C. Mailhol

Prevalence and risk factors for allergic contact dermatitis to topical treatment in atopic dermatitis: a study in 641 children

Background:  There is little information regarding the risk of sensitization associated with topical atopic dermatitis (AD) treatment.

DRESS syndrome sous doxycycline

BACKGROUND While many cases of DRESS reaction to minocycline have been described, few of these involve doxycycline. CASE STUDY A 59-year-old woman of African origin was repatriated after a journey to Ghana for hyperthermia with infiltrated maculopapular exanthema, facial oedema (no mucosal involvement) and polyadenopathy. Laboratory tests revealed hypereosinophilia, hepatic cytolysis and mononucleosis syndrome. Cutaneous histology was non-specific. The patient had been taking doxycycline as antimalarial prophylaxis for three weeks before the onset of symptoms. DRESS to doxycycline was diagnosed. Patch-tests with doxycycline three months later proved negative. The patients HLA phenotype was A3/A30 and B39/B42. DISCUSSION An intrinsic causal relationship with doxycycline was likely in this case (I3). Although patch-test sensitivity and specificity with doxycycline remains unknown in DRESS exploration, a negative result does not necessarily rule out the diagnosis. A number of cases of DRESS to doxycycline have been described recently, possibly as a result of more frequent prescription (malarial prophylaxis, acne). Subjects of African ethnicity or having specific HLA phenotypes are at higher risk of developing drug hypersensitivity. CONCLUSION This patient is the third case of DRESS to doxycycline described in the literature. The originality of this case lies in the allergological investigation using patch-tests and HLA determination.

Acute cutaneous T-cell lymphoma transformation during treatment with alemtuzumab.

SIR, Alemtuzumab (Campath-1) has newly been described as salvage treatment in patients with advanced Sézary syndrome. CD52 is a peptide cell-surface antigen expressed on normal and also malignant T and B lymphocytes. Alemtuzumab is a monoclonal anti-CD52 antibody (IgG1). It is known to induce profound lymphocyte depletion mainly mediated by apoptosis or complement-mediated cell lysis. Overall response rates of 38–55% (complete response in 0–32% of patients) have been observed in advanced T-cell lymphoma, with a median time to treatment failure of 3–12 months. Opportunistic infections, cardiac toxicity and neutropenia have been described during treatment with alemtuzumab. We report a 68-year-old patient diagnosed with cutaneous T-cell lymphoma (CTCL) in May 2006. Clinical examination showed large erythematous plaques and a left temporal nodular lesion. Clonal T-cell receptor Vb22+ CD4+ CD7– CD26– circulating CTCL cells (3000 mm) were observed, with an elevated CD4+ ⁄CD8+ ratio of 15. Histological examination of the temporal lesion disclosed transformed mycosis fungoides. Immunostaining showed that malignant cells were positive for CD4 and CD52. The cells were negative for CD8 and < 10% were CD30+. Bone marrow biopsy and total-body computed tomographic scan were normal. Staging according to the TNM classification was T4N0M0 B1. Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) viral loads were negative. In August 2006, alemtuzumab 30 mg three times per week was started because of disease progression despite treatment with interferon alfa and psoralen and ultraviolet A radiation. The patient was also treated with valaciclovir, co-trimoxazole and fluconazole as a recommended prophylaxis regimen. After the third subcutaneous injection, he presented with severe asthenia and high fever related to septicaemia (Pseudomonas aeruginosa and Staphylococcus aureus). In September 2006, after 3 weeks of alemtuzumab, CMV viraemia was detected (15 600 mL, 4Æ2 log), associated with fever but no organ involvement. Pre-emptive treatment with intravenous ganciclovir was given for 7 days due to the increase of viral load associated with symptoms, then followed by prophylaxis with valganciclovir 450 mg daily. The fever resolved within 5 days and CMV viraemia became negative. One month later, the patient experienced high fever and night sweats (alemtuzumab was stopped for 6 weeks). Clinical examination showed partial remission of skin lesions. Scalp eczema herpeticum was present and was confirmed by polymerase chain reaction. Dramatic diffuse enlargement of lymph nodes and of the left temporal tumour (Fig. 1) occurred. Inguinal lymph node biopsy disclosed transformed CTCL with the presence of CD30+ T cells. The number of Sézary cells in the blood was 275 mm. A dramatic increase of EBV viral load (773 000 mL, i.e. 5Æ9 log) was concomitantly detected. However, in situ hybridization with the EBV-specific EBER probes on a node biopsy was negative. CMV and human herpesvirus type 6 viral load remained negative. Circulating CD3+, CD4+, CD8+ and CD19+ lymphocyte rates were 297, 178, 135 and 20 mm. The patient was treated with a course of chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone. After one course, no obvious clinical response was obtained and chemotherapy was changed to gemcitabine and oxaliplatin. EBV viral load decreased to 2153 copies mL, i.e. 3Æ33 log mL. In addition, persistent microscopic haematuria was discovered, associated with positive JC virus viruria without decoy cells (haemorrhagic cystitis). In our patient, acute diffuse nodal localization of transformed CTCL mimicking Richter syndrome occurred within 2 months after introduction of alemtuzumab in the context of severe immunosuppression associated with CMV viraemia, EBV, JC virus and herpes simplex virus reactivation and bacterial septicaemia, but no fungal infection. At the same time, skin lesions were cleared and the Sézary cell count decreased in the blood. One may hypothesize that such acute transformation may be related to the natural course of the disease. Despite intensive treatment, transformed T-cell lymphoma is the natural evolution of CTCL but such acute worsening is rare Fig 1. Clinical appearance of left temporal nodular lesion.

