Effects of Intravenous Immunoglobulins on Human Innate Immune Cells: Collegium Internationale Allergologicum Update 2024.

BACKGROUND: Intravenous immunoglobulin (IVIg) has been used for almost 40 years in the treatment of autoimmune and systemic inflammatory diseases. Numerous cells are involved in the innate immune response, including monocytes/macrophages, neutrophils, dendritic cells, mast cells, basophils, eosinophils, natural killer cells, and innate lymphoid cells. Many studies have investigated the mechanisms by which IVIg down-modulates inflammatory and autoimmune processes of innate immune cells. However, questions remain regarding the precise mechanism of action in autoimmune or inflammatory conditions. The aim of this work was to review the immunomodulatory effect of IVIg on only human innate immune cells. A narrative review approach was chosen to summarize key evidence on the immunomodulatory effects of commercially available and unmodified IVIg on human innate immune cells. SUMMARY: Numerous different immunomodulatory effects of IVIg have been reported, with some very different effects depending on the immune cell type and disease. Several limitations of the different studies were identified. Of the 77 studies identified and reviewed, 29 (37.7%) dealt with autoimmune or inflammatory diseases. Otherwise, the immunomodulatory effects of IVIg were studied only in healthy donors using an in vitro experimental approach. Some of the documented effects showed disease-specific effects, such as in Kawasaki disease. Various methodological limitations have also been identified that may reduce the validity of some studies. KEY MESSAGE: As further insights have been gained into the various inflammatory cascades activated in immunological diseases, interesting insights have also been gained into the mechanism of action of IVIg. We are still far from discovering all the immunomodulatory mechanisms of IVIg.

[Hypogammaglobulinemia and immunodeficiency in multiple myeloma and chronic lymphoid leukemia]. / Hypogammaglobulinémie et déficits immunitaires dans le myélome multiple et la leucémie lymphoïde chronique.

Infections are among the leading causes of morbidity and mortality in lymphoproliferative malignancies such as multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). The causes of infections are often multifactorial and may be due to disease- or treatment-related factors. New therapies have improved survival in lymphoproliferative malignancies, resulting in an increased incidence of secondary immune deficiencies (SID) in these diseases.

Les infections sont l'une des principales causes de morbidité et de mortalité dans les maladies lymphoprolifératives malignes telles que le myélome multiple (MM) et la leucémie lymphoïde chronique (LLC). Les causes des infections sont souvent multifactorielles et peuvent être secondaires à des facteurs liés à la maladie ou au traitement. Les nouvelles thérapies ont permis d'améliorer le taux de survie des maladies lymphoprolifératives malignes, ce qui a entraîné une augmentation de l'incidence des déficits immunitaires secondaires (DIS) dans ces maladies.

[Management of allergic rhinitis in general practitioner's office]. / Prise en charge de la rhinite allergique au cabinet du généraliste.

In Switzerland, almost 20 % of the population suffers from allergic rhinitis, which has a major impact on patients' quality of life. Allergen avoidance remains the most effective measure but is not always possible. Intranasal corticosteroids, oral antihistamines, or combination of intranasal corticosteroids and antihistamines remain first-line pharmacological treatments. In case of refractory symptoms, despite well-managed symptomatic treatment, when the patient wishes a more long-term effect or for prevention of asthma, the patient can be referred to the allergologist for specific immunotherapy. The specific immunotherapy is the only treatment option that targets the underlying pathophysiology of allergy and therefore shows disease-modifying effects.

En Suisse, près de 20 % de la population sont atteints de rhinite allergique et cette dernière impacte de manière importante la qualité de vie des patients. L'éviction des allergènes reste la mesure la plus efficace mais n'est pas toujours possible. Les corticostéroïdes intranasaux, les antihistaminiques per os, ainsi que les combinaisons de corticostéroïdes et d'antihistaminiques intranasaux demeurent les traitements pharmacologiques de première ligne. En cas de symptômes réfractaires, lorsque le patient souhaite un effet à long terme ou dans un contexte de prévention de l'asthme, il peut être référé chez l'allergologue pour une immunothérapie spécifique. C'est la seule option thérapeutique ciblant la physiopathologie sous-jacente de l'allergie et avec un effet modificateur sur la maladie.

