secondary immunodeficiency
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Author(s):  
Florence Vallelian ◽  
Raphael M. Buzzi ◽  
Marc Pfefferlé ◽  
Ayla Yalamanoglu ◽  
Irina L. Dubach ◽  
...  

AbstractHeme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias, such as sickle cell disease. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Since chronic heme-stress is noxious for macrophages, erythrophagocytes in the spleen are continuously replenished from bone marrow-derived progenitors. Here, we hypothesized that adaptation to heme stress progressively shifts differentiation trajectories of bone marrow progenitors to expand the capacity of heme-handling monocyte-derived macrophages at the expense of the homeostatic generation of dendritic cells, which emerge from shared myeloid precursors. This heme-induced redirection of differentiation trajectories may contribute to hemolysis-induced secondary immunodeficiency. We performed single-cell RNA-sequencing with directional RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation of bone marrow cells towards antioxidant, iron-recycling macrophages, suppressing the generation of dendritic cells in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific CD4 T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype of macrophage expansion with concurrent dendritic cell depletion was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning of hemolytic stress as a driver of hyposplenism-related secondary immunodeficiency.


Immunotherapy ◽  
2022 ◽  
Author(s):  
Roger H Kobayashi ◽  
Jiří Litzman ◽  
Syed Rizvi ◽  
Huub Kreuwel ◽  
Sonja Hoeller ◽  
...  

Most primary immunodeficiency diseases, and select secondary immunodeficiency diseases, are treated with immunoglobulin (IG) therapy, administered intravenously or subcutaneously (SCIG). The first instance of IG replacement for primary immunodeficiency disease was a 16.5% formulation administered subcutaneously in 1952. While most SCIG products are now a 10 or 20% concentration, this review will focus on SCIG 16.5% products with a historical overview of development, including the early pioneers who initiated and refined IG replacement therapy, as well as key characteristics, manufacturing and clinical studies. In determining an appropriate IG regimen, one must consider specific patient needs, characteristics and preferences. There are advantages to SCIG, such as stable serum immunoglobulin G levels, high tolerability and the flexibility of self-administered home treatment.


2021 ◽  
pp. ASN.2021091257
Author(s):  
Stefanie Steiger ◽  
Jan Rossaint ◽  
Alexander Zarbock ◽  
Hans-Joachim Anders

Kidney disease is a known risk factor for poor outcome of COVID-19 and many other serious infections. Vice versa, infection ranks second as cause of death in patients with kidney disease. However, little is known about the underlying secondary immunodeficiency related to kidney disease (SIDKD). In contrast to cardiovascular disease related to kidney disease, which has triggered countless epidemiological, clinical, and experimental research activities or interventional trials, investments in tracing, understanding, and therapeutically targeting SIDKD have been sparse. As a call for more awareness of SIDKD as an immanent unmet medical need that requires rigorous research activities at all levels, too, we review the epidemiology of SIDKD and the numerous aspects of the abnormal immunophenotype of patients with kidney disease. We propose a definition of SIDKD and discuss the pathogenic mechanisms of SIDKD known so far, including more recent insights into the unexpected immunoregulatory roles of elevated levels of FGF23 and hyperuricemia as well as shifts in the secretome of the intestinal microbiota in kidney disease. As an ultimate goal, we should aim to develop therapeutics that can reduce mortality due to infections in patients with kidney disease by normalizing host defense to pathogens and immune responses to vaccines.


Immunotherapy ◽  
2021 ◽  
Author(s):  
Victor Hémar ◽  
Etienne Rivière ◽  
Carine Greib ◽  
Irène Machelart ◽  
Manon Roucoules ◽  
...  

Aim: To describe the effects of a summertime pause (SP) in immunoglobulin replacement therapy (IgRT). Patients & methods: We conducted a prospective single-center observational study, including 44 patients undergoing intravenous IgRT between May and June 2019 in a French teaching hospital. Results: IgRT was interrupted in 23 patients from June to October. Patients who underwent an SP were older, more likely to have secondary immunodeficiency (SID) and received lower doses of immunoglobulin and more antibiotics during winter. Most patients who did not undergo an SP had severe primary immunodeficiency. The SP did not increase the risk of infection, improved the quality of life and reduced treatment costs. Conclusion: SP in IgRT is a safe practice and should be considered for patients with mild SID.


Immunotherapy ◽  
2021 ◽  
Author(s):  
Ulrich Baumann ◽  
Maria Fasshauer ◽  
Christine Pausch ◽  
Helmut Wittkowski ◽  
Corinna Hermann ◽  
...  

Aim: While facilitated subcutaneous immunoglobulin (fSCIG) has been evaluated in pediatric patients with primary immunodeficiency diseases in clinical trials, real-world data are lacking. Materials & methods: This multicenter, retrospective, chart review study assessed fSCIG utilization in 30 patients less than 18 years old, with primary or secondary immunodeficiency diseases. Medical records were reviewed at fSCIG initiation and at 6 months. Results: Most (90%) patients received their first fSCIG infusion at a medical facility; by 6 months, all fSCIG infusions were administered at home by the patient/caregiver, the majority infusing every 3–4 weeks into a single site. No serious adverse drug reactions occurred. Conclusion: This study supports the feasibility and tolerability of administering fSCIG at home to pediatric patients with immunodeficiencies. Clinical Trial Registration: DRKS00015436 ( German Clinical Trials Register )


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 196-196
Author(s):  
Adrian M Shields ◽  
Srinivasan Venkatachalam ◽  
Shankara Paneesha ◽  
Mark Ford ◽  
Tom Sheeran ◽  
...  

Abstract Background: Anti-CD20 B cell depleting agents are amongst the most commonly used immunotherapeutics employed in the treatment of haematological malignancy and autoimmune diseases. By inducing peripheral B cell aplasia, anti-CD20 depleting agents are hypothesised to significantly impair serological responses to neoantigens, including the SARS-CoV-2 spike glycoprotein within SARS-CoV-2 vaccines. Seropositivity following SARS-CoV-2 is the strongest, measurable correlate of protection from severe COVID-19. Understanding the kinetics of B cell reconstitution and vaccine responsiveness following exposure to B cell depleting agents is essential to maximise vaccine efficacy in patients vulnerable to severe COVID-19. Methods: 80 patients with underlying haematological malignancy and 38 patients with underlying rheumatological disease previously treated with anti-CD20 B cell depleting agents were studied following their second dose of a SARS-CoV-2 vaccine (median time to sampling: 46.5d, IQR: 33.8-63.3). Lymphocyte subset (CD4, CD8, CD19, CD56/16) enumeration was performed using 6 colour flow cytometry (BD Trucount). Total anti-SARS-CoV-2 spike glycoprotein antibodies were measured by enzyme-linked immunosorbent assay (The Binding Site, Human Anti-IgG/A/M SARS-CoV-2-ELISA). The relationship between immune reconstitution following B cell depletion and vaccine responsiveness was explored. Results: In the haematology cohort (median age 70y, IQR 60.3-76.0, 62.5% male), overall seropositivity following vaccination was 60.0%. Individuals on active chemotherapy had significantly lower seroprevalence than those vaccinated following the completion of chemotherapy (22.7% vs 74.1%, p<0.0001). In the rheumatology cohort (median age 65y, IQR 58.3-70.8, 39.9% male), overall seropositivity was 69.4%. In both cohorts, vaccine non-responders had significantly smaller populations of peripheral CD19+ B cells (haematology: 0.20 vs 0.02 x10 9/L, p=0.004, rheumatology: 0.07 vs 0.01 x10 9/L, p=0.03). The magnitude of the antibody response following vaccination did not differ between recipients of Tozinameran and Vaxzeveria in either cohort. Vaccine responsiveness was lower in the first 6 months following B cell depletion therapy; 42.9% in the haematology cohort and 33.3% in the rheumatology cohort, increasing to 100% and 75% respectively in individuals receiving their second dose 6-12 months following B cell depletion (Figure 1). B cell reconstitution in the 7-12 month window following B cell depletion was faster in haematology compared to rheumatology patients (77.8% v 22.2% achieving normal B cell count, p=0.005) and associated with improved vaccine responsiveness. However, persistent immunodeficiency occurred in some haematology patients following completion of treatment: 25% of patients who had completed therapy at least 36 months previously failed to respond to vaccination. In this cohort of vaccine non-responders, 83.3% of individuals had B cell numbers within the normal range. These patients had all previously been treated for follicular lymphoma suggesting a specific mechanism for long-range secondary immunodeficiency in these patients. Conclusions: Serological responsiveness to SARS-CoV-2 vaccines is poor during active chemotherapy for haematological malignancy and in the first 6 months following B cell depletion, regardless of underlying disease. Vaccine responsiveness significantly improves in the 7-12 month window following B cell depletion. Compared to haematology patients, B cell reconstitution is slower in rheumatology patients and associated with reduced vaccine responsiveness, possibly due to the use of additional concurrent disease-modifying anti-rheumatic therapies. Furthermore, long-term secondary immunodeficiency occurs in a minority of haematology patients. To maximise the efficacy from SARS-CoV-2 booster vaccination and optimal utilisation of available vaccine doses, immunisations should be delivered at least 6 months following the administration of anti-CD20 depleting drugs. Figure 1: Kinetics of return of vaccine responsiveness following B cell depletion in haematology and rheumatology patients. Figure 1 Figure 1. Disclosures Paneesha: Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria; Celgene: Honoraria. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4071-4071
Author(s):  
Betsy Lahue ◽  
Rajiv Mallick ◽  
Xiang Zhang ◽  
Andrew S. Koenig ◽  
Gabriela Espinoza

