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J Infect Dis. 2021 Mar 16:jiab142. doi: 10.1093/infdis/jiab142. Online ahead of print.

ABSTRACT

Immunoglobulin (IG) lots (N=176) released since March 2020 were tested for SARS-CoV-2 neutralizing antibodies, with first positive results for September 2020 lots, mean = 1.7 IU/ml, 46% of lots positive. From there, values steadily increased, in correlation with the cumulative COVID-19 incidence, to reach a mean of 31.2 IU/ml and 93% of lots positive by January 2021. Extrapolating the correlation, IGs could reach an anti-SARS-CoV-2 potency of ~345 IU/ml by July 2021. At that stage, prophylactic IG treatment for primary/secondary immunodeficiency could contain similar doses of anti-SARS-CoV-2 as convalescent plasma which is used for treatment of COVID-19.

PMID:33725725 | DOI:10.1093/infdis/jiab142

Sci Rep. 2021 Mar 15;11(1):5945. doi: 10.1038/s41598-021-85399-9.

ABSTRACT

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

PMID:33723309 | DOI:10.1038/s41598-021-85399-9

Mol Ther Methods Clin Dev. 2021 Jan 20;20:635-651. doi: 10.1016/j.omtm.2021.01.007. eCollection 2021 Mar 12.

ABSTRACT

X-linked agammaglobulinemia (XLA) is an immune disorder caused by mutations in Bruton’s tyrosine kinase (BTK). BTK is expressed in B and myeloid cells, and its deficiency results in a lack of mature B cells and protective antibodies. We previously reported a lentivirus (LV) BTK replacement therapy that restored B cell development and function in Btk and Tec double knockout mice (a phenocopy of human XLA). In this study, with the goal of optimizing both the level and lineage specificity of BTK expression, we generated LV incorporating the proximal human BTK promoter. Hematopoietic stem cells from Btk ^-/- Tec ^-/- mice transduced with this vector rescued lineage-specific expression and restored B cell function in Btk ^-/- Tec ^-/- recipients. Next, we tested addition of candidate enhancers and/or ubiquitous chromatin opening elements (UCOEs), as well as codon optimization to improve BTK expression. An Eμ enhancer improved B cell rescue, but increased immunoglobulin G (IgG) autoantibodies. Addition of the UCOE avoided autoantibody generation while improving B cell development and function and reducing vector silencing. An optimized vector containing a truncated UCOE upstream of the BTK promoter and codon-optimized BTK cDNA resulted in stable, lineage-regulated BTK expression that mirrored endogenous BTK, making it a strong candidate for XLA therapy.

PMID:33718514 | PMC:PMC7907679 | DOI:10.1016/j.omtm.2021.01.007

World Allergy Organ J. 2021 Feb 22;14(2):100513. doi: 10.1016/j.waojou.2021.100513. eCollection 2021 Feb.

ABSTRACT

Inborn errors of immunity (IEI) are a heterogeneous group of disorders, mainly resulting from mutations in genes associated with immunoregulation and immune host defense. These disorders are characterized by different combinations of recurrent infections, autoimmunity, inflammatory manifestations, lymphoproliferation, and malignancy. Interestingly, it has been increasingly observed that common allergic symptoms also can represent the expression of an underlying immunodeficiency and/or immune dysregulation. Very high IgE levels, peripheral or organ-specific hypereosinophilia, usually combined with a variety of atopic symptoms, may sometimes be the epiphenomenon of a monogenic disease. Therefore, allergists should be aware that severe and/or therapy-resistant atopic disorders might be the main clinical phenotype of some IEI. This could pave the way to target therapies, leading to better quality of life and improved survival in affected patients.

PMID:33717395 | PMC:PMC7907539 | DOI:10.1016/j.waojou.2021.100513

Front Immunol. 2021 Feb 25;12:648951. doi: 10.3389/fimmu.2021.648951. eCollection 2021.

