Dry eye in childhood: Epidemiological and clinical aspects

Because dry eye disease is rare in children and its pathogenesis is less well known than in adults, its diagnosis is often overlooked. It can occur in association with a number of congenital, autoimmune, endocrine, and inflammatory disorders, or under certain environmental and nutritional conditions. In some cases, early detection allows the underlying cause of the dry eye to be successfully treated and eliminated. In other cases, the disease may represent a lifelong problem, whose proper management can prevent ulceration and scarring of the ocular surface. Because of the association of pediatric dry eye with other conditions, a multidisciplinary approach to diagnosis and treatment is usually required. The purpose of this review is to enhance physician awareness of dry eye in children, to describe the most frequently associated conditions, and to discuss the diagnostic and therapeutic options available.

Formes sévères d'hypersensibilité médicamenteuse retardée [Severe delayed drug hypersensitivity reactions].

Although most delayed drug hypersensitivity reactions are mild and show rapid improvement after drug discontinuation, there are severe systemic and/or cutaneous drug reactions which may be life-threatening. These entities are discussed here, namely DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). Early detection of warning signs and symptoms may help to take appropriate measures precociously.

Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests.

To cite this article: Ponvert C, Perrin Y, Bados-Albiero A, Le Bourgeois M, Karila C, Delacourt C, Scheinmann P, De Blic J. Allergy to betalactam antibiotics in children: results of a 20-year study based on clinical history, skin and challenge tests. Pediatr Allergy Immunol 2011; 22: 411-418. ABSTRACT: Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p < 0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p < 0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity.

Immunogenetics of drug-induced skin blistering disorders. Part II: Synthesis

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon examining the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events including Stevens-Johnson syndrome and Toxic epidermal necrolysis). New results from an exemplar study on shared precipitating and perpetuating inner causes with other related disease phenotypes including aphtous stomatitis, Behcets, erythema multiforme, Hashimoto's thyroiditis, pemphigus, periodic fevers, Sweet's syndrome and drug-induced multisystem hypersensitivity are presented. A call for a collaborative, wider demographic profiling and deeper immunotyping in suggested future work is made.

Immunogenetics of drug-induced skin blistering disorders. Part I: Perspective

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon the examination of the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events, including Stevens-Johnson syndrome and toxic epidermal necrolysis). An overarching pharmacogenetic schema is proposed. Immune cognition and early-effector processes are focused upon and a challenging synthesis around systems evolution is explained by a variety of projective analogies. Etiology, human leukocyte antigen-B, immune stability, clysiregulation, pharmacomimicry, viruses and an aggressive ethnically differentiated 'karmic' response are discussed.

Immune pathomechanism of drug hypersensitivity reactions

Drug hypersensitivity research has progressed enormously in recent years, and a greater understanding of mechanisms has contributed to improved drug safety. Progress has been made in genetics, enabling personalized medicine for certain drugs, and in understanding drug interactions with the immune system. In a recent meeting in Rome, the clinical, chemical, pharmacologic, immunologic, and genetic aspects of drug hypersensitivity were discussed, and certain aspects are briefly summarized here. Small chemicals, including drugs, can induce immune reactions by binding as a hapten to a carrier protein. Park (Liverpool, England) demonstrated (1) that drug haptens bind to protein in patients in a highly restricted manner and (2) that irreversibly modified carrier proteins are able to stimulate CD4(+) and CD8(+) T cells from hypersensitive patients. Drug haptens might also stimulate cells of the innate immune system, in particular dendritic cells, and thus give rise to a complex and complete immune reaction. Many drugs do not have hapten-like characteristics but might gain them on metabolism (so-called prohaptens). The group of Naisbitt found that the stimulation of dendritic cells and T cells can occur as a consequence of the transformation of a prohapten to a hapten in antigen-presenting cells and as such explain the immune-stimulatory capacity of prohaptens. The striking association between HLA-B alleles and the development of certain drug reactions was discussed in detail. Mallal (Perth, Australia) elegantly described a highly restricted HLA-B∗5701-specific T-cell response in abacavir-hypersensitive patients and healthy volunteers expressing HLA-B∗5701 but not closely related alleles. Expression of HLA-B∗1502 is a marker known to be necessary but not sufficient to predict carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Han Chinese. The group of Chen and Hong (Taiwan) described the possible "missing link" because they showed that the presence of certain T-cell receptor (TCR) clonotypes was necessary to elicit T-cell responses to carbamazepine. The role of TCRs in drug binding was also emphasized by Pichler (Bern, Switzerland). Following up on their "pharmacological interactions of drugs with immune receptors" concept (p-i concept), namely that drugs can bind directly to TCRs, MHC molecules, or both and thereby stimulate T cells, they looked for drug-binding sites for the drug sulfamethoxazole in drug-specific TCRs: modeling revealed up to 7 binding sites on the CDR3 and CDR2 regions of TCR Vα and Vβ. Among many other presentations, the important role of regulatory T cells in drug hypersensitivity was addressed.

