[Management of hypogammaglobulinemia]. / Conduite à tenir devant une hypogammaglobulinémie.

Hypogammaglobulinemia (hypoγ) is defined as a serum IgG level < 7 g/L. It is most often detected on serum protein electrophoresis. Given the existence of transient hypoγ, its persistence should be checked at distance, preferably by requesting a blood test for IgG, IgA and IgM, which will be needed to characterize a possible primary immune deficiency (PID). In the case of association with a monoclonal component, the first step is to look for a cryoglobulin causing a false hypoγ. Otherwise, the etiological investigation is dictated by the clinical examination. For example, the notion of chronic diarrhea should lead to a search for an enteropathy causing a digestive loss of gammaglobulins (an ambiguous situation because some DIP can be complicated by an enteropathy). In the absence of an obvious explanation, a secondary cause must first be ruled out (secondary immune deficiencies are 30 times more common than PID). The first simple test to perform is 24-hour proteinuria, coupled with urinary protein electrophoresis, to rule out 2 diagnoses: nephrotic syndrome and light chain myeloma. Subsequently, blood immunophenotyping looking for a circulating B clone is recommended, allowing the investigations to be directed towards a lymphoid hemopathy. Drug-induced hypoγ may also be suspected if certain drugs such as corticosteroids, anti-epileptics or immunosuppressive agents (especially anti-CD20) are taken. The profile of a drug-induced hypoγ is different from that of a DIP: it is rarely profound, the IgA level is preserved and there is no deficit in switched memory B lymphocytes. Finally, a thoracoabdominal CT-scan will help to rule out a thymoma and identify a deep tumor syndrome. If all these tests are normal, a PID is suspected, the leader of which in adults remains the common variable immunodeficiency, which is the most frequent symptomatic PID in adults.

[HHV-8 Related immunological and hematological diseases]. / Maladies immunologiques et hématologiques liées à HHV-8.

HHV-8 is an oncogenic Gammaherpesvirinae discovered in 1994 during the HIV pandemic. It is the causative agent of Kaposi's sarcoma, and is also associated with the occurrence of several aggressive B lymphoproliferative disorders. Most of them occur in an immunosuppression setting, usually due to HIV infection. Multicentric HHV8-associated Castleman's disease and KSHV Inflammatory Cytokine Syndrome (KICS) are primarily reactive entities with prominent systemic features. They illustrate the cytokinic storm induced by HHV-8 in its cell host. On the other hand, HHV-8 can drive proliferation and lymphomagenesis of its plasmablastic cell host, and is associated with a risk to develop aggressive lymphomas with plasmacytic differenciation. Primary effusion lymphoma usually localizes in body cavities and may affect other extra-nodal sites ; its prognostic is poor. Diffuse large B-cell lymphoma HHV-8, NOS affect more commonly nodes and blood and evolve from infected cell of HHV-8 associated Castleman disease. On the contrary, germinotropic lymphoproliferative disorders presents mainly as localized adenopathy with indolent course, and show polyclonality. Histology plays a key role in distinguishing these different entities and need expert reviewing, especially since they may be associated with each other. Besides lymphoproliferative disorders, HHV8 is associated with various hematological manifestations. The aim of this review is to provide an update on the presentation, diagnosis, and management of immunologic and hematologic complications associated with HHV-8.

Diagnostics différentiels de la maladie de Castleman.

Clinicians are sometimes confronted with the diagnostic difficulties of the idiopathic form of Castleman's Disease (iMCD). As this review reports with demonstrative clinical cases, iMCD can mimic various serious systemic pathologies such as certain autoimmune diseases, Still's disease, POEMS syndrome, and malignant lymphoproliferations, sharing a very similar histology and identical symptoms. To make a diagnosis of iMCD, the clinician must eliminate all the pathologies mentioned above, but he must first think of it and evoke this diagnosis of rare disease before the first symptoms but also know how to evoke this diagnosis again even after several years of evolution of a disease like those mentioned above whose evolution is not favorable. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

[Common variable immunodeficiency disorders: Updated diagnostic criteria and genetics]. / Les déficits immunitaires communs variables (DICV) : partie 1 : évolution des critères diagnostiques et des connaissances génétiques.