[Urticaria : updates of a chronic condition]. / Urticaire : nouveautés et chronicité.

Urticaria is a frequent disease and exist in an acute or chronic form. The pathophysiology, focused on mast cells and histamine among other mediators, is an active research field but still poorly understood. The medical care focus on the avoidance of triggers and aggravating factors. The recommended drug therapy has not changed. The acknowledgment of chronic urticaria as a chronic disease is essential according to the last international recommendations. Acknowledging the disease morbidity and consequences, in a private, social or professional environment, allows better medical care for patients. The latter should get support on the long term, thanks to multiple diagnostic and therapeutic guidance tools.

L'urticaire est une maladie fréquente pouvant être aiguë ou chronique. Sa physiopathologie, centrée sur les mastocytes et de multiples médiateurs dont l'histamine, fait l'objet de nombreuses recherches mais reste encore mal connue. La prise en charge se concentre sur l'éviction des facteurs déclencheurs et aggravants. Les traitements médicamenteux recommandés n'ont pas changé. La reconnaissance de l'urticaire chronique en tant que maladie chronique est centrale dans les dernières recommandations internationales. La reconnaissance de la morbidité et des conséquences de la maladie, dans les cadres privé, social ou professionnel, permet une meilleure prise en charge des patient-es. Ces dernier-ères devront être accompagné-e-s sur le long terme, grâce à plusieurs outils diagnostiques et d'accompagnement thérapeutique.

[Vaccination and Vaccination Response in Immunodeficiency]. / Impfungen und Impfantwort bei Immundefekten.

Vaccination and Vaccination Response in Immunodeficiency Abstract. Vaccination of patients with immunodeficiencies is challenging. A lack of increase in vaccine antibody titers or vaccine-induced infections may indicate primary immunodeficiency. All vaccines against SARS-CoV-2 licensed in Switzerland can be administered to immunocompromised patients.

[Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy]. / Antikörpermangelsyndrome.

Antibodydeficiencies Epidemiology, Clinical manifestation, Diagnostics and Therapy Abstract. Primary Immune Deficiencies (PID) are caused by a genetically induced malformation/dysfunction of the immune system. Leading symptoms include susceptibility to infection, autoimmune diseases, lymphoproliferative, allergic as well as malignant diseases. They can be divided into ten main groups, including the primary antibody deficiency syndromes (PAD) in adults. The most well-known PADs include the variable immunodeficiency syndrome (CVID), Bruton's agammaglobulinaemia, IgG subclass deficiencies, immunoglobulin A deficiency, Antibody deficiency and transient childhood hypogammaglobulinaemia. Secondary hypogammaglobulinaemia by medicinal products, haematological diseases, malignancies and infections should be excluded. Delayed diagnosis of CVID is associated with a significant increase in morbidity and an increase in mortality. In addition to vaccinations, immunoglobulin replacement therapy is used therapeutically.

The architecture of the IgG anti-carbohydrate repertoire in primary antibody deficiencies.

Immune system failure in primary antibody deficiencies (PADs) has been linked to recurrent infections, autoimmunity, and cancer, yet clinical judgment is often based on the reactivity to a restricted panel of antigens. Previously, we demonstrated that the human repertoire of carbohydrate-specific immunoglobulin G (IgG) exhibits modular organization related to glycan epitope structure. The current study compares the glycan-specific IgG repertoires between different PAD entities. Distinct repertoire profiles with extensive qualitative glycan-recognition defects were observed, which are characterized by the common loss of Galα and GalNAc reactivity and disease-specific recognition of microbial antigens, self-antigens, and tumor-associated carbohydrate antigens. Antibody repertoire analysis may provide a useful tool to elucidate the degree and the clinical implications of immune system failure in individual patients.