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans

Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.

Maculopapular drug eruptions

Maculopapular (exanthematous) reactions are the most common adverse drug eruptions affecting the skin. Several studies indicate that immunological mechanisms including cytotoxic T cells (CD4+ > CD8+), both type 1 (e.g. IFN- γ ) and type 2 (e.g. IL-5) cytokines and various chemokines are critically involved in the pathogenesis of these eruptions. While maculopapular exanthems can virtually be elicited by any drug, antimicrobials (e.g. Β -lactam antibiotic, sulfonamides), anticonvulsants, allopurinol, and NSAIDs are most frequently involved. Clinical manifestations are variable and range from faint macules to widespread erythematous and maculopapular lesions, which usually begin on the trunk, neck and upper extremities and subsequently spread downwards in a symmetrical fashion. Although the clinical course is often relatively mild, these exanthems may sometimes progress to erythroderma or represent the beginning of even more severe drug reactions like Stevens-Johnson syndrome, toxic epidermal necrolysis or a drug rash with eosinophilia and systemic symptoms. In most cases, management includes early withdrawal of the offending drug and usually supportive treatment with emollients, topical corticosteroids and systemic antihistamines depending on the severity of the eruption. Allergological work-up is recommended to provide the patient with appropriate information about the causative drug and possible alternatives for future use.

Medikamentenallergie: Diagnostische Möglichkeiten mit In-vitro-Methoden

Bei Medikamentenallergien kommt es zu Immunreaktionen, die gegen das Medikament gerichtet sind und klinische Symptome verursachen. Man unterscheidet zwischen Hapten- und p-i-bedingten Reaktionen, wobei letztere nur für T-Zell-Reaktionen nachgewiesen wurden. Die häufigsten Immunmechanismen, welche Medikamentenallergien zugrunde liegen, sind Vermehrung von spezifischen IgE-produzierenden B- und/oder spezifischen T-Zellen. IgG-vermittelte Reaktionen, die z.B. eine hämolytische Anämie verursachen können, sind selten. Spezifische IgE können mittels CAP-Technologie nachgewiesen werden. Das Medikament muss an eine Trägersubstanz covalent gebunden werden, was den Nachteil mit sich bringt, dass die entsprechende Bindungsstelle im Medikament für IgE nicht erkennbar ist. Der Basophilenaktivierungstest (BAT) arbeitet meist mit freiem, ungebundenem Medikament. Wie die IgE-Vernetzung stattfindet, ist allerdings unklar. Beide Teste sind nicht genügend sensitiv um den In-vivo-Test (Prick oder i.d.) zu ersetzen. Bei T-Zell-Reaktionen wird in vitro meist die Proliferation der durch das Medikament stimulierten T-Zellen erfasst. Die Blutzellen (antikoaguliertes Blut) sollte innerhalb von 24 h im Labor zur Verarbeitung ankommen, wo die Zellseparation durchgeführt wird, um die Zellen mit dem Medikament zu stimulieren. Diese Stimulation kann durch Messung von Aktivierungsmarker (mittels Flow-Zytometrie), sezernierter Zytokine (ELISA) oder 3H-Thymidin Einbau in die sich teilende Zellen (Lymphozytentransformations- Test, LTT) erfasst werden. Am meisten Erfahrung liegt für den LTT vor. Die Sensitivität wird bei eindeutigen Fällen auf 50 – 70% geschätzt, hängt aber stark vom Krankheitsbild und Medikament ab. Schwere makulopapulöse Reaktionen und DRESS (Drug Rash with Eosinophilia and Systemic Symptoms), AGEP (acute generalized exanthematous pustulosis) sind meist positiv im LTT, aber schwere bullöse Reaktionen (SJS/TEN; Stevens-Johnson Syndrom/toxische epidermale Nekrolyse) werden besser mittels Zytotoxteste und Zytokinsekretion erfasst, da eine T-Zell-Proliferation weniger prominent ist. Trotz der limitierten Sensitivität sind diese Teste gut geeignet um Kreuzreaktionen zu erfassen, bzw. für mechanistische Studien. Da Provokationsteste bei verzögerten Medikamentenallergien nicht zur Verfügung stehen (es ist unklar, wie lange und wie hoch dosiert man das Medikament bei verzögerten Reaktionen geben muss), werden diese Teste in Zukunft eher mehr eingesetzt werden. Wichtig ist, dass sie selten falsch positiv sind, und ein positives Resultat als relevant angesehen werden kann. Für die Abklärung seltener IgG-vermittelter Reaktionen kann man einen modifizierten Coombs-Test versuchen.

