Journal articles on the topic 'Immunosuppression – Maladies'

Bacterial pericarditis is a rare but fulminant disease that requires prompt diagnosis and management. It most commonly occurs from direct extension of an adjacent focus of infection or by hematogenous spread to the pericardium from more distant septic foci. Predisposing risk factors include immunosuppression, uremia, collagen vascular disease and thoracic surgery. We present the case of a 77-year-old gentleman with no previous pericardial disease who was diagnosed with primary Staphylococcus aureus pericarditis. The patient was treated with percutaneous pericardial effusion drainage and appropriate antibiotics resulting in complete resolution of his symptoms. This unusual case emphasizes that although it is frequently associated with significant morbidity and mortality, purulent pericarditis can present in a more indolent manner and in the absence of typical predisposing risk factors. ResumeLa péricardite bactérienne est une maladie rare mais fulgurante qui nécessite un diagnostic et une prise en charge rapides. Elle survient le plus souvent dans le prolongement direct d’un foyer infectieux adjacent ou par propagation hématogène au péricarde à partir de foyers septiques plus éloignés. Les facteurs de risque prédisposants sont l’immunosuppression, l’urémie, les maladies vasculaires du collagène et la chirurgie thoracique. Nous présentons le cas d’un homme de 77 ans, sans antécédents de maladie péricardique, chez qui on a diagnostiqué une péricardite primaire à Staphylococcus aureus. Le patient a été traité par un drainage percutané d’effusion péricardique et des antibiotiques appropriés, ce qui a permis de résoudre complètement ses symptômes. Ce cas inhabituel souligne que, bien qu’elle soit fréquemment associée à une morbidité et une mortalité importantes, la péricardite purulente peut se présenter de manière plus indolente et en l’absence de facteurs de risque prédisposants typiques.

Goal . Neuromeningeal determine the prevalence of disease in PLHIV and identify factors associated with death. Methodology. Retrospective study on descriptive and analytical referred cases hospitalized in the Infectious Diseases department during the period 1 January 2013 to 31 May 2015. Results. One hundred and fifty patients included (10.5% of admissions) with mean age of 41.1 ± 11.8 years (range 19 to 69) women (n = 86, 57.3%), sex ratio of 1,3. were without jobs (n = 68; 45.3%), single (n = 96; 64%), heterosexually infected by HIV-1 (100%). The average time of consultation was 19.2 ± 1.3 days. Fever (n = 99; 66.0%), disorders of consciousness (n = 66; 44.0%) were the main reasons for consultations. Meningeal stiffness (40%), focal signs (n =62; 41,4%) were the main signs consideration. CSF was clear (n = 94; 62.7%), hyperproteinorachique (59.8%), hypoglycorrachique (43.8%). Examining the ink was positive in 39 cases (34.8%) The Gerh was positive in 35 patients .the CT abnormalities were dominated abscess (n = 12; 15.4%).. Thirty four patients were on TDF + FTC + EFV regimen. The average hospital stay was 14.4 ± 9.5 days. Overall mortality was 83.2% mainly due to cerebral herniation (n = 28; 33.3%). Conclusion. The prevalence and lethality of diseases neuromeningeal of HIV are high. The diagnosis delay and TNM influence the prognosis of patients; Hence the importance of early detection of HIV infection for its management to prevent immunosuppression.

Non-traumatic, exudative, bilateral panuveitis associated with extraocular manifestations, Vogt-Koyanagi-Harada disease (VKH) is an autoimmune disease mediated by Th1 lymphocytes reacting against melanocytes. It is a rare disease with female predominance. VKH disease is a diagnostic and therapeutic emergency. Treatment is based mainly on early and aggressive corticosteroid therapy to shorten the duration of the disease, prevent progression to chronicity, and reduce the incidence of extraocular manifestations. It is a corticosteroid-responsive disease, but unfortunately, relapses in the form of anterior uveitis are not rare, mainly at the time or at the end of tapering of corticosteroids. In these situations, or in case of intolerance to prolonged corticosteroid therapy, the use of conventional immunosuppressive agents or immunomodulatory drugs able to suppress the lymphocyte response is recommended. Intravenous immunoglobulins may also be used in patients with relapse or attack of the disease. In the present study, we performed a narrative literature review to summarize the different therapeutic aspects of VKH in the form of treatment algorithm. Panuvéite bilatérale non traumatique, exsudative, associée à des manifestations extraoculaires, la maladie de Vogt-Koyanagi-Harada (VKH) est une maladie auto-immune médiée par les lymphocytes Th1 réagissant contre les mélanocytes. C’est une maladie rare à prédominance féminine. La maladie de VKH est une urgence diagnostique et thérapeutique. Le traitement repose essentiellement sur une corticothérapie précoce et agressive avec possibilité de dégression progressive lente sur plusieurs mois, afin deraccourcir la durée de la maladie, d’empêcher la progression vers la chronicité, et de réduire l’incidence des manifestations extraoculaires. C’est une maladie corticosensible, mais malheureusement des rechutes sous forme d’uvéite antérieure ne sont pas rares, principalement au moment ou en fin de dégression de la corticothérapie. Dans ces situations ou en cas d’intolérance à la corticothérapie prolongée, le recours aux immunosuppresseurs conventionnels ou médicaments immunomodulateurs capables de supprimer la réponse lymphocytaire est de règle. Les immunoglobulines intraveineuses peuvent également être proposées chez les patients présentant une rechute ou une poussée de la maladie. Dans la présente étude, nous réalisons une revue narrative de la littérature en décrivant les différents aspects thérapeutiques de la maladie de VKH afin de les résumer sous forme d’un algorithme thérapeutique.

Encephalite de Rasmussen est une maladie inflammatoire pediatrique evolutive rare correspond a une atteinte chronique et atrophiante du cerveau, possiblement dorigine auto-immune (anticorps anti-glutamatergiques type 3 ou anti-GLUR3) avec composante virale possible (post herpes, post CMV) chez 40% des cas. Cest une pathologie caracterisee par une perte neuronale et une gliose sur plan anatomopathologique concernant un hemisphere et elle se manifeste par une epilepsie severe et rebelle, et/ou un deficit neurologique hemi corporel. LIRM permet lidentification de cette encephalite afin de beneficier dun traitement adapte (une corticotherapie et une immunosuppression) ou envisager une hemispherotomie.

Abstract Purpose Programmed death 1 (PD-1) protein is a key immune-checkpoint receptor expressed by activated T cells and it mediates immunosuppression. It has been recently shown that the blockade of PD-1 or its ligand, PD-L1, by monoclonal antibodies may lead to significant antitumor effects. In diffuse large B-cell lymphoma PD-L1 has been reported expressed by tumor cells and PD-1 by tumor-associated T cells. The dosage of soluble programmed death ligand 1 (sPD-L1) protein in the blood of adults with cancer has never been performed during a clinical trial. We evaluated the clinical impact of PD-L1 level measured at the time of diagnosis for newly diagnosed aggressive diffuse large B-cell lymphomas. Methods Translating a previous study (NEJMed2004; 350: 1287) in the rituximab era, the Groupe Ouest-Est des Leucemies et des Autres Maladies du Sang (GOELAMS) 075 study is a multicenter randomized trial in which adults 18 to 60 years old with untreated histologically proved CD20 positive diffuse large B-cell lymphoma were randomly assigned to receive 8 courses of R-CHOP or, high-dose chemotherapy associated to rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379). Patients were required to have an Ann Arbor stage of I or II with bulk greater or equal to 7 cm or, III or IV with 0 to 3 adverse prognostic factors as defined by the age-adjusted International Prognostic Index. The population of interest consisted of 288 of the 340 consecutively enrolled patients with available plasma collected at the time of diagnosis before any treatment. Soluble PD-L1 was measured using an ELISA assay. The median follow-up was 41.4 months. Results sPD-L1 levels were found significantly increased in the plasma collected at diagnosis for patients compared to healthy -gender and age matched- subjects’ levels (P<0.0001). The optimal cut-off point for PD-L1 measured at diagnosis was found to be equal to 1.52 ng/mL. Eighty-nine (30.9%) patients had a PD-L1 level greater than the cut-off point as compared to two (3%) controls. The high-level sPD-L1 group was significantly associated with bone marrow involvement, more than one extranodal localization and, 2-4 performance ECOG status. None of the other patients' characteristics, including the assigned arms of randomization and, the positive vs. negative FDG-PET scan response at the intermediate evaluation, was associated with high PD-L1 level. The PD-L1 immunohistochemical analysis showed that 55 out of the 73 interpretable tissue microarrays presented at least 5% of PD-L1-positive tumor cells. No association was found between sPD-L1 and tumor PD-L1 expressions (p=0.5). The 73 patients were representative of our 288 patients' cohort, with significantly decreased overall survival for patients with a high level of sPD-L1 compared to those with low sPD-L1 levels (64.6 vs. 86.7%, P=0.007). Cell-of-origin analysis using Hans’s criteria on the tissue microarrays did not shown any correlation between elevated sPD-L1 and GC or non-GC origin. Patients with elevated PD-L1 experienced a poor prognosis with a three-year overall survival of 76 vs. 89 percent (P<0.001). There was no difference of overall survival rates between the two arms of treatment. Univariate analysis identified age greater than 50 years old, high-intermediate and, high age-adjusted International Prognostic Index score, bone marrow involvement, more than one extranodal localization, Ann Arbor stage after FDG-PET scan of III or IV, abnormal lymphocyte-monocyte score and, high level of sPD-L1 as factors associated with poor survival. High level of sPD-L1, bone marrow involvement and, abnormal lymphocyte-monocyte score were found after multivariate analysis to be the only factors remaining significant after adjustment with a P-value <0.05. Soluble PD-L1 was detectable in the plasma and not in the serum, found elevated in lymphoma patients at diagnosis compared to healthy subjects and its level dropped back to normal value for patients in complete remission. The intention-to-treat analysis showed that elevated PD-L1 was associated with a poorer prognosis for patients randomized within the R-CHOP arm (P<0.001). Conclusion Soluble PD-L1 protein expression in peripheral blood at the time of diagnosis is a potent predicting biomarker in diffuse large B-cell lymphoma and may indicate usefulness of alternative therapeutic strategies using PD1 axis inhibitors. Disclosures: Fest: Roche SA France: Research Funding.

