atopy patch test (APT) reactions, allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). In AE, the proportion of NKT cells among CD3+ cells was approximately 5%. NKT cells expressed both IFN-γ and IL-4 in AE, APT and ACD but predominantly IFN-γ in ICD.
Conclusion:  Natural killer T cells are part of the inflammatory infiltrate of AE as well as APT, ACD and ICD, suggesting a pathogenic role of NKT cells in eczematous skin disorders. The pattern of IFN-γ and IL-4 cytokine expression by NKT cells varied depending on the type of eczematous disease.     

Relationship of immediate and delayed hypersensitivity to nasopharyngeal and intestinal growth of Candida albicans in allergic subjects

The growth of C. albicans yeast in the nasopharynx and in the anus as well as allergy symptoms were followed up for 8 months in 67 patients with bronchial asthma, allergic rhinitis and/or atopic eczema. 38 of the patients were skin prick test positive and 29 negative to C. albicans allergen extract. 32 of the patients had positive and 19 negative delayed skin reactions. The nasal, bronchial and skin symptoms of the yeast-sensitive allergic patients were not associated with the nasopharyngeal nor anal occurrence of C. albicans or other yeasts. The use of nasal or inhaled steroids had no effect on the occurrence of Candida in the nasopharynx. It was observed that immediate skin sensitivity had a positive correlation and the delayed sensitivity a negative correlation with the occurrence of C. albicans growth in nasopharynx and anus. These findings are in agreement with the concept that impaired cell-mediated immunity to C. albicans may lead to increased IgE response. This may explain the increased liability towards C. albicans nasopharyngeal and gastrointestinal "saprophytic" growth.     

The link between allergic rhinitis and allergic asthma: a prospective population-based study. The Copenhagen Allergy Study

BACKGROUND: It has been hypothesized that allergic rhinitis and allergic asthma are manifestations of the same disease entity. We aimed to investigate the relationship between allergic rhinitis and allergic asthma. METHODS: Participants in a population-based study of 15-69-year-olds in 1990 were invited to a follow-up in 1998. A total of 734 subjects were examined on two occasions eight years apart. Allergic rhinitis to pollen was defined as a history of nasal symptoms on exposure to pollens and IgE specific to pollen. Allergic asthma to pollen was defined as a history of lower airway symptoms on exposure to pollens and IgE specific to pollen. Similarly, diagnoses of allergic rhinitis and allergic asthma to animals or mite were defined. RESULTS: At follow-up, all subjects with allergic asthma to pollen (n = 52) had in addition allergic rhinitis to pollen. In the longitudinal analysis, there were a total of 28 new (incident) cases of allergic asthma to pollen. They all had allergic rhinitis to pollen at baseline, or had developed allergic rhinitis to pollen at follow-up. Accordingly, allergic rhinitis to animals and mite were ubiquitous in subjects with allergic asthma to animals and mite, respectively. CONCLUSIONS: The results support the hypothesis that allergic rhinitis and allergic asthma are manifestations of the same disease entity.     

Hepatitis E virus infection in haemodialysis patients: a case-control study in Saudi Arabia.

To determine the prevalence of antibody to hepatitis E virus (IgM anti-HEV) among haemodialysis patients and evaluate whether there was an increased risk of infection and exposure to HEV in an area of endemic viral hepatitis, serum samples obtained from 83 Saudi patients on chronic haemodialysis (group 1), 400 sex- and age-matched healthy subjects (group 2) and hospital patients (group 3) were tested for the IgM anti-HEV and IgG anti-HEV. The prevalence of anti-HEV among the patients (group 1) and the healthy controls were 4.8% and 0.3%, respectively. The difference (4.5%) was statistically significant, with a calculated odds ratio (OR) of 20.2 (95% CI = 2.1-481.0; P = 0.0002). In contrast, there was no significant difference in the prevalence rates of IgG anti-HEV (7.2% vs 10.8%) in both groups. In nonhaemodialysis patients with various diseases, 1.6% (1 of 64) of outpatients (group 3) and none (0 of 113) of the ward patients (group 4) was positive for IgM anti-HEV. Thus, the prevalence (4 of 83) of IgM anti-HEV in the haemodialysis patients was significantly higher than the rate (1 of 177) in the combined groups of nonhaemodialysis hospital patients. The calculated OR was 8.9 (95% CI = 0.92, 212.8; P = 0.037). IgM antibody to hepatitis A virus (IgM anti-HAV) was not detected in any subjects, and the prevalence rates of IgG anti-HAV were similar in the patients and controls (72.3% and 74.3% in groups 1 and 2, respectively, and 75.7% combined groups 3 and 4). The study indicated a significantly higher risk of acute HEV infection among patients on chronic haemodialysis. It is possible that these were nosocomial infections acquired by person-to-person transmission in the haemodialysis unit. However, it is more probable that the infections were community acquired, a conclusion supported albeit indirectly by the lack of a significant difference between the prevalence in haemodialysis patients (4.8%) and outpatients (1.6%). In areas of endemic HEV, appropriate strategies should be adopted to prevent the risk of HEV among haemodialysis patients.     

