[Nephropathy associated with monoclonal immunoglobulins: From clonal expansion B to renal toxicity of pathological immunoglobulins]. / Les néphropathies associées aux immunoglobulines monoclonales : de l'expansion clonale B à la toxicité rénale des immunoglobulines pathologiques.

Germinal center regulation pathways are often involved in lymphomagenesis and myelomagenesis. Most of the lymphomas (and multiple myeloma) derive from post-germinal center B-cells that have undergone somatic hypermutation and class switch recombination. Hence, B-cell clonal expansion can be responsible for the presence of a monoclonal component (immunoglobulin) of variable titer which, owing to physicochemical properties, can provoke pathologically defined entities of diseases. These diseases can affect any functional part of the kidney, by multiple mechanisms, either well known or not. The presence of renal deposition is influenced by germinal gene involved, immunoglobulin primary structure, post-translational modifications and microenvironmental interactions. The two ways immunoglobulin can cause kidney toxicity are (i) an excess of production (overcoming catabolism power by proximal tubule epithelial cells) with an excess of free light chains within the distal tubules and a subsequent risk of precipitation due to local physicochemical properties; (ii) by structural characteristics that predispose immunoglobulin to a renal disease (whatever their titer). The purpose of this manuscript is to review literature concerning the pathophysiology of renal toxicities of clonal immunoglobulin, from molecular B-cell expansion mechanisms to immunoglobulin renal toxicity.

Decline of humoral immune responses after natural SARS-CoV-2 infection can be efficiently reversed by vaccination.

Our aim was to analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody level kinetics after coronavirus disease 2019 (COVID-19) infection and determine the efficiency of vaccination on SARS-CoV-2-specific antibody levels. The study included 50 SARS-CoV-2 infected and 70 uninfected cases. Levels of SARS-CoV-2-specific IgG nucleocapsid protein (IgG-NP), IgG spike protein (IgG-SP), IgM nucleocapsid protein (IgM-NP), and IgA spike protein (IgA-SP) antibodies were evaluated by an enzyme-linked immunosorbent assay in sera obtained at baseline, 1st, 3rd, and 6th month follow-up visits for infected cases and at postvaccination visits for all cases. In symptomatic cases (n = 50), IgG-SP levels were decreased in 6 months compared with baseline, while IgA-SP levels were significantly increased. IgG-NP levels were significantly decreased in symptomatic cases at the 6-month visit. After vaccination, IgG-SP levels were increased in symptomatic cases compared with prevaccination levels. Among subjects vaccinated with CoronaVac (the Sinovac COVID-19 vaccine), infected cases had approximately double the IgG-SP level of uninfected cases. SARS-CoV-2-specific antibody levels were higher at the baseline in symptomatic cases. Nevertheless, all infected cases showed significantly reduced IgG-SP levels at the 6th month. Vaccination effectively increased IgG-SP levels.

[Potential implication of the IgA-pIgR system in idiopathic pulmonary fibrosis]. / Implications potentielles du système IgA-pIgR dans la fibrose pulmonaire idiopathique.

Idiopathic pulmonary fibrosis (IPF) is a lethal respiratory disease characterized by the excessive deposition of extracellular matrix in the alveolar zones. The bronchiolar epithelium has been implicated in the development of this disease and is capable of secreting IgA into the airway lumen thanks to its expression of the polymeric immunoglobulin receptor. Several elements indicate a dysregulation of this system, such as raised serum IgA levels in IPF patients and the pro-fibrotic effect of IgA on several key cell types. Our work aims at studying the underlying mechanisms so as to better understand the role of IgA mucosal immunity in this disease.

High False-Positive Rate of (1,3)-ß-D-Glucan in Onco-Hematological Patients Receiving Immunoglobulins and Therapeutic Antibodies.

Immunoglobulins and/or therapeutic antibody preparations are associated with a high rate of false-positive (1,3)-ß-D-glucan (BDG) tests in onco-hematological patients routinely screened for fungal infections. The benefit of BDG monitoring shall be balanced against the risk of false-positive tests leading to unnecessary investigations and costs in this population.

