[Diagnosis and etiology of primary adrenal insufficiency]. / Diagnostic et étiologie de l'insuffisance surrénalienne primaire.

Since its first description in 1855, our understanding of primary adrenal insufficiency has greatly evolved. However, diagnosis is often delayed, as symptoms are frequently nonspecific in the early stages of the disease. In this article, we review the classical manifestations, associated diseases, as well as the diagnostic algorithm for primary adrenal insufficiency, aiming to enable earlier diagnosis.

Depuis la première description en 1855, nos connaissances de l'insuffisance surrénalienne primaire ont beaucoup évolué. Cependant, le diagnostic est souvent retardé, les symptômes étant fréquemment aspécifiques aux premiers stades de la maladie. Dans cet article, nous rappelons les manifestations classiques, les maladies associées, ainsi que l'algorithme diagnostique de l'insuffisance surrénalienne primaire, afin de permettre un diagnostic plus précoce.

[Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology]. / Kutane Vaskulitiden.

Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology Abstract. Vasculitides are a heterogeneous group of diseases that are classified differently, for example according to the size of the affected vessel or according to primary and secondary causes. The skin is most frequently affected; it can be involved both as single organ vasculitis and in the context of systemic forms. The combination of skin lesions, their anatomical location and information on the time course provide clues for a differential diagnosis. Purpura, blisters, necrosis, ulcerations and possibly a livedo are characteristic manifestations. Constitutional symptoms such as weight loss, exhaustion, fever, and arthralgias are indicative of a systemic form. It is important to differentiate vasculitides from vasculopathies, which can manifest similarly. The most common form in adults is cutaneous leukocytoclastic angiitis, in children IgA vasculitis (Schönlein-Henoch purpura). Various triggers are possible: infections, drugs, autoimmune diseases, and malignancies, whereby up to 50% remain etiologically unexplained. Skin biopsies and laboratory parameters, if necessary supplemented with imaging, are important steps in the clarification process. Treatment is primarily directed at the elimination of a possible triggering cause. Idiopathic cutaneous leukocytoclastic angiitis usually resolves spontaneously; treatment is symptomatic. In more severe cases, topical corticosteroids or calcineurin antagonists are primarily used. In case of therapeutic resistance, systemic immunosuppressants are recommended.

Prevalence of large vessel vasculitis in ANCA-associated vasculitis: a retrospective cohort study.

ANCA-associated vasculitis (AAV) in general involves small blood vessels and includes granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). Although reported in a few studies, the prevalence of large vessel vasculitis (LVV) in patients with AAV remains to be further explored. The goal of the present study was to assess the prevalence of LVV in a cohort of patients with AAV and to characterize this population. We conducted a ten-year retrospective study of a single-center cohort of AAV, including 101 patients with GPA (n = 58), EGPA (n = 28), MPA (n = 15), and compared the groups with or without associated LVV. LVV was diagnosed in five patients, two with aortitis and three with temporal arteritis, corresponding to a total prevalence of 5.0% [95% CI 1.6-11.2%]. This value was significantly higher than the estimated prevalence of LVV in the normal Swiss population (OR 234.9 95% CI 91.18-605.2, p < 0.001). All five patients had GPA, whereas no cases with EGPA or MPA were identified. Anti-PR3 antibodies were detected in four out of five patients, anti-MPO in one patient. Since LVV can occur in a significant proportion of patients with GPA, evaluation for LVV may be considered systematically in the diagnostic workup of AAV.

[New tools in the diagnosis of food hypersensitivity reactions: beyond IgE and prick testing]. / Nouveaux outils dans les hypersensibilités alimentaires : par-delà les prick tests et IgE spécifiques.

Food hypersensitivity represents a group of adverse immunological reactions linked to food ingestions such as anaphylaxis or eosinophilic esophagitis. Identification of the responsible food is currently based on a detailed history and complementary exams, mostly prick testing and assessment of serum specific IgE, either by ImmunoCAP or multiplex assay. Other skin and laboratory tools such as functional in vitro or patch testing are currently not validated although some show promising results in the field of food allergy. This article presents the different diagnostic procedures that are commonly and less commonly used in the workup of food allergies and their potential for future use in the workup of food-induced hypersensitivity reactions. Non-immunological reactions, rare entities (Heiner syndrome) and celiac disease will not be addressed in this review.