Point prevalence and risk factors for food allergy in a cohort of 386 children with atopic dermatitis attending a multidisciplinary dermatology/paediatric allergy clinic

There is considerable debate about the prevalence and relevance of food allergy (FA) in atopic dermatitis (AD). The aim of this study was to investigate the prevalence of and risk factors for FA in a cohort of children with AD attending a multidisciplinary paediatric allergy clinic.MethodsThe analysis was performed on 386 children (50.8% boys, median age 4 years) consecutively evaluated for AD. A diagnosis of FA was established on positive skin tests and/or a specific IgE value or a positive oral food challenge.ResultsPoint prevalence of FA was 17.8%. Egg, peanuts, milk, tree nut and mustard accounted for 93% of cases. 37.7% of children had ≥2 positive food reactions. Risk factors associated with FA were young age (OR = 7.9 when ≤2 years compared with ≥5 years), moderate to severe AD (OR = 7.8 for severe and 2.4 for moderate AD) and onset of AD before 3 months of age (OR = 5.7).ConclusionPoint prevalence of FA in children with AD is lower than initially reported in patients recruited in a paediatric allergology setting. Children ≤2 years of age with early-onset or severe AD are at higher risk of FA and may be candidates for FA evaluation.

Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement

BACKGROUND Telangiectasia macularis eruptiva perstans (TMEP) has not been fully characterized. OBJECTIVE We sought to estimate the frequency and clinical characteristics of TMEP in a cohort of adult patients with cutaneous mastocytosis, and to assess the presence of systemic involvement. METHODS We included all consecutive patients evaluated for cutaneous mastocytosis in 2 centers: the Mastocytosis Competence Center of the Midi-Pyrénées from May 2006 to December 2013, and the French Reference Center for Mastocytosis from January 2008 to September 2013. Skin phenotype, histopathology, presence of KIT mutation in the skin, and assessment of systemic involvement according to World Health Organization (WHO) criteria were prospectively investigated. RESULTS Of 243 patients with cutaneous mastocytosis, 34 (14%) were given a diagnosis of TMEP. The diagnosis of systemic mastocytosis was established in 16 patients (47%) with TMEP. Three patients (9%) had aggressive systemic mastocytosis (C-findings according to WHO). In all, 32 patients (94%) exhibited at least 1 mast cell activation-related symptom. LIMITATIONS Patient recruitment was undertaken at 2 referral centers with expertise in the diagnosis and treatment of mastocytosis so that the clinical findings and incidence of systemic involvement may be overestimated in comparison with the overall population of patients with TMEP. CONCLUSION TMEP accounts for about 14% of patients with cutaneous mastocytosis. The disease manifests as mast cell activation symptoms in almost all patients and can be associated with systemic involvement in about 50% of cases.

Bone marrow tryptase as a possible diagnostic criterion for adult systemic mastocytosis

Mastocytosis is difficult to diagnose, especially when systemic mast cell activation symptoms are not present or involve only one extracutaneous organ.