CD8+ T cells and NK cells from blister fluid of an EEM/SJS overlap highly express Fas ligand and Granulysin

INTRODUCTION Erythema exsudativum multiforme majus (EEMM) and Stevens-Johnson Syndrome (SJS) are severe cutaneous reaction patterns caused by infections or drug hypersensitivity. The mechanism by which widespread keratinocyte death is mediated by the immune system in EEMM/SJS are still to be elucidated. Here, we characterized the blister cells isolated from a patient with EEMM/SJS overlap and investigated its cause. METHODS Clinical classification of the cutaneous eruption was done according to the consensus definition of severe blistering skin reactions and histological analysis. Common infectious causes of EEMM were investigated using standard clinical techniques. T cell reactivity for potentially causative drugs was assessed by lymphocyte transformation tests (LTT). Lymphocytes isolated from blister fluid were analyzed for their expression of activation markers and cytotoxic molecules using flow cytometry. RESULTS The healthy 58 year-old woman suffered from mild respiratory tract infection and therefore started treatment with the secretolytic drug Ambroxol. One week later, she presented with large palmar and plantar blisters, painful mucosal erosions, and flat atypical target lesions and maculae on the trunc, thus showing the clinical picture of an EEMM/SJS overlap (Fig. 1). This diagnosis was supported by histology, where also eosinophils were found to infiltrate the upper dermis, thus pointing towards a cutaneous adverse drug reaction (cADR). Analysis of blister cells showed that they mainly consisted of CD8+ and CD4+ T cells and a smaller population of NK cells. Both the CD8+ T cells and the NK cells were highly activated and expressed Fas ligand and the cytotoxic molecule granulysin (Fig. 2). In addition, in comparison to NK cells from PBMC, NK cells in blister fluids strongly upregulated the expression of the skin-homing chemokine receptor CCR4 (Fig 4). Surprisingly, the LTT performed on PBMCs in the acute phase was positive for Ambroxol (SI=2.9) whereas a LTT from a healthy but exposed individual did not show unspecific proliferation. Laboratory tests for common infectious causes of EEMM were negative (HSV-1/-2, M. pneumoniae, Parvovirus B19). However, 6 weeks later, specific proliferation to Ambroxol could no longer be observed in the LTT (Fig 4.).

Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions.

OBJECTIVE To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? METHODS A systematic literature search was performed for HLA-B*15:02 and HLA-A*31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. RESULTS Patients carrying HLA-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A*31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A*31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. SIGNIFICANCE This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B*15:02 and HLA-A*31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Pathway analysis for identification of potential biomarkers in severe cutaneous drug hypersensitivity reactions

Purpose: To construct a cluster model or a gene signature for Stevens-Johnson syndrome (SJS) using pathways analysis in order to identify some potential biomarkers that may be used for early detection of SJS and epidermal necrolysis (TEN) manifestations. Methods: Gene expression profiles of GSE12829 were downloaded from Gene Expression Omnibus database. A total of 193 differentially expressed genes (DEGs) were obtained. We applied these genes to geneMANIA database, to remove ambiguous and duplicated genes, and after that, characterized the gene expression profiles using geneMANIA, DAVID, REACTOME, STRING and GENECODIS which are online software and databases. Results: Out of 193 genes, only 91 were used (after removing the ambiguous and duplicated genes) for topological analysis. It was found by geneMANIA database search that majority of these genes were coexpressed yielding 84.63 % co-expression. It was found that ten genes were in Physical interactions comprising almost 14.33 %. There were < 1 % pathway and genetic interactions with values of 0.97 and 0.06 %, respectively. Final analyses revealed that there are two clusters of gene interactions and 13 genes were shown to be in evident relationship of interaction with regards to hypersensitivity. Conclusion: Analysis of differential gene expressions by topological and database approaches in the current study reveals 2 gene network clusters. These genes are CD3G, CD3E, CD3D, TK1, TOP2A, CDK1, CDKN3, CCNB1, and CCNF. There are 9 key protein interactions in hypersensitivity reactions and may serve as biomarkers for SJS and TEN. Pathways related gene clusters has been identified and a genetic model to predict SJS and TEN early incidence using these biomarker genes has been developed.

The dramatic works of William Shakespeare, from the text of Johnson, Stevens, and Reed;

Mode of access: Internet.

The dramatic works of William Shakspeare, from the text of Johnson, Stevens, and Reed; with glossarial notes, his life, and a critique on his genius & writings

Title vignette.