Common variable immunodeficiency disorders (CVID) are a heterogeneous group of conditions with hypogammaglobulinemia as the common denominator. These are the most common symptomatic primary immunodeficiency disorder in adults. Two different clinical forms are described: one group only develops infections, while a second includes (sometimes without infections, at least at the onset of disease course) a variety of non-infectious autoimmune, inflammatory, granulomatous and/or lymphoproliferative manifestations, sometimes revealing the disease and often observed in Internal Medicine. The international diagnostic criteria for CVID were updated in 2016 and are the subject of several comments in this general review. The recent use of new sequencing techniques makes it possible to better genetically define CVID. The identification of such a genetic disease makes it possible to treat pathophysiologically, in particular autoimmune and lymphoproliferative complications, with targeted treatments, sometimes used in other diseases. Determining a genetic disease in these patients also makes it possible to provide appropriate genetic counseling, and therefore to monitor mutated individuals, symptomatic or not.

[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.

[Management of multirefractory immune thrombocytopenia]. / Prise en charge du purpura thrombopénique immunologique multiréfractaire.

Multirefractory immune thrombocytopenia (ITP) is defined by the absence of response to TPO receptor agonists, rituximab and splenectomy (or contraindicated or refused) and the need of treatment. The approach to multirefractory ITP must be systematic and firstly involves reconsidering the diagnosis. Inherited thrombocytopenia, lymphoid hemopathies and myelodysplastic syndrome are the main causes to be mentioned. Multirefractory ITP is often associated with secondary ITP with signs of clinical or biological autoimmunity, monoclonal gammopathy of undetermined significance and a poor response to corticosteroids. Therapeutic management is complex and is based on the combination of treatments. New treatments are being developed.

[Usefulness of thiopurine methyltransferase polymorphism study and metabolites measurement for patients treated by azathioprine]. / Intérêt de la recherche du polymorphisme de la thiopurine méthyltransférase et du dosage des métabolites chez les patients traités par azathioprine.

Azathioprine is widely used in internal medicine and frequently implicated in occurrence of adverse events. Among these adverse events the bone marrow suppression, a dose-related one, is the most serious because of is potential morbidity and mortality. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism that results in a high variability of its activity with 89% of patients with a normal activity, 11% with an intermediate activity, and 0.3% with very low activity leading to a very high risk of bonne marrow suppression. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques to identify patients for which the standard dose is not advisable. Furthermore, azathioprine metabolites monitoring is helpful for the follow up of patients, especially in therapeutic failure, to distinguish non-compliant patients from under-dosed, "shunters" or resistant patients.

Graft infection after a Bentall procedure: A case series and systematic review of the literature.

INTRODUCTION: The Bentall procedure is a cardiac surgery involving graft replacement of the aortic valve, aortic root and ascending aorta. Graft infection after Bentall's procedure (BGI) is infrequent but severe, and often difficult to diagnose and treat. PATIENTS AND METHODS: A retrospective cohort study was performed using the Bordeaux endocarditis database of adult patients admitted to the Bordeaux University Medical Hospital for BGI between 2008 and 2014. Published case reports were identified in the literature. RESULTS: We identified 10 BGI patients in the database and 13 in the literature. The majority of infections were late-onset (20/23) and occurred as a result of gram positive cocci bacterial infection (16/22). Detailed diagnoses of the described BGI were determined using echocardiography, computed tomography (CT) and positron emission tomography/CT (PET/CT). Labeled-leukocyte scintigraphy was not reported in any case. Prolonged antibiotic therapy and surgery were found to be the treatment of choice for BGI; however it was not always possible to perform a surgical intervention. Clinical relapses occurred even with a negative PET/CT, while PET/CT consistently positive for BGI occurred in the absence of clinical relapse. This suggests that the use of PET/CT for follow-up is questionable. CONCLUSION: Diagnosis of BGI is difficult, due to the combination of clinical, biological, and radiological observations obtained through transesophageal echocardiography and CT. PET/CT is an alternative method to diagnosis BGI, but its impact on clinical management remains unclear. Current data suggests that if surgical replacement of the prosthesis is not possible, patients should be treated with prolonged antibiotic therapy.

NK cell compartment in the peripheral blood and spleen in adult patients with primary immune thrombocytopenia.