Diagnosis and Management of Severe Asthma in Switzerland: Analysis of Survey Results Conducted with Specialists and General Practitioners.

BACKGROUND: Severe asthma commonly affects 5-10% of the asthmatic population and accounts for approximately 50% of the overall asthma costs. OBJECTIVE: This analysis investigated how severe asthma is diagnosed, treated, and managed by specialists and general practitioners (GPs) in Switzerland. METHODS: Two surveys, one each among specialists (N = 44) and GPs (N = 153), were conducted to understand their self-perception on diagnosis, treatment, and management of severe asthma. RESULTS: Fifty-five percent of the specialists felt very confident and 43% confident in recognizing the symptoms of severe asthma and diagnosing severe asthma. In contrast, 9% of the GPs were very confident and 59% confident in diagnosing severe asthma. More specific diagnostic tests for severe asthma, like total and specific immunoglobulin E levels and measurement of the fraction of exhaled nitric oxide, were run by specialists (χ2 = 171.4; df = 15, p < 0.001). GPs and specialists were using different measurements to assess severe asthma (χ2 = 385.2; df = 13, p < 0.001) and their prescribing patterns differed significantly (χ2 = 189.8; df = 10, p < 0.001). GPs referred patients with severe asthma if the diagnosis was unclear (24%), if treatment failure occurred (26%), and if the patients were at high risk (41%). CONCLUSIONS: Oral corticosteroids (OCSs) are considered as background therapy for severe asthma by GPs and specialists. In order to reduce the OCS burden, there is a need to improve the awareness for other add-on therapies. A joint collaboration between GPs and specialists is the key to leverage therapeutic strategies together.

Efficacy of Omalizumab in Mastocytosis: Allusive Indication Obtained from a Prospective, Double-Blind, Multicenter Study (XOLMA Study).

BACKGROUND: Patients with mastocytosis often suffer from a variety of symptoms caused by mast cell mediators where treatments remain difficult, showing various success rates. Omalizumab, a monoclonal anti-IgE antibody, has been postulated to have a positive impact on mastocytosis-associated symptoms such as flush, vertigo, gastrointestinal problems, or anaphylaxis. OBJECTIVE: To investigate the efficacy and safety of omalizumab in systemic mastocytosis. METHODS: Patients with histologically proven mastocytosis were investigated in a multicenter prospective double-blind placebo-controlled trial to receive either omalizumab or placebo, dosed according to IgE and body weight. The primary endpoint was change in the AFIRMM activity score after 6 months of treatment. Different laboratory parameters were analyzed. RESULTS: Sixteen patients were analyzed: 7 to omalizumab and 9 to placebo (mean age 47.7 ± 13.8 vs. 45.4 ± 8.8 years; 66.6 vs. 85.7% were female; mean disease duration 10.0 ± 5.1 vs. 4.5 ± 2.9 years, respectively). After 6 months the median AFIRMM score decreased 50% from 52.0 to 26.0 in the omalizumab group versus 104.0-102.0 in the placebo group (p = 0.286); however, the difference was not significant (p = 0.941). Secondary endpoints, including the number of allergic reactions, changes in major complaints, wheal-and-flare reaction due to mechanical irritation (Darier's sign), and frequency of the use of mastocytosis-specific drugs improved in the omalizumab group, but not significantly. Adverse events like urticaria, bronchospasm, and anaphylactic shock showed no significant difference between the groups. No severe adverse events occurred. FcεRI (Fc-epsilon receptor) expression on basophils decreased after receiving omalizumab versus placebo. CONCLUSION: Omalizumab was safe and showed a tendency to improve mastocytosis-related symptoms, in particular diarrhea, dizziness, flush, and anaphylactic reactions, including the AFIRMM score and secondary endpoints; however, the difference was not significant. Due to the small study size and difference at baseline between the study groups, further studies are required to confirm our findings.