Background: Sickle cell disease (SCD) is associated with chronic haemolysis, immuno-suppression and susceptibility to infections, which may trigger infection-associated haemolysis (IAH). SCD patients are vulnerable to anaemic effect of IAH due to vicious interaction between pre-existing ‘inherited’ chronic haemolysis and ‘acquired’IAH. IAH in SCD manifests as febrile haemolytic crisis with clinical and laboratory features of severe anaemia or pancytopenia. Clinico-pathological perspectives of IAH in SCD are fragmented. This review presents a comprehensive but concise overview of pathogenesis, management and prevention of IAH in SCD.Methodology and results: Online literature search using search terms such as ‘sickle cell disease, viral, bacterial, parasitic, fungal, infections, hyperhaemolytic crisis, haemophagocytic syndrome, severe anaemia, pancytopenia’ in various combinations was done on PubMed/Medline, Google, Google-Scholar and Bing. Overall, 112 relevant publications were retrieved, which included 109 peer reviewed journal articles, 2 World Health Organization (WHO) technical reports, and 1 edited text book. A range of bacterial (Bartonella spp, Mycoplasma spp., Mycobacterium avium complex), viral (Dengue, SARS-CoV-2, Parvovirus-B19, Cytomegalovirus, Epstein-Barr virus), parasitic(Plasmodium spp., Babesia spp.), and fungal (Histoplasma spp.) infections were associated with IAH in SCD. There are two broad types of IAH in patients with SCD; infection associated extra-medullary haemolysis (IAEMH) and infection associated intra-medullary haemolysis (IAIMH). While IAEMH is associated with severe anaemia due to intravascular haemolysis caused by red cell invasion, oxidative injury, auto-antibodies, and/or pathogen-haem interaction, IAIMH is associated with haemophagocytic tri-lineage destruction of haematopoietic precursors in the bone marrow.Conclusion: Various microbial pathogens have been associated with IAH in SCD. SCD patients with fever, severe anaemia or pancytopenia should be investigated for early diagnosis and prompt treatment of IAH, which is a lifethreateninghaematological emergency for which transfusion therapy alone may not suffice. Prompt and sustainable termination of IAH may require therapeutic combination of transfusion, anti-microbial chemotherapy, and immune modulation therapy. SCD patients should also receive counselling on hygiene, barrier protection against vectors, routine chemoprophylaxis for locally endemic diseases, and immunization for vaccine-preventable infections as a long-term preventive strategy against IAH. Contexte: La drépanocytose (SCD) est associée à une hémolyse chronique, à une immunosuppression et à une susceptibilité aux infections, ce qui peut déclencher une hémolyse associée à une infection (HIA). Les patientsatteints de SCD sont vulnérables à l'effet anémique de l'HIA en raison de l'interaction vicieuse entre l'hémolyse chronique "héréditaire" préexistante et l'HIA "acquise". L'HIA dans la SCD se manifeste par une crise hémolytique fébrile avec des caractéristiques cliniques et de laboratoire d'anémie sévère ou de pancytopénie. Les perspectives clinico-pathologiques de l'HIA dans la SCD sont fragmentées. Cette revue présente un aperçu complet mais concis de la pathogenèse, de la gestion et de la prévention de l'HIA dans la drépanocytose.Méthodologie et résultats: Une recherche documentaire en ligne à l'aide de termes de recherche tels que "drépanocytose, virale, bactérienne, parasitaire, fongique, infections, crise hyperhémolytique, syndrome hémophagocytaire,anémie sévère, pancytopénie" dans diverses combinaisons a été effectuée sur PubMed/Medline, Google, Google-Scholar et Bing. Au total, 112 publications pertinentes ont été récupérées, dont 109 articles de revues à comité de lecture, 2 rapports techniques de l'Organisation mondiale de la santé (OMS) et 1 manuel édité. Unegamme bactérienne (Bartonella spp, Mycoplasma spp., Mycobacterium avium complex), virale (Dengue, SARS-CoV-2, Parvovirus-B19, Cytomegalovirus, Epstein-Barr virus), parasitaire (Plasmodium spp., Babesia spp.), et lesinfections fongiques (Histoplasma spp) étaient associées à l'IAH dans la SCD. Il existe deux grands types d'HIA chez les patients atteints de SCD; hémolyse extra-médullaire associée à une infection (IAEMH) et hémolyse intramédullaireassociée à une infection (IAIMH). Alors que l'IAEMH est associée à une anémie sévère due à une hémolyse intravasculaire causée par l'invasion des globules rouges, une lésion oxydative, des auto-anticorps et/ou une interaction pathogène-hème, l'IAEMH est associée à la destruction tri-lignée hémophagocytaire des précurseurshématopoïétiques dans la moelle osseuse.Conclusion: Divers agents pathogènes microbiens ont été associés à l'IAH dans la SCD. Les patients atteints de SCD avec de la fièvre, une anémie sévère ou une pancytopénie doivent être examinés pour un diagnostic précoce et un traitement rapide de l'HIA, qui est une urgence hématologique potentiellement mortelle pour laquelle la thérapie transfusionnelle seule peut ne pas suffire. L'arrêt rapide et durable de l'HIA peut nécessiter une combinaison thérapeutique de transfusion, de chimiothérapie antimicrobienne et de thérapie de modulation immunitaire. Lespatients atteints de drépanocytose devraient également recevoir des conseils sur l'hygiène, la barrière de protection contre les vecteurs, la chimioprophylaxie de routine pour les maladies endémiques locales et la vaccination contreles infections évitables par la vaccination en tant que stratégie préventive à long terme contre l'HIA.

Abstract Solid organ transplantation is a life-saving last resort for many people undergoing end stage organ failure. Currently, immunosuppressive drugs are employed to combat rejection; however, it is at the expense of the host’s immune system, often exposing the patient to a host of maladies, with opportunistic infection and malignancy being the most dire. Thus, it is imperative to find novel ways to induce tolerance in transplant recipients to allografts while maintaining homeostatic immune responses. MicroRNAs (miRNAs) are a class of evolutionarily conserved small non-coding RNAs that regulate gene expression by blocking translation or promoting mRNA degradation. Using a murine model of skin transplantation, microarray analysis was used to evaluate miRNA expression profiles in draining CD4+ T cells from allogenic (allo) and syngenic (syn) grafts. We identified several distinct miRNAs (e.g. miR-27a-5p, 15a-5p and several members of the 466 family) that were increased in response to alloantigen. Using Ingenuity Pathway Analysis software, these miRNAs were found to target several genes in the SMAD and TGFβ pathway that control the differentiation into immuno-suppressive T regulatory (Treg) cells. The current study suggests that targeting miRNA may constitute a novel therapeutic modality to induce Treg generation and potentially program the host’s own cells to restore immunological tolerance, while safely prolonging the health of the transplanted organ.