Les allergies alimentaires représentent un groupe hétérogène de réactions immunologiques secondaires à l'ingestion d'aliments. L'identification des aliments incriminés se base initialement sur l'anamnèse et des examens complémentaires, principalement les prick tests et les recherches d'immunoglobulines E spécifiques par immunoCAP ou tests multiplex. Avant d'envisager des tests de provocation, d'autres tests sont disponibles, notamment les tests fonctionnels in vitro ou les patch tests, qui ne sont pas validés pour cette indication, mais dont certains montrent un potentiel d'utilité à venir. Cet article fait une synthèse des différents outils à disposition actuels et à venir dans le diagnostic des allergies alimentaires. Les intolérances alimentaires non immunomédiées, la maladie cœliaque et les raretés telles que le syndrome de Heiner ne seront pas abordées ici.

IgE-mediated chlorhexidine allergy-Cross-reactivity with other biguanide disinfectants.

BACKGROUND: Chlorhexidine (CHX) is a widely utilized disinfectant that can cause IgE-mediated urticaria/anaphylaxis. The cross-reactivity of patients with IgE-mediated CHX allergy with other disinfectants, which share structural similarities with CHX like polyhexanide (polyhexamethylene biguanide; PHMB), alexidine (ALX), or octenidine (OCT), is unknown. METHODS: Forty-four patients with anaphylaxis or urticaria upon CHX exposure and positive skin prick test (SPT) and/or positive CHX ImmunoCAP test (Phadia TFS, Uppsala, Sweden) were recruited. IgE to the biguanide and/or hexamethylene structure was investigated with PHMB ImmunoCAP (n = 32) and by basophil activation tests (BAT) with CHX and ALX (n = 37). Inhibition tests of CHX and PHMB ImmunoCAPs by CHX, ALX, PHMB, and OCT were performed. RESULTS: IgE reactivity to PHMB as surrogate marker for biguanide/hexamethylene reactivity was detected in 5/32 sera. Seven of 37 patients showed a positive BAT with ALX, but only under optimized conditions. Binding to CHX ImmunoCAP was inhibited by ALX in 1/32 sera, and binding to PHMB was blocked by ALX (1/5) and by OCT in another (1/5). In SPT, 9/10 patients were positive for CHX and 3 of them with ALX (only at highest concentration at 5 mg/mL). A further patient reacted primarily with OCT and showed IgE cross-reactivity with CHX, ALX, and PHMB. CONCLUSION: The IgE response to CHX seems polyclonal. The chloroguanide ending of CHX is the main epitope for the IgE and is suitable as screening assay to detect CHX reactivity. IgE-reactivities with the biguanide or hexamethylene components of other disinfectants (ALX, PHMB) can be detected by SPT, PHMB ImmunoCAP, and ALX-BAT in 15%-33% of CHX-allergic patients.

Specific IgE Decision Point Cutoffs in Children with IgE-Mediated Wheat Allergy and a Review of the Literature.

BACKGROUND: Wheat IgE-mediated food allergy in children is one of the most frequent food allergies in westernized countries, affecting between 0.4 and 1% of children. Although 95% predictive decision points have been determined for major allergens such as peanut, egg, and milk, the diagnostic performances of wheat-specific IgE (sIgE) and wheat component testing are not well established. OBJECTIVES: The aim of this study was to determine sIgE decision point cutoffs in children with IgE-mediated wheat allergy and provide a review of the literature. METHOD: A retrospective review of wheat oral food challenges was performed at the pediatric allergy unit of the University Hospitals of Geneva between 2004 and 2019. Performance characteristics for wheat and ω-5 gliadin sIgE were calculated and positive and negative OFC data were compared using the Mann-Whitney U test. RESULTS: A wheat sIgE cutoff of 2.88 kUA/L had a sensitivity of 95% (negative decision point), whereas a cutoff of 78.1 kUA/L had a specificity of 95% (positive decision point). When giving equal weight to sensitivity and specificity, the optimal cutoff point for wheat sIgE was 12 kUA/L, which gave a specificity of 70% and a sensitivity of 66.67%. CONCLUSIONS: These findings suggest a high positive decision point for wheat sIgE (78.1 kUA/L). This reinforces the importance of considering OFC in children with IgE-mediated wheat allergy to confirm diagnosis even in patients with relatively high wheat sIgE values, as there is a risk of falsely mislabeling these patients as allergic.

[MRGPRX2, pseudo-allergies reloaded: a step forward and two backwards]. / MRGPRX2, le retour des pseudo-allergies†: un pas en avant et deux en arrière.