Development of allergies and asthma in infants and young children with atopic dermatitis--a prospective follow-up to 7 years of age

BACKGROUND: The prognosis of atopic dermatitis is usually good, but the risk of developing asthma and allergic rhinitis is very high. The aim of this study was to follow children with atopic eczema up to school age to chart the course of sensitization and development of clinical allergy, as well as to study risk factors of sensitization. METHODS: Ninety-four children with atopic dermatitis were followed up to 7 years of age. The children were examined twice a year up to 3 years of age, and thereafter once yearly. At each visit, a clinical examination was performed, and a blood sample was taken. After 3 years of age, skin prick tests (SPTs) with inhalation allergens were performed at each visit. Information was obtained about atopy in the family, feeding patterns during infancy, symptoms of atopic disease, infections, and environmental factors. RESULTS: During the follow-up, the eczema improved in 82 of the 94 children, but 43% developed asthma and 45% allergic rhinitis. The risk of developing asthma was higher in children with a heredity of eczema. Presence of severe eczema at the time of inclusion in the study was associated with an increased tendency to produce food-specific IgE. An early onset of eczema was associated with an increased risk of sensitization to inhalant allergens, and development of urticaria. Early allergic reactions to food were associated with later reactions to food, allergic rhinitis, urticaria, and sensitization to both food and inhalant allergens. Early feeding patterns, time of weaning, and introduction of solid food did not influence the risk of development of allergic symptoms. A large number of periods or days with fever during the follow-up was associated with an increased risk of developing allergic rhinitis and urticaria. CONCLUSIONS: Our results confirm the good prognosis for the dermatitis and the increased risk of developing asthma and allergic rhinitis. Development of other allergic symptoms or sensitization was associated with the following factors: a family history of eczema, age at onset of eczema and its severity, early adverse reactions to foods, and proneness to infections.     

Eczema, atopy and allergen exposure in adults: a population-based study

BACKGROUND: There are few published studies on geographical variation in prevalence of eczema in adults or its association with recognised risk factors for allergic disease. OBJECTIVE: To describe the geographical variation in prevalence of eczema in adults, assess the associations with sociodemographic risk factors, serum-specific IgE and IgG, and exposure to allergen. METHODS: A community-based sample of 8206 adults aged 27-56 years, in 25 European centres and Portland, USA, provided questionnaire information on symptoms of eczema. Serum-specific IgE to house dust mite (HDM), cat, grass and Cladosporium, and IgG and IgG4 to HDM and cat were measured. Mattress levels of mite and cat allergen were assessed. RESULTS: Overall prevalence of eczema was 7.1% (range between countries of 2.2-17.6%). Eczema was associated with female gender [odds ratio (OR) 1.25; 95% confidence interval (CI) (1.01-1.55)], family history of atopic disease (OR 1.43; 95% CI 1.18-1.74), IgE sensitization to at least one allergen (OR 1.50; 95% CI 1.19-1.90), particularly Cladosporium (OR 3.65; 95% CI 1.81-7.37), and total IgE. Eczema was negatively associated with age and no clear associations were observed with sibship size, mattress mite and cat allergen levels or with cat and HDM-specific IgG or IgG4. CONCLUSIONS: There is geographical variation in the prevalence of eczema in adults both within and between countries. Although the disease is associated with IgE sensitization, in this study it was not related to mattress mite or cat allergen levels.     

Association between TNFA-308 G/A polymorphism and sensitization to para-phenylenediamine: a case-control study

Background:  Para -phenylenediamine (PPD) and related chemicals are common contact sensitizers, frequently causing allergic contact dermatitis (ACD). The cytokine tumor necrosis factor-alpha (TNF-α) plays a key role in contact sensitization.
Methods:  In this case–control study, we evaluated the distribution of variations in the regulatory region of the gene for TNF-α ( TNFA-308 G/A ) in 181 Caucasian individuals with a history of ACD and sensitization to PPD and 161 individuals with no history of sensitization to PPD.
Results:  The frequency of GA or AA TNFA genotypes was significantly higher in individuals sensitized to PPD than in age- and gender-matched controls giving an odds ratio (OR) of 2.16 (95% confidence interval, CI: 1.35–3.47; P  = 0.0016). This relation was even more pronounced when restricting cases to females over 45 years (OR = 3.71; 95% CI: 1.65–8.31; P  = 0.0017) vs younger females (less than or equal to 45 years; OR = 2.41; 95% CI: 1.03–5.65; P  = 0.044) or males (OR = 1.05; 95% CI: 0.449–2.47; P  = 1.0). In addition, a logistic regression model revealed a significant effect for TNFA-308 AA and AG vs GG genotype (point estimate = 2.152; 95% Wald CI: 1.332–3.477).
Conclusions:  These findings suggest a possible role for the TNFA-308 genetic polymorphism as a susceptibility factor for chemically induced ACD.     

Psoriasis vs allergic contact dermatitis in palms and soles: a quantitative histologic and immunohistochemical study

Cesinaro AM, Nannini N, Migaldi M, Pepe P, Maiorana A. Psoriasis vs allergic contact dermatitis in palms and soles: a quantitative histologic and immunohistochemical study. APMIS 2009; 117: 629–34. A systematic histologic and immunohistochemical study of cases of psoriasis (PSO) and allergic contact dermatitis (ACD) in palmo‐plantar skin was performed to find differences between these two diseases that usually show overlapping features in these specific sites. Skin biopsies from 42 (22 female, 20 male) patients were evaluated for several histopathologic parameters and immunohistochemistry was applied to quantify keratinocytic proliferation, the number of dendritic cells (DCs) and the phenotype of the mononuclear cell infiltrate. Regular epidermal hyperplasia and marked parakeratosis were found to be more frequent in PSO than in ACD cases, but only the first parameter reached the level of significance (p = 0.03). The number of S100 protein‐positive DCs was significantly higher in ACD (p = 0.006), whereas keratinocytic proliferation, studied with Mib‐1, was found to be higher in PSO than in ACD, but the difference was not statistically significant. No significant difference was detected in the number of CD4⁺, CD8⁺ and bcl2⁺ lymphocytes in PSO and ACD cases. In the palms and soles, the finding of irregular epidermal hyperplasia and the detection of a higher number of S100 protein‐positive DCs favor the diagnosis of ACD over PSO. The differential diagnosis between PSO and ACD can be practically approached using a histopathologic parameter and a commercially available antibody.     

Allergy to betalactam antibiotics in children: a prospective follow-up study in retreated children after negative responses in skin and challenge tests

BACKGROUND: Up to 10% of the patients in whom suspected betalactam hypersensitivity (HS) has been excluded by skin and challenge tests report suspected allergic reactions during subsequent treatments with the same or very similar betalactams. It has been suggested that the reactions may result from a resensitization induced by the challenge performed at the time of the allergological work-up. However, most patients did not undergo a second allergological work-up, to determine if the reactions resulted from betalactam HS or not. OBJECTIVES: We aimed to determine if children diagnosed nonallergic to betalactams have tolerated subsequent treatments with the initially suspected and/or other betalactams, and, in case of a reaction, if the reaction resulted from betalactam HS. Methods: We sent a questionnaire concerning the clinical history of their children to the parents of 256 children previously diagnosed nonallergic to betalactams. A second allergological work-up was performed in the children reporting suspected allergic reactions during subsequent treatments with the same and/or other betalactams. Skin tests were performed with the soluble form of the suspected (or very similar) betalactams and other betalactams from the same and other classes. Skin test responses were assessed at 15-20 min (immediate), 6-8 h (semi-late) and 48-72 h (late). Oral challenge (OC) was performed in children with negative skin tests, either at the hospital (immediate and accelerated reactions), or at home (delayed reactions). RESULTS: A response was obtained from 141 children (55.3%). Forty-eight (34%) of those children had not been treated with the betalactams for whom a diagnosis of allergy had been ruled out previously. Seven (7.5%) of the 93 children who had been treated again reported suspected allergic reactions. Skin tests and OC were performed in six of those children, and gave negative results in five children. In one child previously diagnosed nonallergic to amoxicillin associated with clavulanic acid, we diagnosed a delayed HS to clavulanic acid and a serum sickness-like disease to cefaclor. Thus, the frequency of reactions resulting from betalactam HS in children with negative skin and challenge tests is very low, and does not exceed 2.1% (2/93) if we consider that the child which refused a second allergological work-up is really allergic to betalactams. CONCLUSION: Our results in a very large number of children show that reactions presumed to result from betalactam HS are rare in children in whom the diagnosis of betalactam allergy has been ruled out previously. Moreover, they suggest that, as shown for the initial reactions, most of the reactions during subsequent treatments are rather a consequence of the infectious diseases for whom betalactams have been prescribed than a result of betalactam HS. Finally, they suggest that the risk of resensitization by OC is very low, and do not support the notion that skin testing should be repeated in children diagnosed nonallergic to betalactams.     