BackgroundMyocarditis is generally a self-limited illness with a benign course. Certain pathogens—such as cytomegalovirus (CMV)—can cause severe/fulminant forms of myocarditis leading to congestive heart failure or sudden cardiac death (SCD). Case PresentationA 54-year-old female was diagnosed with systemic lupus erythematosus (SLE) in hospital and received inpatient immunosuppression due to significant multi-organ involvement. After a prolonged admission, she later died of an in-hospital cardiac arrest. Autopsy revealed CMV myocarditis involving the anterior wall of the left ventricle and cardiac conduction system. We postulated that both CMV and complications of SLE caused the patient’s SCD. DiscussionMyocarditis can vary in its presentation, severity, and diagnostic workup. Immunocompromised hosts are at risk of opportunistic infections such as CMV and are therefore prone to developing more severe forms of myocarditis. When caring for this patient population, it becomes necessary for clinicians to consider atypical manifestations of opportunistic pathogens in their diagnostic approach. RESUME Contexte La myocardite est généralement une maladie autolimitée dont l’évolution est bénigne. Certains agents pathogènes, tels que le cytomégalovirus (CMV), peuvent provoquer des formes graves/ fulminantes de myocardite entraînant une insuffisance cardiaque congestive ou une mort cardiaque subite (MCS). Présentation de casUne femme de 54 ans a reçu un diagnostic de lupus érythémateux disséminé (LED) à l’hôpital et a été hospitalisée pour une immunosuppression due à une importante atteinte de plusieurs organes. Après une longue hospitalisation, elle est décédée d’un arrêt cardiaque à l’hôpital. L’autopsie a révélé une myocardite à CMV impliquant la paroi antérieure du ventricule gauche et le système de conduction cardiaque. Nous avons émis l’hypothèse que le CMV et les complications du LED étaient tous deux à l’origine de l’arrêt cardiaque de la patiente. DiscussionLa myocardite peut varier dans sa présentation, sa gravité et son diagnostic. Les hôtes immunodéprimés sont exposés au risque d’infections opportunistes telles que le CMV et sont donc susceptibles de développer des formes plus graves de myocardite. Lorsqu’ils s’occupent de cette population de patients, les cliniciens doivent tenir compte des manifestations atypiques des agents pathogènes opportunistes dans leur approche diagnostique.

Pasteurella multocida (P. multocida) is the most commonly isolated pathogen in human cat bite wounds. We describe the case of a healthy 56-year-old man who presented with constitutional symptoms and a swollen right arm. He was found to have multi-focal abscesses secondary to P. multocida, with the portal of entry likely being a small wound on his right hand.P. multocida is thought to cause disease in humans either through direct inoculation or colonization of the human nasopharynx and subsequent reactivation during an immunocompromised state. Our case describes a rare presentation of invasive P. multocida infection in an immunocompetent host, occurring through either hematogenous or lymphatic spread. RésuméPasteurella multocida (P. multocida) est l’agent pathogène isolé le plus souvent dans les blessures par morsure de chat. Nous décrivons le cas d’un homme de 56 ans en bonne santé présentant des signes généraux et un œdème du bras droit. Il s’est avéré qu’il présentait des abcès multifocaux secondaires à P. multocida, le point de pénétration de la bactérie étant probablement une petite blessure sur sa main droite.P. multocida provoquerait la maladie chez l’humain soit par inoculation directe ou par colonisation du nasopharynx et une réactivation ultérieure au cours d’une immunosuppression. Notre cas décrit une présentation rare d’infection invasive à P. multocida chez un hôte immunocompétent, survenant par l’intermédiaire d’une dissémination par voie hématogène ou lymphatique.

Objective: This study is aimed at highlighting the challenges associated with the management of kidney transplant recipients in a centre without a transplant program.Methods: This is a retrospective study that enrolled all post renal transplant patients seen at Usmanu Danfodiyo University Teaching Hospital (UDUTH), Sokoto, North-western Nigeria between October 2010 and June 2019. Data obtained included cause of renal disease, pre-transplant dialysis details, type of donor, country of the kidney transplant, sponsor, type of maintenance immunosuppression, frequency of follow up, complications and outcome of the kidney transplant. Data obtained was analysed using statistical package for the social sciences software (SPSS) version 25 (IBM Inc. 2010).Results: Of the 16 patients who were enrolled in this study, 10 (62.5%) were males with a mean age of 36.5 ± 13.2 years. Twelve (75%) subjects reported challenges in obtaining their post-transplant immunosuppressants. Only one (6.25%) subject had allograft biopsy despite the fact that 5 (71.4%) out of the 7 patients that died had allograft dysfunction. The majority of the participants (81.3%) had no serum tacrolimus level test done throughout their follow up period.Conclusions: The management of post-transplant recipients in our centre is associated with challenges ranging from difficulty in procurement of post-transplant medications, poor laboratory support for monitoring of drug levels and inadequate facilities for management of allograft dysfunction. Keywords: Kidney transplant; End-stage renal disease; follow-up French Title: Défis dans la prise en charge des receveurs de transplantation rénale dans un centre sans programme de transplantation rénale: Une expérience dans un seul centreIntroduction : Cette étude vise à mettre en évidence les défis associés à la prise en charge des greffés rénaux dans un centre sans programme de transplantation.Méthode de l'étude : Il s'agit d'une étude rétrospective qui a recruté tous les patients après transplantation rénale vus à l'hôpital universitaire Usmanu Danfodiyo (HUUD), Sokoto, dans le nord-ouest du Nigéria entre octobre 2010 et juin 2019. Les données obtenues comprenaient la cause de la maladie rénale, les détails de la dialyse de pré-transplantation, le type du donner, du pays de la transplantation rénale, du promoteur et d'immunosuppression. Les données obtenues ont été analysées à l'aide du progiciel statistique du logiciel de sciences sociales (PSLSS) version 25 (IBM Inc. 2010).Résultat de l'étude : Sur les 16 patients inclus dans cette étude, 10 (62,5%) étaient des hommes avec un âge moyen de 36,5 ± 13,2 ans. Douze (75%) sujets ont signalé des difficultés à obtenir leurs immunosuppresseurs après la transplantation. Un seul sujet (6,25%) a eu une biopsie d'allogreffe malgré le fait que 5 (71,4%) des 7 patients décédés avaient un dysfonctionnement de l'allogreffe. La majorité des participants (81,3%) n'ont eu aucun test du taux de tacrolimus sérique effectué tout au long de leur période de suivi.Conclusion : La gestion des receveurs post-transplantation dans notre centre est associée à des défis allant de la difficulté à se procurer des médicaments post-transplantation, un soutien de laboratoire médiocre pour la surveillance des niveaux de médicaments et des installations inadéquates pour la gestion du dysfonctionnement des allogreffes. Mots-clés: Greffe de rein, phase terminale de la maladie rénale