ABSTRACT

Gene therapy is an innovative treatment for Primary Immune Deficiencies (PIDs) that uses autologous hematopoietic stem cell transplantation to deliver stem cells with added or edited versions of the missing or malfunctioning gene that causes the PID. Initial studies of gene therapy for PIDs in the 1990-2000’s used integrating murine gamma-retroviral vectors. While these studies showed clinical efficacy in many cases, especially with the administration of marrow cytoreductive conditioning before cell re-infusion, these vectors caused genotoxicity and development of leukoproliferative disorders in several patients. More recent studies used lentiviral vectors in which the enhancer elements of the long terminal repeats self-inactivate during reverse transcription (“SIN” vectors). These SIN vectors have excellent safety profiles and have not been reported to cause any clinically significant genotoxicity. Gene therapy has successfully treated several PIDs including Adenosine Deaminase Severe Combined Immunodeficiency (SCID), X-linked SCID, Artemis SCID, Wiskott-Aldrich Syndrome, X-linked Chronic Granulomatous Disease and Leukocyte Adhesion Deficiency-I. In all, gene therapy for PIDs has progressed over the recent decades to be equal or better than allogeneic HSCT in terms of efficacy and safety. Further improvements in methods should lead to more consistent and reliable efficacy from gene therapy for a growing list of PIDs.

PMID:33717203 | PMC:PMC7946985 | DOI:10.3389/fimmu.2021.648951

Front Immunol. 2021 Feb 26;12:619246. doi: 10.3389/fimmu.2021.619246. eCollection 2021.

ABSTRACT

Primary immunodeficiency (PID) with immune dysregulation may present with early onset gastrointestinal autoimmune disorders. When gastrointestinal autoimmunity is associated with multiple extraintestinal immune system dysfunction the diagnosis of PID is straightforward. However, with the advent of next generation sequencing technologies, genetic defects in PID genes have been increasingly recognized even when a single or no extraintestinal signs of immune dysregulation are present. A genetic diagnosis is especially important considering the expanding armamentarium of therapies designed to inhibit specific molecular pathways. We describe a boy with early-onset severe, refractory autoimmune gastritis and biallelic mutations in the LRBA gene causing a premature STOP-codon who was successfully treated with CTLA4-Ig, abatacept, with long term clinical and endoscopic remission. The case underscores the importance to consider a monogenetic defect in early onset autoimmune disorders, since the availability of targeted treatments may significantly improve patient prognosis.

PMID:33717114 | PMC:PMC7952427 | DOI:10.3389/fimmu.2021.619246

J Allergy Clin Immunol. 2021 Mar 10:S0091-6749(21)00365-1. doi: 10.1016/j.jaci.2021.02.034. Online ahead of print.

ABSTRACT

Health disparities are health differences linked with economic, social and environmental disadvantage. They adversely affect groups that have systematically experienced greater social or economic obstacles to health. Renewed efforts are needed to reduced health disparities in the US, highlighted by the disparate impact on racial minorities during the coronavirus pandemic. Institutional or systemic patterns of racism are promoted and legitimated through accepted societal standards and organizational processes within the field of medicine and contribute to health disparities. Herein, we review current evidence regarding health disparities in allergic rhinitis, asthma, atopic dermatitis, food allergy, drug allergy, and primary immune deficiency disease in racial and ethnic underserved populations. Best practices to address these disparities involve addressing social determinants of health and adopting policies to improve access to specialty care and treatment for the underserved through telemedicine and community partnerships, cross cultural provider training to reduce implicit bias, inclusion of underserved patients in research, implementation of culturally competent patient education, and recruitment and training of healthcare providers from underserved communities. Addressing health disparities requires a multi-level approach involving patients, health providers, local agencies, professional societies and national governmental agencies.

PMID:33713767 | DOI:10.1016/j.jaci.2021.02.034

J Clin Immunol. 2021 Mar 13. doi: 10.1007/s10875-021-01017-3. Online ahead of print.

ABSTRACT

X-linked agammaglobulinemia is a rare primary immunodeficiency due to a BTK mutation. The patients are characteristically deficient in peripheral B cells and serum immunoglobulins. While they are susceptible to infections caused by bacteria, enteroviruses, and parasites, fungal infections are uncommon in XLA patients. Here, we report a boy of Malay ethnicity who suffered from recurrent upper respiratory tract infections and severe progressive necrotizing fasciitis caused by Saksenaea erythrospora. Immunological tests showed a B cell deficiency and hypogammaglobulinemia. Whole-exome sequencing identified a dinucleotide deletion (c.1580_1581del) in BTK, confirmed by Sanger sequencing and predicted to be disease causing by in silico functional prediction tools (Varsome and MutationTaster2) but was absent in the gnomAD database. This mutation resulted in a frameshift and premature termination (p.C527fs), which disrupted the protein structure. The mother was heterozygous at the mutation site, confirming her carrier status. Flow cytometric analysis of monocyte BTK expression showed it to be absent in the patient and bimodal in the mother. This study describes a novel BTK mutation in a defined hotspot and an atypical fungal phenotype in XLA. Further studies are required to understand the pathogenesis of fungal infection in XLA.