[Coronary artery aneurysm in Kawasaki disease and its risk factors : a retrospective study about 65 Tunisian children]. / Les complications coronaires de la maladie de Kawasaki et ses facteurs de risque : à propos de 65 cas d'enfants tunisien.

INTRODUCTION: Kawasaki syndrome (KS) is a systemic vasculitis of unknown etiology that affects medium and small blood vessels. The aim of our study is to analyze coronary artery lesions in children with KS and their risk factors. MATERIAL AND METHODS: All children under the age of 15 years-old presenting KS and admitted in the pediatric department of three university hospital (Sahloul hospital, and Farhat Hached hospital of Sousse, Ibn El Jazzar hospital of Kairoun) from January 2000 to December 2018 were included. RESULTS: Sixty-five patients were included in our study. The mean age at diagnosis was of 29.9 months [2-120 months] and the sex ratio was of 1.7. Echocardiography was performed in all patients. It showed coronary dilation in 37% of patients with coronary artery diameter of 4.2 mm on average [3.2-7mm]. The coronary aneurysm was small in 19 cases and medium in 5 cases. No giant aneurysm has been identified. In univariate analysis, the predictors of coronary artery lesions were male sex, atypical form, fever duration more than 10 days, hepatic cytolysis, thrombocytosis and anemia. In multivariate analysis, only the last four parameters were the predictive factors of the coronary artery involvement. CONCLUSION: Several risk factors can be used to determine which children are predisposed to develop coronary dilations. In case of patient with risk factors, intravenous immunoglobulins should be initiated early to avoid these serious complications.

Practical considerations for the management of immune thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is a rare hematological disorder with an autoimmune-mediated, often dramatic reduction of platelets in peripheral blood. Thrombocytopenia results from a reduced life span of thrombocytes and an additionally decreased production in bone marrow. For decades, the first-line therapy for ITP has been corticosteroids. As significant thrombocytopenic bleedings occur, the use of additional medication may be needed. Recent updates on therapy guidelines recommend the shortest possible use of corticosteroids. Thrombopoietin-receptor agonists are often used second line. Today splenectomy, which was previously recommended after unsuccessful first-line therapy, is usually considered much later. Patients who do not respond even after multiple lines of therapy continue to pose a major challenge. New drugs for ITP treatment are now available after steroid failure and will be discussed. This review gives a short summary on actual therapy guidelines taking into account newly available therapy options. In addition, comparisons between selected published data and experience at our department are made.

[Placental transfer of monoclonal antibodies: The example of anti-TNF alpha drugs]. / Le passage placentaire des anticorps monoclonaux : exemple des anti-TNF alpha.

Anti-TNF alpha monoclonal antibodies are used in the treatment of chronic inflammatory diseases, which commonly affect women of childbearing age. Due to their similar structure to native immunoglobulins, the evaluation of their placental transfer by a pharmacological approach of the mechanisms involved is an interesting source of information, useful to the risk-benefit assessment of drugs in pregnant women.

[IgG4-Related Disease: A rare cause of severe interstitial lung disease]. / La maladie associée aux IgG4 : une cause rare de pneumopathie infiltrante hypoxémiante sévère.

BACKGROUND: The intrathoracic manifestations of IgG4-related disease include a range of conditions and severity, and can on occasion cause acute respiratory failure as reported in the case described here. OBSERVATION: A 69-year-old male former smoker, was admitted to our hospital with dyspnea, fever, cough, fatigue, and a 3-month history of weight loss. He received high flow oxygen therapy and non-invasive ventilation for severe respiratory failure. Chest computed tomography revealed multifocal condensations and ground glass opacities, accompanied by thickening of the perilymphatic interstitium, mediastinal lymphadenopathy and bilateral pleural effusion. Elevated serum concentrations of IgG4 suggested an IgG4-Related Disease. He developed renal failure and underwent a renal biopsy. Histopathological analysis of which supported the diagnosis by showing dense lymphocytic infiltrate with a count of IgG4+ cells/hpf higher than 60, and storiform fibrosis - a swirling, "cartwheel" pattern of fibrosis which may have a patchy distribution. The patient responded well to steroid therapy. CONCLUSION: Although respiratory symptoms are usually mild in IgG4-relatd disease, thoracic features can evolve into acute respiratory failure with few extra thoracic manifestations.