Since the description in 2015 of the MRGPRX2 receptor on mast cells, responsible for pseudo-allergies, our knowledge of this type of allergy-like drug reaction is growing, as has the list of drugs -supposed to be able to induce this type of reaction. Unlike IgE--mediated reactions, these pseudoallergic reactions do not require a prior sensitization, are dose-dependent and predictable, and could be prevented, if the offending drug has to be re-administered, -simply with a reduced rate of perfusion or dose. Genetic factors seem to play a role in the predisposition to this type of reactions, but we do not yet have clinically available tools to diagnose them. This literature review summarizes the discoveries of the last 4 years in this field that seem to challenge many dogmas in allergology.

Depuis la description en 2015 du récepteur MRGPRX2 sur les mastocytes, responsable des pseudo-allergies, nos connaissances concernant ce type de réaction médicamenteuse ressemblant à une allergie ne cessent d'augmenter, tout comme la liste de ­médicaments qui pourraient induire ce type de réaction. Con­trairement aux réactions IgE-médiées, les réactions pseudo-­allergiques sont dose-dépendantes et prévisibles, et pourraient être prévenues, en cas de nouvelle administration du médi­cament incriminé, simplement par réduction de la dose ou de la vitesse d'administration. Malheureusement, nous ne disposons pas encore d'outils en clinique permettant de les diagnostiquer. Cette revue de la littérature résume les découvertes des quatre dernières années, qui remettent beaucoup de dogmes en ­question.

[How to manage giant cell arteritis]. / Allergologie-immunologie - Prise en charge de l'artérite gigantocellulaire en 2019.

Giant cell arteritis (GCA) is the most common vasculitis in adults over 50 years, which requires an urgent treatment with corticosteroids to reduce ischemic complications. Because of their side-effects, a valid diagnosis is necessary. Histological confirmation remains the gold-standard but non-invasive imaging along specific clinical criteria can nowadays diagnose GCA, particularly temporal artery ultrasound. Alternatives to corticosteroids are being studied and recently, the addition of tocilizumab to corticosteroids has been validated by international institutions and is approved by Swissmedic. Similarly to tocilizumab, methotrexate has been shown to decrease the total dose of corticosteroids and the number of relapses. We will also discuss newer potential therapies (abatacept and ustekinumab).

L'artérite à cellules géantes est une vasculite des gros vaisseaux fréquentes après 50 ans, nécessitant un traitement par corticostéroïdes dès le diagnostic pour diminuer les complications ischémiques. En raison des effets secondaires du traitement, une certitude diagnostique est importante. Bien que la confirmation histologique reste le gold standard, l'imagerie permet désormais de poser un diagnostic non invasif en présence de critères bien définis. Des alternatives aux stéroïdes sont étudiées et récemment, l'adjonction de tocilizumab a été validée par Swissmedic, entre autres dans le but de diminuer la dose totale de stéroïdes et le nombre de rechutes. Le méthotrexate, alternative au tocilizumab, existe et est toujours d'actualité. Nous discuterons également de l'abatacept et de l'ustékinumab, molécules prometteuses en cours d'évaluation.

Identifying True Celiac Disease and Wheat Allergy in the Era of Fashion Driven Gluten-Free Diets.

BACKGROUND: Diagnosing both celiac disease (CD) and wheat allergy (WA) might be challenging due to the increasingly popular gluten-free diets. OBJECTIVES: This study investigates the value of anti-tissue transglutaminase IgA (tTGIgA) and wheat-specific IgE (WIgE), and identifies clinical and serological features associated with CD and WA. METHOD: Serological markers of autoimmunity and allergy along with medical charts of patients assessed for tTGIgA and WIgE between 2010 and 2016 were evaluated. RESULTS: During the last years, an increasing number of patients have been tested for tTGIgA, while the number of positive results decreased linearly. Among the 2,965 patients included, 128 patients showed at least once a positive tTGIgA. All patients with tTGIgA levels higher than the 12-fold upper normal limit had CD. The ratio of tTGIgA/total IgA did not perform better as a diagnostic test for CD compared to tTGIgA. tTGIgA and anti-nuclear antibodies were significantly associated. WA was only rarely investigated, particularly in adults. However, positive WIgE were found in nearly 50% of the cases. WIgE and tTGIgA values were negatively correlated. CONCLUSIONS: tTGIgA were increasingly tested, while the rate of positive results decreased in recent years, possibly reflecting the impact of current alimentary trends on clinical practice. Associated autoimmune disease was frequently found in CD. High levels of tTGIgA accurately predicted CD diagnosis. WA was rarely investigated and deserves more attention, in particular in children with atopic background. WA does not seem to be associated with CD.