Abstract Abstract 2100 Background: Autoimmune hemolytic anemia (AIHA) in children is in more than half cases characterized by a severe course, with prolonged need of immunosuppressive therapy. Rituximab is a chimeric anti-CD20 monoclonal antibody increasingly used for treating severe autoimmune diseases. Paediatric experience in AIHA is only made of case reports and short series. The Rare Disease Plan gave us the opportunity to conduct national studies on those rare pediatric diseases. Design and methods: At the end point of August 1, 2011, data from the CEREVANCE French national prospective cohort of auto-immune cytopenia were extracted, and a retrospective study of children who underwent rituximab for isolated AIHA was conducted. Patients with post bone marrow transplantation AIHA or underlying characterised primitive immune deficiency were excluded. Medical data and procedures were checked from patients' medical records. Complete remission (CR) was defined by haemoglobin count of more than 11 g/dL and reticulocytes count of less than 120 G/L, continuous complete remission (CCR) was defined as CR with no relapse or treatment for at least one year (Aladjidi et al, Haematologica 2011). Efficiency, safety and immunologic tests were evaluated after therapy. Results: Rituximab was administered in 42 children with isolated AIHA between 1999 and 2010. Associated immunologic disorders were noticed in 16 children before AIHA or during the follow-up. The median age at rituximab initiation was 5.4 years (0.1 to 17.5), with 15 children being younger than 2. The median duration of AIHA before rituximab was 6.2 months (0.1 to 74). The number of lines of treatments before rituximab varied from 1 (steroids alone for 23 children) to 5. Nineteen children received 4 weekly doses of 375 mg/m2, 6 received less than 4 courses and 7 received more than 4 courses (6 to 12). Rituximab allowed CR obtention in 85% of evaluable children, and all immunosuppressive treatment cessation in 67%. For failure or relapse, 21 children required 1 to 3 further lines of treatments. Systematic intravenous immunoglobulin (IVIg) substitution was administered in 55% of children, for a median duration of 18 months (1–140). Rituximab was well tolerated and severe neutropenia with sepsis happened in one child 6 months after rituximab. With a median follow-up of 3.6 years (0.2 to 11.3) after rituximab treatment, 22 children were in CCR, 7 children were in CR without treatment, 10 children were in CR with continuous treatment, 2 children were not in remission, 1 child died from associated giant cell hepatitis. Six children still required IgIV substitution at the last follow up, mainly younger and heavily treated children. Comparisons with rituximab efficiency and tolerance in chronic ITP and in AIHA/Evans syndrome are available from this national cohort. Conclusion: This collaborative national study confirms the excellent benefit-risk ratio of rituximab for childhood refractory AIHA. Early introduction could allow avoiding prolonged steroid treatments. However, the benefit of more than 4 courses was not demonstrated in this cohort. AIHA and chronic ITP are different diseases: the prolonged IVIg substitution required in 14% of children imposes to carefully search prior underlying immune deficiency before beginning an anti-CD20 treatment. Acknowledgments to the Association Française pour le Syndrome d'Evans (AFSE), the GIS-Institut des Maladies Rares-INSERM, and the French Health Ministry (Programme Hospitalier de Recherche Clinique 2005, Rare Diseases Plan 2007). Disclosures: No relevant conflicts of interest to declare.

This study delved into the immune functionality of individuals grappling with anemia, tuberculosis, and Candida albicans infection. The findings conclusively revealed that this cohort manifested a pronounced state of immunosuppression, thereby emphasizing the intricate interplay of these concurrent maladies on the immune landscape. Subsequent investigations should aim to unravel the underlying mechanisms orchestrating this immunosuppressive milieu and to contemplate potential interventions aimed at alleviating its impact on immune response dynamics.

AbstractBalanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.

Introduction. Infectious are common and source of high morbidity and mortality in patients with systemic diseases. In Madagascar, there is no data about these infectious complications. The aim of this study was to determine the prevalence of infections, to describe their clinical, biological and therapeutic features in patients with systemic diseases. Methods. We performed a retrospective and descriptive study over a seven-years period concerning the infectious complications of systemic diseases in an Universitary Hospital in Antananarivo. Results. On 69 patients with systemic diseases over seven-years period, twenty one (30.4%) patients (16 women and 5 men) had infectious episodes. The sex ratio was 0.31 and median of age 51 years. Systemic lupus erythematosous (54.5%) and rheumatoid arthritis (14.3%) were most associated with infectious complications. One patient did not have corticosteroïds and/or immunosuppressive treatment on diagno- sis. Fifty infectious episodes were reported. Most of them (90%) were community acquired, and 28% of them were severe. The mean delay between systemic disease and the infectious episodes was 8.31 months. The most common infectious localizations involved lung (36%) and digestive tract (28%). The identified pathogens were: nine Mycobacterium tuberculosis and 7 Escherichia coli. Six deaths (28.5%) were noted. Two deaths were related to tuberculosis.