Prevalence and risk factors for fragility fracture in systemic mastocytosis

OBJECTIVES Systemic mastocytosis (SM) is characterized by the accumulation of mast cells in tissues other than the skin. Bone involvement although frequent has not been thoroughly evaluated. Primary objective was to determine risk factors associated with fragility fractures (FF) in SM. Secondary objectives were to evaluate the ability of bone marrow tryptase (BMT) level to identify patients with FF, and to describe bone involvement in SM. METHODS We analyzed retrospectively all consecutive patients seen in our expert center, with a diagnosis of SM according to the 2001 WHO criteria, and with complete bone assessment. We collected data about lifetime fractures, types of cutaneous manifestations, degranulation symptoms, blood and BMT levels, bone mineral density assessed by densitometry and KIT mutation. We performed a univariate analysis investigating the factors associated with FF and then a logistic multivariable regression analysis. We assessed the ability of bone marrow tryptase to identify patients with FF. RESULTS Eighty-nine patients with SM were included. Thirty-six patients (40.4%) suffered from osteoporosis and twenty-five (28.1%) experienced lifetime FF. Univariate analysis identified age at diagnosis and disease onset, presence of telangiectasia macularis eruptiva perstans, digestive symptoms, mast cells activation symptoms, elevated BMT, low femoral and lumbar BMD, as associated with FF. Multivariate analysis identified elevated BMT, low femoral T score and older age at diagnosis as independently associated with FF. CONCLUSIONS Low femoral T-score, BMT level, and older age at diagnosis are markers associated with FF in SM. BMT may represent an important biomarker to predict FF in SM patients.

Specific immunotherapy in grass pollen allergy

Since its description by Noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases.

Are changes necessary in the medical management of a patient with snakebite regarding the incidence of hypersensitivity reaction to antivenom polyvalent immune fab

We read with interest the case reported by Rizer et al. [1], in which the authors suspected Crotalidae polyvalent immune Fab (CroFab) hypersensitivity related to a-gal allergy. This hypothesis was put forward because the patient presented with allergic symptoms, while FabAV was administered. The blood level of specific a-1,3 galactose IgE was therefore tested and was measured at 45,000U/L (normal <3500U/L). We disagree with the authors, as it is not possible to affirm that the clinical reaction observed after CroFab administration was related to a-gal hypersensitivity. First, CroFab sensitization was not confirmed by a cutaneous test (skin prick tests and intradermal reactions). Second, although the a-gal epitope has been identified on many medications including antivenoms, it has never been demonstrated that this epitope is structurally expressed on CroFab [2]. It would have been of interest to perform inhibition of thyroglobulin ImmunoCAP by antivenom using sera from patients harboring specific IgE (sIgE) against a-gal to affirm the presence of the a-gal epitope [2]. Third, although the blood level of sIgE was high when measured after the antivenom had been administered, these results should be interpreted with particular caution as prevalence of a-gal sIgE positivity shows considerable variation and has been reported to range from 5.5% to 24.5% in Europe [3]. The new question raised by this case report [1] is: are changes necessary in the medical management of a patient with snakebite? In the United States, the incidence of hypersensitivity reaction to Crotalidae polyvalent immune Fab ranges from 23% to 56% depending on study methodology, but the most recent results evaluate this incidence at 8% [4]. In France, ViperFAVVR (which contains purified F(ab0)2 fragments of equine antibodies) is the most common antivenom for the treatment of Vipera aspis and Vipera berus envenomation. Unlike CroFab, national guidelines in France recommend the use of only one dose of ViperFAVR . In Europe, the incidence of hypersensitivity reactions has not been precisely reported, but some authors described immediate hypersensitivity reactions in 21/37 cases of which seven were anaphylactic [5]. Such adverse reactions may explain why the administration protocol of ViperFAVR recommends the placement of two perfusion lines before administration. The first intravenous line is used to give the antivenom and the second to manage the potential hypersensitivity reaction. Should patients admitted to the emergency department for snakebite be systematically asked about a past history of hypersensitivity to meat or to antivenoms with the presence of a-gal sensitization? Is measurement of a-gal sIgE enough to affirm the diagnosis of hypersensitivity? If a-gal sIgE is found to be high in the patient’s serum, should the antivenom be administered, since symptoms of hypersensitivity, should they appear, are usually mild and easily treated symptomatically? After discharge, physicians should refer the patient to an allergy specialist for skin testing and immunological tests such as immunoCAP inhibition confirming a-gal epitope implication in the allergic reaction. Nonetheless, the first step would be to prove the presence of the a–gal epitope using monoclonal anti-a-gal antibody on every antivenom available.

Safety of ultra-rush protocols for hymenoptera venom immunotherapy in systemic mastocytosis

Michihiro Hide Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan Department of Immunobiology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan PRESTO, Japan Science and Technology Corporation, Saitama, Japan PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan LEAP, Japan Agency for Medical Research and Development, Tokyo, Japan AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan