COVID-19 in Children with Nephrotic Syndrome on Anti-CD20 Chronic Immunosuppression.
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ABSTRACT:
SUBMITTER: Angeletti A
PROVIDER: S-EPMC7536764 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rituximab, a chimeric anti-CD20 monoclonal antibody originally licensed for lymphoma, is emerging as a novel steroid-sparing agent for idiopathic nephrotic syndrome in children. The potential use of anti-CD20 monoclonal antibodies in idiopathic nephrotic syndrome has contributed to shifting the view of podocytopathies from T cell-mediated to more complex immunomediated disorders that can benefit from targeting B cells and other mediators of the early immune response. Clinical data on the use of rituximab also have implications on disease management and classification. In this review, we present results of clinical studies that support rituximab as an effective steroid-sparing agent in steroid-dependent idiopathic nephrotic syndrome. Recent randomized controlled trials suggest that potential benefits of rituximab therapy in steroid-dependent forms of idiopathic nephrotic syndrome vary depending on whether children are dependent on steroids alone or on both steroids and calcineurin inhibitors, with greater probabilities to achieve drug-free remission in the former group. Multiple-drug dependence may identify a different disease state with different prognosis and treatment options. Insufficient data are available on optimal use of rituximab as a maintenance steroid-sparing agent in these steroid-sensitive forms of the disease, including how often and for how long rituximab infusions should be repeated to maximize expected benefits and minimize potential harms. Finally, one randomized controlled trial in children with steroid-resistant idiopathic nephrotic syndrome yielded negative results. New anti-CD20 antibodies are under study in this patient population.
| S-EPMC4822672 | biostudies-literature
Project description: Not available
| S-EPMC8993668 | biostudies-literature
Project description:AimsAnti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.MethodsWe investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years).ResultsInfusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed.ConclusionOverall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.
| S-EPMC5980330 | biostudies-literature
Project description:Anti-CD20 therapy is effective in idiopathic nephrotic syndrome (INS). However, transient or sustained hypogammaglobulinemia predisposing to an increased risk of infectious diseases can follow treatment in some patients. We analyzed the long-term effects of anti-CD20 therapy on immunological memory in 27 frequently-relapsing/steroid-dependent INS pediatric patients after more than 4 years from the first and at least 2 years from the last anti-CD20 infusion. Twenty-one INS children, never treated with anti-CD20 and under an intense oral immunosuppression with prednisone, mycophenolate mofetil, and calcineurin inhibitors were also included as control group. Levels of circulating B-cell subpopulations, total serum immunoglobulins and IgG and memory B cells directed against hepatitis B virus (HBV) and tetanus were determined and correlated with clinical characteristics. Nine patients never relapsed after more than 2 years from the last anti-CD20 administration (5 after the first, 3 after the second, and 1 after the fifth infusion). At last follow-up, most patients showed a complete recovery and normalization of total (27/27), transitional (27/27), and mature-naïve B cells (25/27). However, a sustained and significant reduction of total memory (20/27) and switched memory (21/27) B cells was found in most patients. 11/27 patients showed hypogammaglobulinemia at last follow-up and, among these, four presented with a severe hypogammaglobulinemia (IgG < 160 mg/dl). In contrast, no patient in the control group developed a severe hypogammaglobulinemia. Age at the time of first anti-CD20 administration was positively associated with IgG levels at last follow-up (p = 0.008); accordingly, younger patients had an increased risk of hypogammaglobulinemia (p = 0.006). Furthermore, severe hypogammaglobulinemia and delayed switched memory B-cell reconstitution were more frequent in non-relapsing patients. Reduced IgG levels against HBV and tetanus were observed at baseline and further declined at last follow-up. Antigen-specific memory B-cells were induced by re-immunization, but specific IgG titers remained low. In conclusion, anti-CD20 therapy can be disease-modifying in some INS patients. However, a prolonged impairment of immunological memory occurs frequently, independently from the number of anti-CD20 infusions, particularly in younger patients. Re-immunization may be necessary in these patients.
| S-EPMC6646679 | biostudies-literature
Project description:Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by SARS-CoV-2 antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that the hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature.
2022-11-05 | GSE217370 | GEO
Project description:Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.
| S-EPMC7405500 | biostudies-literature
Project description:ObjectiveTo study the risk of acquiring Corona Virus Disease 2019 (COVID-19) and its outcomes in patients on immunosuppressive therapy (IST) for chronic autoimmune neuromuscular disorders (aNMD) and multiple sclerosis (MS).MethodsWe used TriNetX, a global health collaborative clinical research platform collecting real-time electronic medical records data, which has one of the largest known global COVID-19 database. We included patients with chronic autoimmune neuromuscular disorders (aNMD) [myasthenia gravis (MG), inflammatory myositis, and chronic inflammatory neuropathies (CIN)] and MS, based on the International Classification of Disease-10 (ICD-10) coding for one year before January 20th, 2020. We examined the use of IST, rate of COVID- 19, hospitalization, intubation, and mortality among the patients with aNMD and MS.ResultsA total of 33,451 patients with aNMD and 42,899 patients with MS were included. Among them, 111 (0.33%) patients with aNMD and 115 patients (0.27%) with MS had COVID-19. About one third of them required hospitalization. IST did not appear to have a significant impact on overall infection risk in either group; however, risk of hospitalization for immunosuppressed patients with aNMD was higher (Odds ratio 2.86, p-value 0.011).ConclusionsIST use does not appear to make patients with aNMD and MS more vulnerable to COVID-19. IST may be continued during the pandemic, as previously suggested by expert opinion guidelines. However, it is important to consider individualizing immunotherapy regimens in some cases. Additional physician reported registry-based data is needed to further confirm these findings.
| S-EPMC7837234 | biostudies-literature
Project description:Purpose: This study aims to characterize the early innate and adaptive responses induced by SARS-CoV-2 infection in children and adults over time up to 8 weeks post symptoms onset (POS). We report the gene signature of COVID-19 over the course of the disease in both age groups. The kinetic of infection was divided in 5-time intervals according to the calculated days POS: interval 1 (0-5), interval 2 (6-14), interval 3 (15-22), interval 4 (23-35), and interval 5 (36-81). Methods: RNA extraction was performed automatically via the PAXgene Blood miRNA Kit and the QIAcube instrument (Qiagen) following the manufacturer’s protocol. RNA concentration and quality were assessed by using the Qubit instrument (Invitrogen) and the Agilent 2100 Bioanalyzer, respectively. The Stranded Total RNA Ribo-Zero Plus kit from Illumina was used for the library preparation with 100 ng of total RNA as input. Library molarity and quality were assessed with the Qubit and Tapestation using a DNA High sensitivity chip (Agilent Technologies). Libraries were pooled at 2 nM for clustering and sequenced on an Illumina HiSeq 4000 sequencer for a minimum of 30 million single-end 100 reads per sample. Main results: (I) we observed an antiviral-IFN-signature and innate-cell-activation within the first 5 days post symptoms onset (POS), while genes associated with CD4 T-cell responses, plasma cells and immunoglobulin were upregulated in both age groups during the first two weeks POS, indicative of SARS-CoV-2-specific adaptive immune responses; (II) in adults, genes associated with IFN antiviral responses and activated dendritic cells were maintained during the second week of disease, and subsided only after 14 days. By contrast, those transcriptome changes subsided already after 5 days in children.
2021-09-22 | GSE166190 | GEO
Project description:Introduction: The COVID-19 outbreak has become a worldwide public health emergency. The renal histopathological features of acute tubular necrosis or thrombotic microangiopathy have been previously reported in adults with severe COVID-19 infections. In children, the renal manifestations associated with COVID-19 disease are not widely reported. Here we describe a case report of a child with new-onset nephrotic syndrome associated with COVID-19 infection. Case Presentation: An 8-year-old boy with no previous significant medical history presented with bilateral eyelid and facial swelling soon after his parents were diagnosed with COVID-19 infection. He had diarrhea but no fever or shortness of breath. At 1 week after the onset of swelling, the boy tested positive for the COVID-19 virus. Based on clinical findings of significant proteinuria (urine protein and creatinine ratio of 11.4), hypoalbuminemia (serum albumin of 2 g/dl), and hypercholesterolemia (total cholesterol of 384 mg/dl), he was diagnosed with nephrotic syndrome. He responded well to standard-dose prednisone treatment for nephrotic syndrome. At 1 week after starting the prednisone treatment, he went into clinical remission. Lymphopenia continued to be present for 4 weeks after the onset of symptoms. There were no complications related to clot formation or secondary infections with this presentation. Conclusion: COVID-19 can be associated with new-onset nephrotic syndrome in children. The patient responded well to the standard-dose prednisone treatment that is typically used for new-onset nephrotic syndrome. Summary: We describe the unique presentation of COVID-19 in a child as new-onset nephrotic syndrome. We offer insight on the success of standard treatment of nephrotic syndrome with COVID-19.
| S-EPMC7469478 | biostudies-literature
Project description:In children, sporadic nephrotic syndrome can be related to a genetic cause, but to what extent genetic alterations associate with resistance to immunosuppression is unknown. In this study, we designed a custom array for next-generation sequencing analysis of 19 target genes, reported as possible causes of nephrotic syndrome, in a cohort of 31 children affected by sporadic steroid-resistant nephrotic syndrome and 38 patients who exhibited a similar but steroid-sensitive clinical phenotype. Patients who exhibited extrarenal symptoms, had a familial history of the disease or consanguinity, or had a congenital onset were excluded. We identified a genetic cause in 32.3% of the children with steroid-resistant disease but zero of 38 children with steroid-sensitive disease. Genetic alterations also associated with lack of response to immunosuppressive agents in children with steroid-resistant disease (0% of patients with alterations versus 57.9% of patients without alterations responded to immunosuppressive agents), whereas clinical features, age at onset, and pathologic findings were similar in steroid-resistant patients with and without alterations. These results suggest that heterogeneous genetic alterations in children with sporadic forms of nephrotic syndrome associate with resistance to steroids as well as immunosuppressive treatments. In these patients, a comprehensive screening using such an array may, thus, be useful for genetic counseling and may help clinical decision making in a fast and cost-efficient manner.
| S-EPMC4279734 | biostudies-literature