Results of standard series patch testing in patients with occupational allergic contact dermatitis

BACKGROUND: In the workplace, the skin is at high risk of exposure to chemicals and other contaminants, and occupational dermatitis is an important field of study. METHODS: We evaluated 230 patients referred to our clinic because they were affected by dermatitis suspected to be of occupational and allergic origin. They were tested with the allergens of the GIRDCA standard series, and with supplementary series when indicated. RESULTS: Among the 230 subjects, 49 were positive only to supplementary series (26.3% of all allergic contact dermatitis), while 130 (69.9% of all allergic contact dermatitis) were considered to have an occupational allergic contact dermatitis diagnosed by the standard series alone. The most frequent occupations of the patients were health care workers and hairdressers/beauticians. The most common agents responsible for occupational allergic contact dermatitis were metals and para-phenylenediamine. CONCLUSIONS: As the standard series detected a relatively low proportion of occupational allergic contact dermatitis, it is not adequate to recognize an occupational allergic contact dermatitis, certain supplementary series should also to be tested. However, even if such occupational series are used, we remain likely to continue to underestimate the frequency of occupational allergic contact dermatitis, because workers come into contact with a large number of substances that are often unknown.     

Differential expression of the calcium-binding proteins MRP8 and MRP14 in granulomatous conditions: an immunohistochemical study.

MRP14 and MRP8 are well-characterized calcium-binding proteins present in myeloid cells and mononuclear phagocytes. These antigens can easily be visualized in paraffin-embedded tissue, making use of monospecific polyclonal antibodies. This study evaluates MRP14 and MRP8 expression in mononuclear phagocytes in various granulomatous conditions. MRP14 is strongly expressed in all granulomatous conditions. MRP8 is variably expressed. Mononuclear phagocytes in granulomas of foreign body type, cat-scratch disease and erythema nodosum strongly express MRP8. In contrast, MRP8 expression is weak or absent in mononuclear phagocytes of sarcoidosis and tuberculosis. These results show differences in immunophenotype between non-phagocytic mononuclear phagocytes in delayed hypersensitivity type granulomas and phagocytic mononuclear phagocytes in non-hypersensitivity and non-immunological granulomas.     

Different subclasses and isotypes of antibodies against phosphorylcholine in haemodialysis patients: association with mortality

The risk of premature death is high among patients on haemodialysis (HD patients). We previously determined that immunoglobulin (Ig)M antibodies against phosphorylcholine (anti-PC) are negatively associated with increased risk of cardiovascular disease (CVD), atherosclerosis, some autoimmune diseases and mortality among HD patients in this cohort. Here, we also study other subclasses and isotypes of anti-PC in HD patients in relation to mortality, inflammation and gender. The study group is a cohort of 209 prevalent HD patients [median age = 66 years, interquartile range (IQR) = 51–74], vintage time = 29 months (IQR = 15–58; 56% men) with a mean follow-up period of 41 months (IQR = 20–60). Fifty-six per cent were men. We also divided patients into inflamed C-reactive protein (CRP) > 5·6 mg/ml and non-inflamed CRP. Antibody levels were determined by in-house enzyme-linked immunosorbent assay. IgG1 anti-PC below median was significantly associated with increased all-cause mortality (after adjustment for confounders: P = 0·02), while IgG, IgA and IgG2 anti-PC were not associated with this outcome. Among non-inflamed patients, IgM and IgG1 anti-PC were significantly associated with mortality (P = 0·047 and 0·02). IgG1 anti-PC was significantly associated with mortality among men (P = 0·03) and trending among women (P = 0·26). IgM (as previously reported) and IgG1 anti-PC are negatively associated with survival among HD patients and non-inflamed HD patients, but among inflamed patients there were no associations. IgG, IgA or IgG2 anti-PC were not associated with survival in these groups and subgroups. Further studies are needed to determine if raising anti-PC levels, especially IgM and IgG1 anti-PC, through immunization is beneficial.