Manish Butte

J Clin Immunol. 2021 Jul 29. doi: 10.1007/s10875-021-01098-0. Online ahead of print.

ABSTRACT

PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an inherited inborn error of immunity, characterized by autoinflammation (recurrent fever), vasculopathy (livedo racemosa, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency, lymphoproliferation, immune cytopenias, and bone marrow failure (BMF). Tumor necrosis factor (TNF-α) blockade is the treatment of choice for the vasculopathy, but often fails to reverse refractory cytopenia. We aimed to study the outcome of hematopoietic cell transplantation (HCT) in patients with DADA2.

METHODS: We conducted a retrospective study on the outcome of HCT in patients with DADA2. The primary outcome was overall survival (OS).

RESULTS: Thirty DADA2 patients from 12 countries received a total of 38 HCTs. The indications for HCT were BMF, immune cytopenia, malignancy, or immunodeficiency. Median age at HCT was 9 years (range: 2-28 years). The conditioning regimens for the final transplants were myeloablative (n = 20), reduced intensity (n = 8), or non-myeloablative (n = 2). Donors were HLA-matched related (n = 4), HLA-matched unrelated (n = 16), HLA-haploidentical (n = 2), or HLA-mismatched unrelated (n = 8). After a median follow-up of 2 years (range: 0.5-16 years), 2-year OS was 97%, and 2-year GvHD-free relapse-free survival was 73%. The hematological and immunological phenotypes resolved, and there were no new vascular events. Plasma ADA2 enzyme activity normalized in 16/17 patients tested. Six patients required more than one HCT.

CONCLUSION: HCT was an effective treatment for DADA2, successfully reversing the refractory cytopenia, as well as the vasculopathy and immunodeficiency.

CLINICAL IMPLICATIONS: HCT is a definitive cure for DADA2 with > 95% survival.

PMID:34324127 | DOI:10.1007/s10875-021-01098-0

Front Immunol. 2021 Jul 12;12:703780. doi: 10.3389/fimmu.2021.703780. eCollection 2021.

ABSTRACT

Common variable immunodeficiency disorders (CVID) are a group of rare diseases of the immune system and the most common symptomatic primary antibody deficiency in adults. The “variable” aspect of CVID refers to the approximately half of the patients who develop non-infective complications, mainly autoimmune features, in particular organ specific autoimmune diseases including thyroiditis, and cytopenias. Among these associated conditions, the incidence of lymphoma, including mucosal associated lymphoid tissue (MALT) type, is increased. Although these associated autoimmune disorders in CVID are generally attributed to Systemic Lupus Erythematosus (SLE), we propose that Sjogren’s syndrome (SS) is perhaps a better candidate for the associated disease. SS is an autoimmune disorder characterized by the lymphocytic infiltrates of lacrimal and salivary glands, leading to dryness of the eyes and mouth. Thus, it is a lymphocyte aggressive disorder, in contrast to SLE where pathology is generally attributed to auto-antibody and complement activation. Although systemic lupus erythematosus (SLE) shares these features with SS, a much higher frequency of MALT lymphoma distinguishes SS from SLE. Also, the higher frequency of germ line encoded paraproteins such as the monoclonal rheumatoid factor found in SS patients would be more consistent with the failure of B-cell VDJ switching found in CVID; and in contrast to the hypermutation that characterizes SLE autoantibodies. Thus, we suggest that SS may fit as a better “autoimmune” association with CVID. Examining the common underlying biologic mechanisms that promote lymphoid infiltration by dysregulated lymphocytes and lymphoma in CVID may provide new avenues for treatment in both the diseases. Since the diagnosis of SLE or rheumatoid arthritis is usually based on specific autoantibodies, the associated autoimmune features of CVID patients may not be recognized in the absence of autoantibodies.

PMID:34322134 | PMC:PMC8311857 | DOI:10.3389/fimmu.2021.703780

Int J Gen Med. 2021 Jul 21;14:3707-3717. doi: 10.2147/IJGM.S323591. eCollection 2021.

ABSTRACT

BACKGROUND: The study aims to analyze the expression levels of kinesin family member 1A (KIF1A) in ovarian cancer (OC) and explore its clinical significance in the development of OC and its potential regulatory network.

METHODS: The Cancer Genome Atlas (TCGA) OC data was used to examine the expression differences between OC and normal tissue and explore the correlation with tumor stage. The relationship between KIF1A expression and prognosis was analyzed using Oncomine and Kaplan-Meier plotter tools. The co-expression network of KIF1A in TCGA OC was analyzed based on the application of cBioPortal, GO cluster, and KEGG analyses were performed based on the co-expression network. Immune-infiltration analysis were used to analyze the significant involvement of KIF1A in function.