[Widal's triad : clinical manifestations, pathophysiology and therapeutic advances]. / Syndrome de Widal : manifestations cliniques, physiopathologie et avancées thérapeutiques.

NSAID-Exacerbated respiratory disease (also known as Samter's or Widal's triad, aspirin-exacerbated respiratory disease) is characte- rized by asthma, nasal polyposis and hypersensitivity to NSAIDs. The pathogenesis of this chronic inflammation arises from an imbalance in arachidonic acid metabolism, leading to an increase in pro- inflammatory cysteinyl-leukotrienes. The treatment is based on drug management of asthma and polyps and, in advanced situations, surgical management of polyposis. Monoclonal antibodies have shown promising results in the further medical treatment of this entity.

Le syndrome de Widal (SW) (également connu sous le nom de triade de Samter, maladie respiratoire exacerbée par l'Aspirine) est une entité clinique caractérisée par la triade comprenant un asthme, une polypose nasale et une intolérance aux AINS. La physiopathologie de cette maladie, bien qu'incomplètement élucidée, est caractérisée par un déséquilibre dans le métabolisme de l'acide arachidonique (AA) en faveur de la voie des cystéinyl- leucotriènes (cysLT). Son traitement repose sur une prise en charge médicamenteuse agressive de l'asthme et des polypes et, dans des situations avancées, la prise en charge chirurgicale de la polypose. L'avènement des traitements par anticorps monoclo- naux a montré des résultats encourageants pour les alternatives thérapeutiques futures.

[A first-line guide to the evaluation of « Penicillin Allergy ¼ in general medical practice]. / Proposition de prise en charge de l'« allergie à la pénicilline ¼ en médecine interne et de premier recours.

« Penicillin allergy ¼ is a common finding in patient's medical files (up to 10 %). Although it is important not to neglect such records (due to the serious and life-threatening reactions an allergic patient may suffer from), most of the time these reported notions of allergy are wrong and lead to the unfortunate avoidance of all betalactamins. This in turn leads to increased risks of antibiotic resistance and increased health costs. This review aims to summarize the current knowledge on penicillin allergy epidemiologic data and proposes a first-line guide for general practitioners to the evaluation of the patient with a history of « penicillin allergy ¼.

La « notion d'allergie à la pénicilline ¼ dans les dossiers des patients est une trouvaille assez fréquente (jusqu'à 10 %) et généralement erronée. Cette dernière peut mener à une sous-utilisation des bêtalactamines avec des conséquences négatives sur l'émergence de germes résistants, la prise en charge et les coûts médicaux. D'un autre côté, il s'agit néanmoins d'un diagnostic à ne pas ignorer ni à banaliser (notamment devant une anamnèse incomplète) étant donné la sévérité des réactions qu'une exposition pourrait occasionner. Cet article propose un résumé des connaissances actuelles des données épidémiologiques sur le sujet, et un algorithme de prise en charge en première intention des « notions d'allergie à la pénicilline ¼.

[The diagnostic challenge of primary immunodeficiencies in adults]. / Défi diagnostique des immunodéficiences primaires chez les adultes.

Primary immunodeficiencies (PID) constitute a heterogeneous group of genetic disorders caused by defects in the development and/or function of the immune system resulting in an increased susceptibility to recurrent infections. In addition to a predisposition to infections, PID patients present an increased vulnerability to autoimmunity, lymphoproliferation, allergies and malignancies. Studies performed in the past decade revealed that the prevalence of PID in adults was largely underestimated. These have also demonstrated that the disease burden of PID is not less than in children. PID is more common than generally thought.