Immune thrombocytopenic purpura (ITP) is a disease characterized by antibody-mediated platelet destruction. The T- and B-cell subsets have been extensively studied in primary ITP, but the NK cell compartment has been less thoroughly explored. We investigated the NK cell receptor repertoire and the functionality of NK cells in the peripheral blood and spleen in patients with primary ITP. An immunophenotypic analysis of peripheral blood lymphocytes from patients revealed that the numbers of CD19+ B lymphocytes, CD4+ and CD8+ T lymphocytes and CD3-CD56+ NK cells were within the normal range. No major alteration to the expression of distinct inhibitory or activating NK cell receptors was observed. The functionality of NK cells, as evaluated by their ability to degranulate in conditions of natural cytotoxicity or antibody-dependent cell cytotoxicity (ADCC), was preserved in these patients. By contrast, these stimuli induced lower levels of IFNγ production by the NK cells of ITP patients than by those of healthy controls. We then compared the splenic NK cell functions of ITP patients with those of cadaveric heart-beating donors (CHBD) as controls. The splenic NK cells of ITP patients tended to be less efficient in natural cytotoxicity conditions and more efficient in ADCC conditions than control splenic NK cells. Finally, we found that infusions of intravenous immunoglobulin led to the inhibition of NK cell activation through the modulation of the interface between target cells and NK cells.

[Prevention of infections in adults and adolescents with systemic lupus erythematosus: Guidelines for the clinical practice based on the literature and expert opinion]. / Prévention des infections au cours du lupus systémique chez l'adulte et l'adolescent : élaboration de recommandations pour la pratique clinique, à partir d'une analyse de la littérature et de l'avis d'experts.

PURPOSE: To develop French recommendations about the management of vaccinations, the screening of cervical cancer and the prevention of pneumocystis pneumonia in systemic lupus erythematosus (SLE). METHODS: Thirty-seven experts qualified in internal medicine, rheumatology, dermatology, nephrology and pediatrics have selected recommendations from a list of proposition based on available data from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Inactivated vaccines do not cause significant harm in SLE patients. Experts recommend that lupus patient should receive vaccinations accordingly to the recommendations and the schedules for the general public. Pneumococcal vaccination is recommended for all SLE patients. Influenza vaccination is recommended for immunosuppressed SLE patients. Live attenuated vaccines should be avoided in immunosuppressed patients. Yet, recent works suggest that they can be considered in mildly immunosuppressed patients. Experts have recommended a cervical cytology every year for immunosuppressed patients. No consensus was obtained for the prevention of pneumocystis pneumonia. CONCLUSION: These recommendations can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.

[Paroxysmal nocturnal hemoglobinuria: An unknown cause of thrombosis?]. / L'hémoglobinurie paroxystique nocturne : une cause méconnue de thrombose ?

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. Somatic mutation in the phosphatidylinositol glycan class A (PIG-A), X-linked gene, is responsible for a deficiency in glycosphosphatidylinositol-anchored proteins (GPI-AP). The lack of one of the GPI-AP complement regulatory proteins (CD55, CD59) leads to hemolysis. The disease is diagnosed with hemolytic anemia, marrow failure and thrombosis. Thromboembolic complication occurs in 30% of patient after 10 years of follow-up and is the first event in one out of 10 patients. The two most common sites are hepatic and cerebral veins. These locations are correlated with high risk of death. Currently, these data are balanced with the use of a monoclonal antibody (Eculizumab), which has significantly improved the prognosis with a survival similar to general population after 36 months of follow-up. Anticoagulant treatment is recommended after a thromboembolic event but has no place in primary prophylaxis.

[Screening and management of cardiovascular risk factors in systemic lupus erythematosus: Recommendations for clinical practice based on the literature and expert opinion]. / Dépistage et prise en charge du risque cardiovasculaire au cours du lupus systémique : élaboration de recommandations pour la pratique clinique, à partir d'une analyse de la littérature et de l'avis d'experts.

PURPOSE: To develop French recommendations about screening and management of cardiovascular risk factors in systemic lupus erythematosus (SLE). METHODS: Thirty-nine experts qualified in internal medicine, rheumatology and nephrology have selected recommendations from a list developed based on evidence from the literature. For each recommendation, the level of evidence and the level of agreement among the experts were specified. RESULTS: Experts recommended an annual screening of cardiovascular risk factors in SLE. Statins should be prescribed for primary prevention in SLE patients based on the level of LDL-cholesterol and the number of cardiovascular risk factors, considering SLE as an additional risk factor. For secondary prevention, experts have agreed on an LDL-cholesterol target of <0.7 g/L. Hypertension should be managed according to the 2013 European guidelines, using renin-angiotensin system blockers as first line agents in case of renal involvement. Aspirin can be prescribed in patients with high cardiovascular risk or with antiphospholipid antibodies. CONCLUSION: These recommendations about the screening and management of cardiovascular risk factors in SLE can be expected to improve clinical practice uniformity and, in the longer term, to optimize the management of SLE patients.