RESULTS: KIF1A was highly elevated in OC tissues and KIF1A expression was significantly correlated with the FIGO stage (P=0.015) and age (P=0.020). High KIF1A expression of OC predicted the poor prognosis including overall survival (OS) (HR: 1.27; 95% CI: 1.11-1.45; P=0.00046) and post-progression survival (PFS) (HR: 1.18; 95% CI: 1.03-1.35; P=0.015). GO and KEGG analysis showed KIF1A had a potential role in the biological process of ATP-dependent chromatin remodeling, transcription, DNA-templated cytolysis, positive regulation of T cell proliferation, positive regulation of transcription, DNA-templated via cell adhesion molecules (CAMs), primary immunodeficiency, oxidative phosphorylation, NF-kappa B signaling pathway, pathways in cancer and Wnt signaling pathway, and immune infiltrating cells.

CONCLUSION: KIF1A was highly expressed and correlated with poor survival and immune infiltration in OC, and it may be a prognostic biomarker in OC.

PMID:34321916 | PMC:PMC8312510 | DOI:10.2147/IJGM.S323591

BMJ Open. 2021 Jul 28;11(7):e045904. doi: 10.1136/bmjopen-2020-045904.

ABSTRACT

INTRODUCTION: Children with primary immunodeficiency disorders (PID) are more susceptible to developing viral infections and are at a substantially increased risk of developing paralytic poliomyelitis. Such children, if given oral polio vaccines tend to excrete poliovirus chronically that may lead to the propagation of highly divergent vaccine-derived poliovirus (VDPV). Consequently, they may act as a reservoir for the community by introducing an altered virus potentially imposing a risk to global polio eradication. However, the risks of chronic and prolonged excretion are not well characterised in the study context. This study seeks to establish a pilot surveillance system for successful identification and monitoring of VDPV excretion among children with PID. It will assess whether the Jeffrey Modell warning signs of PID can be used as an appropriate screening tool for PID in Pakistan.

METHODS AND ANALYSIS: In this pilot surveillance, recruitment of PID cases is currently done at participating hospitals in Pakistan. Potential children are screened and tested against the Jeffrey Modell Foundation (JMF) warning signs for immunodeficiency and their stool is collected to test for poliovirus excretion. Cases excreting poliovirus are followed until the two consecutive negative stool samples are obtained over a period of 6 months. The data will be analysed to calculate hospital-based proportions of total Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases over a 2-year period and to determine the sensitivity and specificity of the JMF signs.

ETHICS AND DISSEMINATION: This protocol was reviewed and approved by the WHO (WHO Reference-2018/811124-0), Aga Khan University (AKU ERC-2018-0380-1029) and National Bioethics Committee (Ref No. 4-87 NBC-308-Y2). The results will be published in an open access peer-reviewed scientific journal and presented to the iVDPV Working Group members, policy-makers, paediatric consultants and fellow researchers with the same domain interest. It may be presented in scientific conferences and seminars in the form of oral or poster presentations.

PMID:34321293 | DOI:10.1136/bmjopen-2020-045904

Clin Exp Immunol. 2021 Jul 26. doi: 10.1111/cei.13645. Online ahead of print.

ABSTRACT

Leukocyte adhesion deficiency type I is rare primary immunodeficiency disorder characterized by mutations in the ITGB2 gene encoding CD18. We present clinical and immunological features of 15 patients with leukocyte adhesion deficiency type I (LAD-I). Targeted next-generation sequencing was performed with either a primary immunodeficiency gene panel comprising 266 genes or a small LAD-panel consisting of five genes for genetic analysis. To measure the expression level of integrins on the leukocyte surface, flow cytometry analysis was performed. The median age of the patients at diagnosis was 3 (1-48) months. Eleven (73%) of the 15 patients had LAD-I diagnosis in their first 6 months, and fourteen (93%) patients had consanguineous parents. Delayed separation of the umbilical cord was present in 80% (n=12) of the patients in our cohort, whereas omphalitis was observed in 53% (n=8) of the patients. Leukocytosis with neutrophil predominance was observed in 73% (n=11) patients. Nine distinct variants in the ITGB2 gene in 13 of the 15 patients with LAD-I were characterized, of which two (c.305_306delAA and c.779_786dup) are novel homozygous mutations of ITGB2. Four unrelated patients from Syria had a novel c.305_306delAA mutation that might be a founder effect for patients of Syrian origin. Four (27%) patients underwent HSCT. Two of them died because of HSCT complications, and the other two are alive and well. Early differential diagnosis of the patients is critical in the management of the disease and genetic evaluation provides a basis for family studies and genetic counseling.

PMID:34310689 | DOI:10.1111/cei.13645

Arch Argent Pediatr. 2021 Aug;119(4):e370-e374. doi: 10.5546/aap.2021.e370.