[Common variable immunodeficiency disorders: Part 2. Updated clinical manifestations and therapeutic management]. / Les déficits immunitaires communs variables (DICV) : partie 2. Mise à jour clinique et thérapeutique.

Common variable immunodeficiency disorders (CVID) are the most common symptomatic primary antibody deficiency in adults with an estimated prevalence of 1/25,000. The most frequent clinical manifestations are upper respiratory tract infections (including pneumonia, bronchitis, and sinusitis) predominantly with Streptococcus pneumoniae or H. influenzae. However, CVID are complicated in 20 to 30 % of cases of non-infectious manifestations which have been well characterized in recent years. Several complications can be observed including autoimmune, lymphoproliferative, granulomatous or cancerous manifestations involving one or more organs. These complications, mostly antibody-mediated cytopenias, are correlated with a decrease in the number of circulating switched memory B cells. Replacement therapy with polyvalent gammaglobulins has greatly improved the prognosis of these patients but it remains poor in the presence of digestive complications (especially in the case of chronic enteropathy and/or porto-sinusoidal vascular disease), pulmonary complications (bronchiectasis and/or granulomatous lymphocytic interstitial lung disease) and when progression to lymphoma. Much progress is still to be made, in particular on the therapeutic management of non-infectious complications which should benefit in the future from targeted treatments based on knowledge of genetics and immunology.

[Challenges and potential solutions in first-line treatments for immune thrombocytopenia in adults]. / Traitements de première ligne au cours du purpura thrombopénique immunologique de l'adulte : état des lieux et perspectives.

The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.

[New aspects of rabies control]. / Nouveaux aspects de la lutte contre la rage.

Rabies still causes about 60,000 human deaths per year, mainly in poor populations in Africa and Asia. However, since Louis Pasteur developed the first vaccine 130 years ago, prophylactic measures have been considerably improved and simplified. They now consist of the vaccine combined with purified rabies immunoglobulins of equine or human origin. In general, however, post-exposure prophylaxis protocols are long and expensive. Furthermore, the immunoglobulins used for associated serotherapy are costly and not widely available in developing countries. Approaches have been developed to deal with these two issues that offer hope for a paradigm shift for the benefit of exposed populations. Finally, mass rabies vaccination in dogs, which are the most cost-effective measure for preventing rabies in humans, are difficult to implement and sometimes have moderate effectiveness. The identification and analysis of the epidemiological drivers conditioning the circulation of the virus in dog populations allow a better understanding of the key control points that need to be associated with these campaigns for a better efficacy.

ANCA-associated vasculitides: Recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance.

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

[Chronic inflammatory demyelinating polyneuropathy: Diagnosis and therapeutic update]. / Polyradiculoneuropathies inflammatoires démyélinisantes chroniques : mise au point diagnostique et thérapeutique.

Chronic inflammatory demyelinating polyradiculoneuropathies are acquired demyelinating neuropathies belonging to the group of autoimmune neuropathies. Since specific biological markers are present in less than 10% of cases, the diagnosis is based on the clinical and electrophysiological analysis of each patient. Furthermore, a decision-making algorithm ranking all other available paraclinical tools will guide the physician to the diagnosis of atypical forms. In nearly 80% of cases, these dysimmune neuropathies are responsive to first-line treatments, namely intravenous immunoglobulins, corticosteroids and plasma exchanges. A second line treatment may be proposed in case of no response, intolerance or inaccessibility to the three reference treatments. While some immunosuppressants or monoclonal antibodies can sometimes be very effective, there is currently no predictive marker or recommendation available to determine which treatment will be most appropriate for which patient.

Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course.