[Evaluation of the new algorithm in ANCA testing]. / Présentation des nouveaux algorithmes de dosage d'ANCA.

Testing for ANCA is useful for the diagnosis and monitoring of disease activity in ANCA associated vasculitis. ANCA testing is also sometimes requested for other indications. The relevance of indirect immunofluorescence in ANCA testing is controversial and has recently been the object of new international recommendations. The new approach certainly improves the performance of this test, particularly in Switzerland where, due to the large number of requests, the pre-test probability of ANCA associated vasculitis is relatively low. However, in this article we discuss the possible flaws of the new algorithm based on two recent cases, and highlight the importance of a good communication with the laboratory in order to improve the interpretation of the results.

La recherche des ANCA est utilisée pour le diagnostic et le suivi de l'activité des vasculites associées aux ANCA, mais aussi parfois pour d'autres indications plus controversées. La place de l'immunofluorescence indirecte dans l'algorithme de dépistage et de suivi des vasculites à ANCA est contestée depuis plusieurs années et a récemment fait l'objet de nouvelles recommandations internationales. Cette nouvelle approche améliore certainement le rendement de ce test, en particulier en Suisse où, en raison du grand nombre d'analyses demandé, la probabilité prétest d'une vasculite à ANCA est relativement faible. Cependant, nous discutons dans cet article les possibles failles de la nouvelle approche en nous basant sur deux cas récents au laboratoire et rendons les prescripteurs attentifs sur l'importance de la communication avec le laboratoire afin d'améliorer l'interprétation des résultats.

[Livedo : physiopathology and diagnosis]. / Le livedo : physiopathologie et diagnostic.

The livedo is a purplish erythema forming more or less regular mesh on the skin. This phenomenon is caused by blood deoxygenation and stasis in the dermal venules. It is important to differentiate between a benign form, usually associated with cold exposure, and a secondary form necessitating further investigations of an underlying disease. The purpose of this article is to discuss the pathophysiology and causes of this phenomenon. Treatment is not covered in this article because of its complex and often multidisciplinary approach.

Le livedo est un érythème violacé formant des mailles plus ou moins marquées et régulières sur la peau. Il s'agit d'un phénomène causé par une désoxygénation et une stase au niveau des veinules dermiques. Lors de son apparition, il est important de différencier une forme bénigne, souvent liée à l'exposition au froid, d'une forme pathologique qui peut être le premier signe d'une maladie sous-jacente qu'il convient de rechercher. Le but de cet article est de discuter de la physiopathologie et des causes de ce phénomène. La prise en charge thérapeutique n'est pas traitée dans cet article en raison de son caractère complexe et souvent multidisciplinaire en cas d'origine secondaire.

Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or "Innate Hypersensitivity"?

Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo-allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE-mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions.

Non-IgE-Dependent Hypersensitivity to Rocuronium Reversed by Sugammadex: Report of Three Cases and Hypothesis on the Underlying Mechanism.

We present 3 cases of pseudoallergic (anaphylactoid) reactions to perioperatively administered rocuronium, which rapidly resolved after sugammadex injection. Allergological workup showed no evidence for immediate-type hypersensitivity to the drugs used for anesthesia, including rocuronium. However, rocuronium induced an irritative reaction in skin tests in all 3 patients and in 3 healthy individuals. This reaction was specifically suppressed by adding sugammadex at a 1:1 molecular proportion to rocuronium before the skin tests. This observation suggests that the patients suffered from a pseudoallergic reaction, and indicates that sugammadex might act via the inhibition of non-IgE mediated MRGPRX2 (Mas-related G-protein-coupled receptor member X2)-triggered mast cell degranulation induced by rocuronium.

[Drug reaction with eosinophilia and systemic symptoms]. / Syndrome DRESS (drug reaction with eosinophilia and systemic symptoms).

Cutaneous drug eruptions are delayed type hypersensitivity reactions that can be potentially life threatening. Severe cutaneous adverse reactions encompass the acute generalized exanthematous pustulosis (AGEP), the drug reaction with eosinophilia and systemic symptoms (DRESS), the Stevens-Johnson syndrome (SJS) and the toxic epidermal necrolysis (TEN, synonym: Lyell syndrome). In this article, we focus on the DRESS syndrome, which associates skin eruption and systemic symptoms. Its mortality rate is estimated at 10%. Therefore early diagnosis and the interruption of the culprit drug are crucial. In this review, we discuss the physiopathology, the most common eliciting drugs, the diagnostic criteria and the proposed treatments of DRESS.