Background: In Nigeria, immunocompromised persons, particularly those living with HIV, are at an increased risk of developing invasive pulmonary aspergillosis caused by Aspergillus fumigatus. Interestingly, this condition produces symptoms that can be easily mistaken for those of COVID-19. This misdiagnosis results in their treatment with zinc and hydroxychloroquine (HCQ). To better understand the pathophysiology of aspergillosis and determine the therapeutic and toxic effects of zinc and HCQ, this study examined liver and renal functions in experimental rat models. Methodology: Twenty-eight Albino rats, randomised into 7 groups (n=4 each) designated A to G, were used for this study. Group A rats received standardized rat chow and distilled water only. Group B rats received moderate dose of HCQ only. Group C to G rats received immunosuppressive agents (an alkylating agent: cyclo- phosphamide and a steroid: hydrocortisone) to simulate an immunocompromised state before being infected with A. fumigatus suspension (AFS). Group C rats received AFS without treatment. Group D rats simultaneously received AFS and low dose of HCQ. Group E rats simultaneously received AFS and moderate dose of HCQ. Group F rats simultaneously received AFS and high dose of HCQ, and Group G rats simultaneously received AFS and moderate dose of HCQ and zinc. Serum levels of interleukin (IL)-6 and IL-10, liver enzymes, and renal parameters were measured using standard methods. The weights of the lungs, liver, and kidneys of each rat were measured after being sacrificed. One-way analysis of variance (ANOVA) was used to compare the means (±SD) of the biochemical variables and relative weight of the organs, while Post Hoc test was used for group comparison. Pearson's correlation was used to determine relationship between parameters, with significant levels established at p<0.05. Results: Higher levels of serum alanine transaminase, creatinine, and urea and lower relative lung weight were observed in group C rats (infected but untreated) compared to rats in other groups (p<0.001). Higher IL-6 levels and IL-6/IL-10 ratio were also observed in group C rats compared to rats in other groups (p>0.05). Conclusion: This study revealed that HCQ and zinc ameliorate oxidative stress and hepato-renal damage induced by A. fumigatus in Albino rats. Contexte: Au Nigeria, les personnes immunodéprimées, en particulier celles vivant avec le VIH, courent un risque accru de développer une aspergillose pulmonaire invasive causée par Aspergillus fumigatus. Il est intéressant de noter que cette maladie produit des symptômes qui peuvent facilement être confondus avec ceux du COVID-19. Cette erreur de diagnostic entraîne leur traitement au zinc et à l'hydroxychloroquine (HCQ). Pour mieux comprendre la physiopathologie de l'aspergillose et déterminer les effets thérapeutiques et toxiques du zinc et de l'HCQ, cette étude a examiné les fonctions hépatiques et rénales dans des modèles expérimentaux de rats. Méthodologie: Vingt-huit rats albinos, randomisés en 7 groupes (n=4 chacun) désignés de A à G, ont été utilisés pour cette étude. Les rats du groupe A ont reçu uniquement de la nourriture pour rats standardisée et de l'eau distillée. Les rats du groupe B ont reçu uniquement une dose modérée de HCQ. Les rats des groupes C à G ont reçu des agents immunosuppresseurs (un agent alkylant: cyclophosphamide et un stéroïde: hydro- cortisone) pour simuler un état d'immunodépression avant d'être infectés par une suspension d'A. fumigatus (AFS). Les rats du groupe C ont reçu de l'AFS sans traitement. Les rats du groupe D ont reçu simultanément de l'AFS et une faible dose de HCQ. Les rats du groupe E ont reçu simultanément de l'AFS et une dose modérée de HCQ. Les rats du groupe F ont reçu simultanément de l'AFS et une dose élevée de HCQ, et les rats du groupe G ont reçu simultanément de l'AFS et une dose modérée de HCQ et de zinc. Les taux sériques d'interleukine (IL)-6 et d'IL-10, les enzymes hépatiques et les paramètres rénaux ont été mesurés à l'aide de méthodes standard. Le poids des poumons, du foie et des reins de chaque rat a été mesuré après sacrifice. Une analyse de variance unidirectionnelle (ANOVA) a été utilisée pour comparer les moyennes (±SD) des variables biochimiques et du poids relatif des organes, tandis que le test Post Hoc a été utilisé pour la comparaison de groupes. La corrélation de Pearson a été utilisée pour déterminer la relation entre les paramètres, avec des niveaux significatifs établis à p<0,05. Résultats: Des taux sériques plus élevés d'alanine transaminase, de créatinine et d'urée et un poids relatif inférieur des poumons ont été observés chez les rats du groupe C (infectés mais non traités) par rapport aux rats des autres groupes (p<0,001). Des taux d'IL-6 et un rapport IL-6/IL-10 plus élevés ont également été observés chez les rats du groupe C par rapport aux rats des autres groupes (p>0,05). Conclusion: Cette étude a révélé que l'HCQ et le zinc atténuent le stress oxydatif et les lésions hépato-rénales induites par A. fumigatus chez les rats albinos.