Abstract Secondary immunodeficiency (SID) is an acquired condition caused by several factors including, but not limited to, B-cell malignancies, and may result in frequent, burdensome, and possibly life-threatening infections. Treatment guidelines recommend immunoglobulin replacement therapy (IgRT) in certain settings to prevent recurrent, persistent, or major (severe) infections. This retrospective analysis of a US healthcare database characterized patients (pts) with suspected SID, who experienced infections, and were or were not treated with IgRT (IgPro10 [Privigen ®]). Data were collected from 26 US healthcare organizations from TriNetX DataWorks™ Network between 1/1/09 - 1/31/20. Pts were required to have the following: suspected SID (defined as ≥1 underlying conditions related to SID such as: solid organ transplant [SOT], non-Hodgkin lymphoma [NHL], multiple myeloma [MM], and chronic lymphocytic leukemia [CLL]), ≥1 severe infection (defined as requiring hospitalization and/or treatment with intravenous antibiotics or anti-viral medication) or ≥2 non-severe infections between underlying condition diagnosis date and the index date, the absence of diagnosed primary immunodeficiency, and an available medical history of ≥12 months pre-index and ≥3 months post-index. The index date refers to first IgPro10 use or the corresponding date for pts not receiving IgPro10 (unexposed cohort). In the IgPro10 cohort, pts were required to have had ≥2 consecutive IgPro10 administrations within 90 days. Between the pre- and post-index periods, the following variables were compared for both cohorts: pts' treatment, underlying conditions, baseline characteristics, and change in annualized infection rate (for infections of any severity and severe infections). Pre-index immunoglobulin G (IgG) (or calculated globulin [CG]) levels were recorded as: hypogammaglobulinemia (HGG) (IgG <6 g/L or CG <18 g/L), normal (IgG ≥6 g/L or CG ≥18 g/L), or missing. A generalized estimation equation (GEE) model with logit link was used to compare the change in the proportion of pts with an annualized infection rate of zero from the pre- to the post-index period across both cohorts. The final sample comprised 222 IgPro10 pts and 11,226 unexposed pts. In the IgPro10 cohort, 143 pts were on IgPro10 for <6 months, 41 pts for 6-12 months, and 38 pts for >12 months. In both the IgPro10 and the unexposed cohorts, SOT was the most frequent underlying condition (45.5% and 44.6%, respectively), followed by NHL (21.6% and 28.2%, respectively), MM (14.4% and 10.1%, respectively), and CLL (11.3% and 7.6%, respectively). Age (mean [SD], 57.2 [13.9] vs 57.9 [17.0] years old, respectively) and sex distribution (male:female, 56.3%:43.7% vs 51%:48.8%, respectively) were similar in the IgPro10 and unexposed cohort. During the pre-index period, the IgPro10 cohort, compared with the unexposed cohort, received a greater number of antibiotic courses (median [interquartile range], 7 [20] vs 1 [5], respectively), had a substantially higher proportion of pts with HGG (HGG: 34.7% vs 3.0%; normal IgG: 43.7% vs 57.8%; missing: 21.6% vs 39.2%, respectively), and a lower proportion of pts with an annualized infection rate of zero (for infections of any severity and severe infections) (Figure 1). There was an approximate four-fold increase in the proportion of pts with no infections of any severity following IgPro10 administration; this increase was significantly larger than in the unexposed cohort (p<0.0001) (Figure 1). Additionally, there was an increase in the proportion of pts with no severe infections following IgPro10 administration. Again, this increase was significantly larger than in the unexposed cohort (p<0.0001) (Figure 1). This real-world study found that compared with pts not receiving IgRT, pts who subsequently went on to receive IgPro10 experienced more infections pre-treatment. Following IgPro10 administration, more pts had an annualized infection rate of zero (for infections of any severity or severe infections) compared with the pre-index period. Moreover, the increase in the proportion of pts with no infections was greater in the IgPro10 cohort than in the unexposed cohort, for both infections of any severity and severe infections. Taken together, these findings suggest effectiveness of IgPro10 in pts with SID, but further study, such as a prospective randomized controlled trial, is needed to confirm these initial findings. Figure 1 Figure 1. Disclosures Lahue: CSL Behring: Consultancy; Alkemi Health: Current Employment, Current holder of stock options in a privately-held company. Mallick: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Zhang: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Koenig: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. Espinoza: CSL Behring: Current Employment, Current holder of individual stocks in a privately-held company. OffLabel Disclosure: IgPro10 (Privigen®, CSL Behring, King of Prussia, PA, U.S.), a type of immunoglobulin replacement therapy, is currently approved in the U.S. to treat patients with primary immunodeficiency (PI), chronic inflammatory demyelinating polyneuropathy (CIDP), and chronic immune thrombocytopenic purpura (ITP).


2021 ◽  
Vol 59 (5) ◽  
pp. 625-630
Author(s):  
O. A. Golovina ◽  
N. V. Demidova ◽  
A. V. Alekseeva

Sarcoidosis is a rare multisystem disease which may accompany various autoimmune diseases in 17,6% cases. Despite of the fact that T-cell immunity impairments play a key role in these two conditions, their combination is extremely rare. It is difficult to choose therapy for patients with coexisted diseases, and it is even harder in case of comorbid pathology. In this article we considered a complicated case of treatment patient with a coexistence of rheumatoid arthritis and sarcoidosis, which had occurred during rituximab therapy. In addition to the combination of two autoimmune diseases, the selection of therapy for this patient was complicated by secondary immunodeficiency and intolerance to the main basic drugs.


CNS Drugs ◽  
2021 ◽  
Author(s):  
Fabian Szepanowski ◽  
Clemens Warnke ◽  
Gerd Meyer zu Hörste ◽  
Anne K. Mausberg ◽  
Hans-Peter Hartung ◽  
...  

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