Les immunodéficiences primaires (IDP) constituent un groupe hétérogène génétique, causées par des défauts de développement et/ou de fonctionnement du système immunitaire, entraînant une susceptibilité aux infections récurrentes. Les patients atteints d'une IDP présentent une prédisposition au développement de pathologies auto-immunes, lymphoprolifératives, allergiques ou malignes. Les études réalisées au cours de la dernière décennie ont corrigé les sous-estimations de la prévalence des IDP adultes et ont montré que la morbidité n'est pas moins lourde chez les adultes que chez les enfants. Les IDP sont en effet plus fréquentes qu'on ne le pense.

[The efficacy of omalizumab in the treatment of chronic rhinosinusitis with nasal polyps: a discussion of 2 refractory cases]. / Efficacité de l'omalizumab dans la polypose nasale: à propos de deux cas.

Nasal polyposis is a specific phenotype of chronic rhinosinusitis (CRS). Some cases can be managed with topical and infrequent use of systemic steroids, while many patients require surgery. Despite postoperative, regular steroid administration, recurrences may be found especially in patients suffering from Aspirin exacerbated respiratory disease (AERD), a particularly severe form of CRS with polyps, asthma and non-steroid-anti-inflammatory-drug (NSAID) intolerance. We report two cases of difficult-to-treat AERD patients following revision surgery, treated with monoclonal anti-IgE antibody (omalizumab) and successful control of the disease and symptoms. Omalizumab may be a promising alternative in selected cases of CRS with nasal polyps to avoid overuse of systemic steroids and frustrating repetition of paranasal sinus surgeries.

La rhinosinusite chronique (RSC) touche 15 % de la population et se caractérise par l'obstruction et l'écoulement nasaux pendant plus de trois mois. Les formes sévères de la RSC sont associées à la présence de polypes nasaux. Le traitement de première ligne sont des corticoïdes topiques, qui ne sont pas toujours efficaces et certains patients ont besoin de plusieurs cures de stéroïdes per os et chirurgies nasales répétitives pour stabiliser la maladie. Ce cercle vicieux s'observe souvent dans le syndrome de Widal (polypes, asthme et intolérance aux AINS). On rapporte deux cas de Widal avec interruption de cette boucle, obtenue par l'application de l'anticorps monoclonal anti-IgE omalizumab. L'omalizumab pourrait être une alternative dans certains cas de RSC pour limiter la surutilisation de stéroïdes et la répétition frustrante de chirurgie nasale.

[Mastcell activation syndrome]. / Syndrome d'activation mastocytaire.

Mast cell activation syndrome (MCAS) encompasses a heterogeneous group of pathologies, which are characterized by the existence of clinical symptoms secondary to the systemic effects of mediators released by activated mast cells. MCAS-related symptoms may be mild, moderate, severe, or even life-threatening. Detailed knowledge of the pathogenesis and complexity of MCAS can help in the management and treatment of these patients.

Le syndrome d'activation mastocytaire (MCAS) englobe un groupe hétérogène de pathologies qui sont caractérisées par la présentation des symptômes cliniques secondaires aux effets systémiques des médiateurs libérés par les mastocytes activés. Les symptômes liés au MCAS peuvent être légers, modérés, graves ou même mortels. Une connaissance détaillée de la pathogenèse et de la complexité du MCAS peut aider dans la prise en charge et le traitement de ces patients.

[Allergology and clinical immunology]. / Allergologie et immunologie clinique.

Hereditary angioedema (HA) is a disabling and potentially fatal condition. The management of HA includes treatment of acute attacks, short-term prophylaxis to prevent an attack, and long-term prophylaxis to minimize the frequency and severity of recurrent attacks. In this article, we will present new therapeutic alternatives for long term prophylaxis. Glucocorticoids (GC) usage leads to a number of severe side-effects. In giant cell arteritis, the use of tocilizumab in conjunction with low doses of GC reduces the number of relapses. In ANCA-associated vasculitis the use of an anti-C5R (avacopan) alone or in conjunction with low doses of GC results in similar remission rates to those induced by high dose GC.