PMID:33713249 | DOI:10.1007/s10875-021-01017-3

Indian Pediatr. 2021 Mar 15;58(3):246-249.

ABSTRACT

BACKGROUND: Primary immunodeficiency disorders are genetically heterogeneous immune disorders with a wide range of infectious and non-infectious manifestations.

OBJECTIVE: To describe a single-center experience of primary immunodeficiency disorders.

DESIGN: Retrospective analysis from January 2015 to January 2020.

SETTING: Tertiary care children’s hospital.

PARTICIPANTS: One hundred and twelve children (<18 years) diagnosed with primary immunodeficiency disorders.

OUTCOME MEASURE: Diagnostic spectrum, clinical features, and outcome.

RESULTS: The median (IQR) age of the first clinical manifestation and lag time in diagnosis was 10 (27) and 11 (18) months, respectively. Twenty-seven children (24%) were diagnosed during their first presentation. Thirty-six (32%) children had phagocytic disorders, 20 (17.8%) had combined/cellular defects, 18 (16%) had predominant antibody deficiencies and 17 (15%) had disorders of immune dysregulation. Non-infectious manifestations were seen in 54 (48%). Eight children underwent hematopoietic stem cell transplantation, 44 (39%) children were on antimicrobial prophylaxis and supportive therapy, 36 (32%) were lost to follow-up and 24 (21%) children died.

CONCLUSION: Congenital defects of phagocyte function, followed by combined/cellular defects are the commonest primary immune deficiencies (PIDs) identified in southern India. Long lag time in diagnosis and high mortality in our cohort emphasizes the need for early diagnosis and early referral.

PMID:33713060

Pediatr Rheumatol Online J. 2021 Mar 12;19(1):26. doi: 10.1186/s12969-021-00518-0.

ABSTRACT

BACKGROUND: Prevention of illness due to infection by influenza viruses is important for children with rheumatic diseases. Biological disease modifying antirheumatic drugs have become increasingly important in the treatment of juvenile idiopathic arthritis, and combinations of immunosuppressive drugs are used for the treatment of systemic disorders, which increase the risk of secondary immunodeficiency. Therefore, we investigated whether children with rheumatic disease can mount a protective antibody response after influenza immunization.

METHODS: The prospective multicentre cohort study was conducted in Denmark during the influenza season 2015-2016. Children with rheumatic disease aged six months to 19 years were eligible. Controls were immunologically healthy children. A blood sample was collected before and after vaccination and analysed by haemagglutination inhibition (HI) assay for the 2015-2016 influenza vaccine-strains. In case of flu-like symptoms the child was tested for influenza. For statistical analyses the patients were grouped according to medical treatment or disease.

RESULTS: A total of 226 patients and 15 controls were enrolled. No differences were found for the increase of antibodies from pre-vaccine to post-vaccine between the groups in our primary analyses: A/Cal H1N1pdm09 (p = 0.28), A/Swi H3N2 (p = 0.15) and B/Phu Yamagata (p = 0.08). Only when combining patients across groups a lower increase in antibodies was found compared to controls. Among all patients the pre-vaccine rates for seroprotection using the HI-titer cut-off ≥ 40 were 93.1-97.0 % for all three strains. For seroprotection using the HI-titer cut-off ≥ 110 the pre-vaccine rates for all patients were 14.9-43.6 % for all three strains and an increase in the proportions of patients being seroprotected after vaccination was found for A/Cal H1N1pdm09 and A/Swi H3N2. None of the children with flu-like symptoms tested positive for the vaccine strains.

CONCLUSIONS: Children with rheumatic diseases increase in antibody titres after influenza immunization, however, it remains uncertain whether a protective level is achieved.

PMID:33712043 | DOI:10.1186/s12969-021-00518-0