While the definition of high-dose corticosteroids depends on the indication, it is typically defined as greater than 15–20 mg for greater than 2–4 weeks. Corticosteroids have a variety of indications such as autoimmune, gastrointestinal, rheumatologic, respiratory, and hematologic conditions and after organ or hematopoietic stem cell transplantation. They can predispose these patients to infections such as pneumococcal pneumonia, Pneumocystis jirovecii (carinii) pneumonia (PJP), hepatitis B reactivation, active tuberculosis, and disseminated strongyloides infection. This article outlines ways to modify these risks in these patients. Prophylaxis is of utmost importance to those at risk for PJP with trimethoprim/sulfamethoxazole, lamivudine for those at risk of hepatitis B reactivation, isoniazid (INH) for latent tuberculosis and ivermectin for those with positive strongyloides serology. Equally important in mitigating disease risk is the appropriate timing of vaccines to elicit an adequate immune response as well as offering additional vaccines such as the pneumococcal vaccine.RésuméLa notion de dose élevée de corticostéroïdes varie selon les indications, mais elle est généralement définie comme correspondant à plus de 15‑20 mg sur une période de plus de deux à quatre semaines. Les corticostéroïdes sont indiqués dans nombre de conditions auto‑immunes, gastro-intestinales, rhumatologiques, respiratoires et hématologiques, ainsi qu’à la suite d’une transplantation d’organe ou de cellules souches hématopoïétiques. Ils peuvent toutefois prédisposer les patients à diverses infections comme la pneumonie pneumococcique et la pneumonie à Pneumocystis jirovecii (carinii) ou PCP, à une réactivation de l’hépatite B, à une tuberculose active et à une strongyloïdose disséminée. Le présent article passe en revue différentes façons de réduire ces risques chez les patients concernés. Voici des mesures de prophylaxie qui s’avèrent être de la plus haute importance pour les personnes à risque : le triméthoprime ou le sulfaméthoxazole pour celles à risque de PCP; la lamivudine pour celles à risque de réactivation de l’hépatite B; l’isoniazide (INH) dans les cas de tuberculose latente; et l’ivermectine pour les personnes montrant une sérologie positive aux strongyloïdes. De plus, pour réduire le risque de maladie, un calendrier de vaccination approprié est tout aussi important, en vue de susciter une réponse immunitaire adéquate et de pouvoir offrir d’autres vaccins comme le vaccin antipneumococcique.Corticosteroids were first used in clinical practice in 1949 for rheumatoid arthritis.1 The number of patients on high-dose corticosteroids is not well known but the use of corticosteroids is becoming increasingly common for a number of indications: An estimated 1% of the general population in the UK is treated with corticosteroids, and this rate increases with age to almost 2.5% in those aged 70–79. 4“High-dose corticosteroids” as a risk factor for infections is typically defined as greater than 15–20 mg of prednisone (or its’ equivalent) for greater than 2–4 weeks, although this definition does vary slightly depending on the infection considered. Notably, this definition is different from the standard definition of high-dose corticosteroids for treatment purposes used in the literature – which is usually defined as greater than 30 mg but less than 100 mg/day – as this dose results in almost complete cytosolic receptor saturation. 2Corticosteroids are used commonly for their anti-inflammatory effects in many conditions with an element of autoimmune disease. The mechanism is to induce transient lymphocytopenia by altering lymphocyte circulation, inducing lymphocyte death and inhibiting cytokines to prevent T-cell activation.3 For example, they are used to induce remission in inflammatory bowel disease (IBD) or to maintain symptom control in rheumatologic diseases like polymyalgia rheumatica. They are also used to prevent organ rejection in solid organ transplantation. Other indications include autoimmune hepatitis, other rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematous, vasculitis, respiratory conditions such as interstitial lung disease, sarcoidosis, hematologic disorders such as lymphoma, leukemia, idiopathic thrombocytopenic purpura, hemolytic anemia), endocrine disorders like Graves disease to prevent opthalmopathy and other conditions like multiple sclerosis.The relative risk of bacterial infections was found to be 5-fold higher in IBD patients on corticosteroids alone, 4-fold higher for other infections like strongyloides and tuberculosis, and only 1.5 fold higher for viral infections.5 However, the absolute individual risk of infectious complications from corticosteroid use remains fairly small. Nevertheless, the burden is significant at a population level due to the high frequency of corticosteroid use. 4 Thus, most practitioners eventually come across these complications during their career.VaccinationsOne of the first considerations in patients on high-dose corticosteroids is the timing of the administration of vaccines to be given to these patients. Immunizations with inactivated vaccines can be given up to 2 weeks before high-dose corticosteroids are initiated, whereas live vaccines need to be given 4 weeks before the high-dose corticosteroids are begun. If the vaccines cannot be given prior to the start of a corticosteroid treatment, both live and inactivated vaccines must wait for 4 weeks after the steroids are completed to elicit an adequate immune response and prevent infectious complications with live vaccines.6Equally important to the timing of the vaccines, patients on high-dose corticosteroids (defined as anyone receiving ³ 20 mg/day for 14 days or more) should receive additional vaccines. A single dose of an inactivated pneumococcal conjugate vaccine (Prevnar), at least one year after any previous dose of pneumococcal vaccine polyvalent (Pneumovax), followed by a single dose of Pneumovax 8 weeks later with a booster of Pneumovax 5 years later is recommended for those on high-dose corticosteroids.7,8 Pneumocystis jiroveci infectionThe following patient groups are considered to be at higher risk forPneumocystis jiroveci pneumonia (PJP; formerly known as Pneumocystis carinii pneumonia [PCP])if exposed to prednisone at doses as low as 20 mg/day for at least 4 weeks9: patients with an underlying immunosuppressive disorder (including autologous HSCT and malignancy), or those with chronic obstructive pulmonary disease and interstitial lung disease secondary to polymyositis/dermatomyositis. Also, patients receiving the same dose of prednisone plus TNF-alpha inhibitors, cyclophosphamide, methotrexate, or temsirolimus should also receive PJP prophylaxis. The first-line agent for prophylaxis is trimethoprim/sulfamethoxazole 80/400 mg (single strength) daily or 160/800 mg (double strength) three times per week (e.g., Monday/Wednesday/Friday). While adverse events are rare on such low doses, thrombocytopenia is possible given that this is an idiosyncractic reaction but pancytopenia is usually observed at much higher (i.e., treatment) doses. Also possible are hyperkalemia, increased serum creatinine and aseptic meningitis. A more rare but devastating adverse event is Stevens-Johnson syndrome. A second line agent for PJP prophylaxis is dapsone but this requires glucose-6-phosphate dehydrogenase (G6PD) testing first, as those who are deficient in this erythrocytic enzyme show a two-fold higher predisposition to dapsone-induced hemolytic anemia. Other alternatives for PJP prophylaxis are atovaquone 1500 mg daily, but this is a costly option, or inhaled pentamidine via a nebulizer at 300 mg every month. Correct administration of inhaled pentamidine is crucial and due to the route of administration, disseminated PCP disease is still possible. 