[Omalizumab in the treatment of chronic urticaria: what's new in 2013?]. / Allergologie. Omalizumab dans le traitement de l'urticaire chronique: quoi de neuf en 2013 ?

In 2013, new crucial data dealing with the treatment options for chronic idiopathic and physical urticaria have been published. In this article, after a short introduction where we discuss the classification and the pathogenesis of the disease, we will focus on the therapeutic approach in patients with chronic urticaria. In particular, considering the data available on the treatment with omalizumab, we will discuss the indications and treatment modalities of chronic urticaria.

Anti-neutrophil cytoplasmic antibodies in rheumatoid arthritis: two case reports and review of literature.

BACKGROUND: Anti-neutrophil cytoplasmic antibodies are typically detected in anti-neutrophil cytoplasmic antibody associated vasculitis, but are also present in a number of chronic inflammatory non-vasculitic conditions like rheumatoid arthritis. Rare cases of granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis, a vasculitic disorder frequently associated with the presence of anti-neutrophil cytoplasmic antibodies) in patients with rheumatoid arthritis have been described in literature. CASE PRESENTATION: We report two middle-aged female patients with rheumatoid arthritis who developed anti-neutrophil cytoplasmic antibodies and symptoms reminiscent of granulomatosis with polyangiitis. Despite the lack of antibodies specific for proteinase 3 and the absence of a classical histology, we report a probable case of granulomatosis with polyangiitis in the first patient, and consider rheumatoid vasculitis in the second patient. CONCLUSION: Taken together with previous reports, these cases highlight that anti-neutrophil cytoplasmic antibodies have to be evaluated very carefully in patients with rheumatoid arthritis. In this context, anti-neutrophil cytoplasmic antibodies detected by indirect immunofluorescence appear to have a low diagnostic value for granulomatosis with polyangiitis. Instead they may have prognostic value for assessing the course of rheumatoid arthritis.

Atypical pulmonary phaeohyphomycosis due to Aureobasidium spp. - case report and brief literature review.

We report on a case of probable invasive Auerobasidium spp. pulmonary infection in a patient with myelodysplastic syndrome. The patient was successfully treated with liposomal amphotericin B monotherapy, with transition to orally administered isavuconazole. This case shows an atypical initial radiological presentation with diffuse ground-glass opacities, as previously demonstrated in cases of Aureobasidium spp. hypersensitivity pneumonitis. Moreover this case further highlights the difficulties associated with the diagnosis and complexity in the management of Aureobasidium spp. infections.

Three cases of BRAF mutation negative Erdheim-Chester disease with a challenging distinction from IgG4-related disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis with slow progression over the years that is particularly difficult to diagnose. CASES: Here we report three cases of ECD without BRAF mutation presenting with a renal mass, hairy kidney appearance, and a rather benign course, for which the diagnosis of ECD was delayed, characterized by multiple investigations and unsuccessful treatments attempts. In two cases the distinction from IgG4-related disease required multiple investigations and reevaluation of the clinical, radiological, histological, and immunological characteristics. CONCLUSION: A correct diagnosis of ECD may take several years and often requires revisiting previous hypotheses. Reassessment of histological slides and more modern complementary exams such as PET-CT or BRAF and MAPK-ERK mutation analysis can help to confirm the diagnosis of ECD and to select effective therapy.

Adverse drug reactions to biologics.

The use of biologics has rapidly expanded since the introduction of the first diagnostic antibodies; they are now widely employed in oncology, autoimmune disorders, inflammatory diseases and transplantation medicine. Their widespread use has resulted in an increase in adverse drug reactions. Adverse effects result from both direct pharmacological actions and immunological actions, as well as through induction of a specific immune response. The nomenclature, particularly of the monoclonal antibodies, identifies the target structure and organ as well as the species of origin, which then helps predict their effects and antigenic properties. Depending on the extent of foreign protein, anti-allotypic or anti-idiotypic antibodies with or without neutralizing properties may be induced. Adverse drug reactions from biologics often depend on the target and may be explained by activation or inhibition of particular cytokine pathways. Adverse drug reactions are classified by their pathomechanism, which enhances understanding of the pathogenesis and facilitates both allergologic diagnostic measures and planning of premedication in future treatments. This review emphasizes immunostimulatory and hypersensitivity reactions.