[Hydrocycarbamide induced fever: four cases and literature review]. / Hyperthermie induite par l'hydroxyurée : à propos de 4 cas et revue de la littérature.

PURPOSE: Hydroxyurea (HU) or hydroxycarbamide is an antimetabolite chemotherapy frequently used in the treatment of chronic myeloproliferative disorders. This treatment is usually well tolerated but a few cases of fever induced by the molecule have been reported in the literature. The aim of the study was to describe the clinical and biological characteristics of HU induced fever. METHODS: We performed a cross sectional study of patients treated with HU and followed-up in an internal medicine department between 2006 and 2012. We added our cases of HU induced fever with those reported in the literature (Pubmed and Cochrane databases) since 1981. RESULTS: We identified 38 cases of HU induced fever, including our 4 cases. The mean age was 65±10.9 years and the sex-ratio 1/2. The fever appeared after a median duration of treatment of 21 days and was usually high (40°C) but clinically well tolerated. A biological inflammatory syndrome (CRP: 131±92 mg/L) was constant and one third of the patients also presented with hepatitis or lung disease. A probabilistic antibiotic treatment was introduced for 34% of the patients. For the half of the patients, HU-reintroduction test was performed, and was positive for all the patients but one. As soon as HU was withdrawn, the fever disappeared in a median of 24 hours. CONCLUSION: HU induced fever is unusual. Clinical presentation is very stereotyped. When this adverse effect is suspected, an infectious disease must first be ruled out. If infection is excluded, HU has to be stopped.

Autoimmune disorders and quadrivalent human papillomavirus vaccination of young female subjects.

OBJECTIVES: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects. DESIGN: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France. PARTICIPANTS AND SETTING: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice. ANALYSIS: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs. RESULTS: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis. CONCLUSIONS: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs.

[Large granular lymphocyte leukemia: clinical and pathogenic aspects]. / Les leucémies à grands lymphocytes granuleux : de la clinique à la physiopathologie.

Large granular lymphocyte leukemia (LGL) is a hematologic disorder characterized by a monoclonal expansion of large lymphocytes containing azurophilic granules with a T CD3(+)CD57(+) or Natural Killer (NK) CD3(-)CD56(+) phenotype. The World Health Organization (WHO) classification identifies three entities: the T LGL, the chronic lymphoproliferative disorder of NK-cells, and the aggressive NK-cell leukemia. T LGL and chronic lymphoproliferative disorder of NK-cells are indolent diseases frequently associated with cytopenias and a wide spectrum of auto-immune manifestations. Neutropenia can lead to recurrent bacterial infections, which represent an indication of initiating a treatment in most of the cases. Immunosuppressive therapies are usually used in this context. In contrast, aggressive NK-cell leukemia follows a fulminant course with a poor prognosis because patients are refractory to most of the treatments. There is now a considerable interest in the pathophysiology of the disease with the perspective of new therapeutic options.

[Intravascular large B cell lymphoma: a case series of three patients and update]. / Lymphome à grandes cellules B intravasculaire : trois cas et mise au point.

PURPOSE: Intravascular large B cell lymphoma (IVLBCL) is a rare and aggressive variant of non-Hodgkin's lymphoma, characterized by multifocal proliferation of lymphoma cells exclusively within small and medium blood vessels. IVLBCL can be systemic and quite polymorphic, which often makes it difficult to diagnose, thus delaying appropriate treatment. PATIENTS AND METHODS: We report three patients of atypical IVLBCL, through the study of which we overview recent knowledge about IVLBCL. RESULTS: The first patient initially presented with peripheral thrombocytopenia and splenic destruction of platelets, later completed with an interstitial pulmonary syndrome. The second patient, of African origin, we believe is the first case of a black patient with IVLBCL described in the medical literature. The third belongs to the rare group of occidental patients that present an IVLBCL associated with a hemophagocytic syndrome. CONCLUSION: Intravascular large B cell lymphoma is a systemic and polymorphic disease. Awareness of this entitiy should allow rapid and appropriate management.