9 Hepatitis B ReactivationFurthermore, patients on corticosteroids of at least 20 mg/day for at least 4 weeks, have an 11–20% chance of reactivation if they are hepatitis B surface Ag carriers. An inactive carrier is hepatitis B surface antigen positive for greater than 6 months without detectable hepatitis B e antigen (HbeAg), presence of anti-hepatitis B e antibodies (anti-Hbe), and undetectable or low levels of hepatitis B DNA, repeatedly normal ALT levels, and no or minimal liver fibrosis. Inactive carriers comprise the largest group of chronic hepatitis B infected individuals with an estimated 250 million people worldwide and can convert to active disease under such immunosuppression.Therefore, it is prudent to prescribe hepatitis B prophylaxis to these patients although no high-level evidence supporting this approach is available.11 Lamivudine is considered first choice for these patients if they do not otherwise meet treatment criteria for hepatitis B. Tenofovir is considered first line in areas highly prevalent for resistance to lamivudine, which tends to occur with prolonged lamivudine exposure. For example, lamivudine resistance develops in up to 90% of HBV-HIV co-infected individuals after 4 years of lamivudine therapy.12.In the setting of isolated anti-Hb-core antibody positivity, prophylaxis is not recommendedgiven that the rate of reactivation is less than 1%.10 Instead, patients should have serial measurements of liver function, hepatitis B serology and hepatitis B DNA every 1–3 months during the period of immunosuppressive treatment and if there is any elevation in these markers, antiviral prophylaxis or treatment (depending on the results) should be offered.So, when assessing patients for the need for PCP or hepatitis B prophylaxis, both the intended duration as well as the dose of the corticosteroids need to be considered.Strongyloides stercoralis InfectionStrongyloides stercoralis can persist for several decades and can reactivate with glucocorticoid exposure causing a severe and sometimes fatal disseminated infection. Strongyloides infection can be asymptomatic and can be acquired walking barefoot on soil in the developing world.13 Strongyloides serology is therefore recommended for refugees from low-income countries in Southeast Asia and Africa where strongyloides is endemic before starting high-dose corticosteroid treatement.14 If positive, patients should be treated with 2 doses of ivermectin to prevent the development of hyperinfection. TuberculosisPatients with latent tuberculosis on higher dose and/or longer duration of glucocorticoid use are also at risk of conversion to active disease. A one-step tuberculin skin test (TST) ³ 5 mm is considered positive when a patient is on prednisone doses ³ 15 mg/day for one month or more. First-line treatment for latent tuberculosis is isoniazid over 9 months. Patients should begin therapy ideally at least 4 weeks before starting such immunosuppression to prevent conversion to active disease.15,16. If this is not possible, the recommendation is to start isoniazid and the corticosteroids at the same time. ConclusionsSerious and potentially fatal infections are just one of the many potential complications of being on high-dose corticosteroids for a long period of time – others include diabetes, hypertension, psychosis, osteoporosis, adrenal insufficiency and the development of cushingoid features.17 Infectious diseases that are either latent or inactive may reactivate under high-dose corticosteroids including tuberculosis, pneumocystis jirovecii pneumonia, Strongyloides stercoralis, and hepatitis B. Screening and treatment for such conditions prior to starting high-dose corticosteroids, or at least once the corticosteroids are started, can prevent these complications. Furthermore, the timing of both inactivated and live vaccines is crucial for the patients’ ability to mount an appropriate immune response and to avoid complications from live vaccines. Finally, patients on high-dose corticosteroids are at higher risk for illnesses that may require additional vaccinations not otherwise given to such individuals – for example the pneumococcal vaccine.DisclosureThere are no conflicts of interest for either author on this manuscript. References1. Zoorob RJ and Cender D. A different look at corticosteroids. American Family Physician. 1998 Aug 1; 58(2): 443-450. 2. Buttgereit F, Da Silva JAP, Boers M et al. Standardised nomenclature for glucocorticoid dosages and glucocorticoid treatment regimens: current questions and tentative answers in rheumatology. Ann Rheum Dis 2002; 61: 718-722. 3.Hall BM and Hodgkinson SJ. Corticosteroids in autoimmune diseases. Aust Prescr 1999; 22: 9-11. 4. T.P. van Staa, H.G. Leufkens, L. Abenhaim, B. Begaud, B. Zhang, C. Cooper. Use of oral corticosteroids in the United Kingdom. QJM. 2000 Feb; 93(2): 105–111. 5. Paul Brassard, Alain Bitton, Alain Suissa, Liliya Sinyavskaya, Valerie Patenaude and Samy Suissa. Oral Corticosteroids and the Risk of Serious Infections in Patients With Elderly-Onset Inflammatory Bowel Diseases. The American Journal of Gastroenterology. 2014 Nov; 109: 1795-1802. 6. PHAC: Canadian Immunization Guide - section 3 - Vaccination of specific populations (acquired/secondary immunodeficiency) - http://www.phac-aspc.gc.ca/publicat/cig-gci/p03-07-eng.php#a4. Accessed July 19 2015. Modified December 5th 2013. 7. PHAC: Canadian Immunization Guide – Section 4 – Active Vaccines: Pneumococcal Vaccine - http://www.phac-aspc.gc.ca/publicat/cig-gci/p04-pneu-eng.php#tab1. Accessed July 19 2015. Modified March 24th 2015. 8. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2012 Oct 12; 61(40): 816. 9. 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Appendix 8: Intestinal parasites – Strongyloides and Schistosoma: evidence review for newly arriving immigrants and refugees. CMAJ . 2011; 183(12): E824-925. 15. Pai M, Kunimoto D, Jamieson F, et al. Canadian Tuberculosis Standards – 7th edition. Centre for Communicable Diseases and Infection Control - Public Health Agency of Canada. February 2014: 75. 16. Singh JA, Furst DE, Bharat A et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Care & Research 2012; 64(5): 625–639. 17. Liu D, Ahmet A, Ward L et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy, Asthma & Clinical Immunology. 2013, 9:30.