L'angiœdème héréditaire (AH) est une maladie invalidante et potentiellement mortelle. La prise en charge de l'AH comprend le traitement des crises aiguës, la prophylaxie à court terme pour prévenir une attaque et la prophylaxie à long terme pour minimiser la fréquence et la gravité des crises récurrentes. Nous discutons les nouvelles alternatives thérapeutiques pour la prophylaxie à long terme. L'utilisation des glucocorticoïdes (GC) est grevée d'effets secondaires multiples et graves. Dans l'artérite gigantocellulaire l'adjonction d'un anti-IL6 à des doses faibles de GC a permis de réduire le nombre de rechutes. Dans les vascularites à ANCA, un anti-C5R (avacopan) a permis de réduire la quantité de GC nécessaire pour atteindrela rémission.

Immunoglobulin deficiency in patients with chronic rhinosinusitis: Systematic review of the literature and meta-analysis.

BACKGROUND: Several studies have shown a high prevalence of immunoglobulin deficiencies in patients with chronic rhinosinusitis (CRS). OBJECTIVE: We sought to perform a systematic review and meta-analysis to estimate this prevalence more precisely and to identify patients who need substitution treatment. METHODS: All case series published after 1990 describing patients with CRS, which was defined as symptomatic rhinosinusitis for more than 12 weeks and documented immunoglobulin deficiencies (including deficiencies of IgG with subclasses, IgA, and IgM; specific antibody deficiencies; and potential common variable immunodeficiency), were retrieved. A meta-analysis of the proportion of any combination of common variable immunodeficiency, IgG deficiency, IgA deficiency, and IgM deficiency in patients with CRS was performed by using logit transformation of the prevalence. Recurrent CRS was defined as rhinosinusitis not controlled by appropriate conservative management for 4 months, and difficult-to-treat CRS was defined as noncontrollable rhinosinusitis despite successful sinus surgery and appropriate conservative management for at least 1 year. RESULTS: The meta-analysis revealed a prevalence of pooled IgG, IgA, and IgM deficiencies in 13% of patients with recurrent CRS and 23% of patients with difficult-to-treat CRS. The prevalence of IgG subclass deficiency (5% to 50%) and specific antibody deficiency (8% to 34%) was increased in patients with CRS, as was the prevalence of respiratory allergies in patients with recurrent CRS (31% to 72%). CONCLUSION: Immunoglobulin deficiency is a frequent condition in patients with CRS. An even higher prevalence of atopy was observed in patients with recurrent CRS. Therefore immunoglobulin titers and accurate allergy diagnostic workups are strongly recommended in these patients to provide specific treatments for symptom alleviation. However, there is a need for larger prospective studies addressing the effect of specific therapeutic interventions for CRS.

[Understanding primary immunodeficiencies: usefulness of a register]. / Comprendre les immunodéficiences primaires: utilité d'un register.

Primary Immunodeficiency Diseases (PID) comprise inborn defects of the immune system which are and therefore difficult to study For this reason, the European Society for ImmunoDeficiencies (ESID) has set up an internet-based international patient and research database which integrates research data with more detailed clinical information. These disorders are not only found in children, but also in adults resulting in a wide range of clinical manifestations. Primary immunodeficiency adults are much less known and may remain undiagnosed.

[Sulfonamide allergy and cross-reactivity]. / Allergie aux sulfamides et réactivité croisée.

Beside beta-lactams, sulfonamide antibiotics are among the most common causes of drug allergy. Hypersensitivity to sulfonamides including IgE-mediated immediate, delayed cell-mediated mechanisms, and severe life-threatening reactions are still incompletely understood. Unfounded concerns of cross-reactivity between sulfonamide antibiotics and a variety of non-antibiotic-containing sulfonamide drugs render pharmacotherapy unnecessarily difficult. Here, the history, clinical manifestations, diagnosis and treatment of sulfonamide allergy are briefly reviewed.