BACKGROUND: In multiple sclerosis (MS), the frequency of hypogammaglobulinemia is unknown. We aimed to evaluate the frequency of reduced immunoglobulin (Ig) concentrations and its association with immunotherapy and disease course in two independent MS cohorts. METHODS: In our retrospective cross-sectional study, MS patients and control patients with head or neck pain from Bern University Hospital (Bern, Switzerland) and Eginition University Hospital (Athens, Greece) were included. The lower limits of normal (LLN) for serum Ig concentration were IgG < 700 mg/dl, IgM < 40 mg/dl, and IgA < 70 mg/dl. Mann-Whitney U test, analysis of variance test, and multiple linear regression analysis were employed. RESULTS: In total, 327 MS patients were retrospectively identified (Bern/Athens: n = 226/101). Serum IgG concentrations were frequently under LLN in both MS cohorts (Bern/Athens: 15.5%/14.9%), even when considering only untreated patients (Bern/Athens: 7.9%/8.6%). MS patients (n = 327) were significantly more likely to have IgG concentrations below LLN and below 600 mg/dl in comparison with controls (n = 58) (p = 0.015 and 0.047, respectively). Between both patient groups, no significant differences were found in frequencies of IgA and IgM concentrations under LLN [n (MS patients/controls): IgA 203/30, IgM 224/24]. Independently of age, secondary progressive MS patients had lower IgG concentrations than relapsing-remitting and primary progressive patients (both: p ⩽ 0.01). After adjusting for sex, age, and disease course, IgG concentrations were lower in patients treated with rituximab (p = 0.001; n = 42/327), intravenous corticosteroids (p < 0.001; n = 16/327), natalizumab (p < 0.001; n = 48/327), and fingolimod (p = 0.003; n = 6/327). CONCLUSION: Our study demonstrated high prevalence rates of reduced serum IgG concentrations in MS patients with and without disease-modifying treatments. The significance of lower IgG concentrations at the levels noted is unclear considering that infections or interference with antibody production generally occur when IgG levels are much lower, at or below 400 mg/dl. However, the information is useful to monitor IgG levels especially with anti-B-cell therapies and consider IgG substitution when levels drop below 400 mg/dl.

Diagnosis and immediate treatment of acquired von Willebrand syndrome revealed by recurrent cerebral hemorrhage.

We report the case of a French woman with acquired von Willebrand syndrome who presents recurrent subarachnoid and intra-cerebral hemorrhage since 2012. She had no family or personal bleeding history. In the biologic explorations, APTT was abnormally high with no anticoagulant drugs (it was normal, historically). Two monoclonal IgG and IgM kappa proteins were detected without any lymphoproliferative disorder. Intravenous infusion of immunoglobulin is very effective in AVWS with immunoglobulin G monoclonal gammapathie of undetermined significance. We had a satisfactory correction of coagulation factors for about 30 days. The exploration of APTT is surely essential for the diagnosis and treatment.

[Use of intravenous and subcutaneous human immunoglobulins]. / Utilisation des immunoglobulines humaines intraveineuses et sous-cutanées.

Immunoglobulin preparations are medicines derived from blood used as a replacement therapy for immunodeficiencies or as an immunomodulator. While they are generally well-tolerated, side effects, rarely severe, can nevertheless occur when administered intravenously. They are usually related to an excessive perfusion rate. The recent arrival of safer products administered subcutaneously represents progress in the treatment of patients.

[A case of bronchiectasis due to light chain deposition disease]. / Histoire naturelle d'une forme bronchectasiante de la maladie à dépôts de chaînes légères.

INTRODUCTION: The natural history of orphan lung diseases is often unclear. We report the long-term follow-up of a case of bronchiectasis due to pulmonary non amyloid light chain deposition disease (LCDD). CASE REPORT: A 50-year-old woman who was a smoker, was diagnosed with diffuse thin walled bronchiectasis of uncertain origin after presenting with a respiratory tract infection. Ten years later, the combination of bronchiectasis, the appearance of pulmonary cysts and the identification of increased kappa free light chains evoked the diagnosis of pulmonary LCDD. The diagnosis was confirmed by lung biopsy. No immunoproliferative disorder was identified. During the 12 years follow-up, dyspnea worsened progressively and bronchiectasis and lung cysts extended leading to multicystic lung disease. Pulmonary function tests did not show any ventilatory defect but a small decrease in carbon monoxide transfer factor occurred. CONCLUSION: We describe the evolution of a rare presentation of isolated pulmonary LCDD, characterized by cystic diffuse atypical bronchiectasis with thin walls, associated with progressive cystic destruction of the lung parenchyma. The possibility of pulmonary LCDD should be considered in cases of atypical bronchiectasis of unknown etiology.