ABSTRACT

Atopic dermatitis is the most common form of eczema often developed before the first year of life. Nevertheless, when the presentation is atypical or related to infections the diagnostic represents a challenge for the pediatricians. It is important to maintain a high index of suspicion for the detection of primary immunodeficiency associated to severe eczema. One of them is the autosomal dominant hyper-IgE syndrome characterized by recurrent skin and respiratory infections, atopic dermatitis, eosinophilia, and high serum IgE concentrations. In this paper, we report a 1 months and 29 days old baby girl diagnosed with hyper-IgE and a skin involvement since birth.

PMID:34309321 | DOI:10.5546/aap.2021.e370

Front Pediatr. 2021 Jul 8;9:702546. doi: 10.3389/fped.2021.702546. eCollection 2021.

ABSTRACT

Introduction: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is a rare primary immune regulatory disorder caused by heterozygous gain of function mutation in the PIK3R1 gene encoding PI3Kδ regulatory p85α subunit and resulting in PI3Kδ hyperactivation. Clinical features range from recurrent infections to manifestations of immune dysregulation like autoimmunity, inflammation, systemic lymphoproliferation, and increased risk of cancer. We describe a new dominant PIK3R1 mutation causing APDS2 presenting with lymphoma and systemic refractory autoimmunity. Case Presentation: A 30-year-old woman was referred to the Immunology Unit of our hospital for uncontrolled systemic lupus erythematosus, including chilblains lesions, systemic lymphoproliferation and IgA deficiency. At 19 years of age, she was diagnosed with Hodgkin’s lymphoma. Subsequently, she presented systemic lupus erythematosus onset, with episodes of severe exacerbation, including autoimmune hemolytic anemia and pleuro-pericarditis. Initial clinical response to conventional treatments was reported. Immunological investigations performed during our first observation showed severe lymphopenia, IgA deficiency, elevated IgM with reduced IgG2 levels, and low vaccination antibody titers. Quantitative real-time polymerase chain reaction (PCR) assay for Cytomegalovirus and Epstein-Barr virus showed low viral loads for both viruses in serum. An increase of serum inflammatory markers highlighted persistent systemic hyperinflammation. The next-generation sequencing (NGS)-based gene panel tests for primary immunodeficiency showed a heterozygous A>G substitution in the splice acceptor site at c.1300-2 position of PIK3R1, leading to exon-skipping. Conclusion: This case emphasizes the importance of suspecting primary immune regulatory disorders in young adults, predominantly showing a severe, aggressive, and refractory to treatment immune dysregulation phenotype, even in the absence of major infectious diseases at the onset. Different treatments can be promptly started, and a delayed diagnosis can highly impact the outcome. Targeted therapy against PI3Kδ pathway defect effectively improves drug-resistant autoimmunity, lymphoproliferation, and risk of progression to malignancy; eligible patients could benefit from its use even as a bridge therapy to transplantation, currently the only definitive curative treatment. Therefore, identifying genetic mutation and prompt targeted treatment are essential to control disease manifestations, prevent long-term sequelae, and enable curative HSCT in APDS2 patients.

PMID:34307262 | PMC:PMC8295470 | DOI:10.3389/fped.2021.702546

Front Pediatr. 2021 Jul 7;9:648022. doi: 10.3389/fped.2021.648022. eCollection 2021.

ABSTRACT

Nuclear factor κappa-B (NFκB) is a family of transcription factors involved in regulating inflammation and immunity. Mutations in the NFκB1 pathway are associated with primary immune defects and underlie the most common monogenic etiology of common variable immunodeficiency (CVID). However, little is known about how NFκB1 defects or primary immunodeficiency (PID) complicate pregnancy. We present a previously healthy 34-year-old patient who suffered from poor wound healing and sterile sepsis during the post-partum period of each of her three pregnancies. She was otherwise asymptomatic, but her daughter developed Evans Syndrome (ES) with hypogammaglobulinemia prompting expanded genetic testing which revealed a novel monoallelic variant in NFκB1. This case highlights that pregnancy-related complications of PID can be difficult to recognize and may portend adverse patient outcomes. For these reasons, guidance regarding diagnosis and management of women of childbearing age with PID is warranted.

PMID:34307247 | PMC:PMC8292645 | DOI:10.3389/fped.2021.648022

Front Immunol. 2021 Jul 8;12:707463. doi: 10.3389/fimmu.2021.707463. eCollection 2021.

ABSTRACT

We report here the results of a phase 3 study to assess the efficacy, safety, and tolerability of GC5107, a new 10% liquid intravenous immunoglobulin (IVIG) in preventing serious bacterial infections in patients with primary immunodeficiency (ClinicalTrials.gov: NCT02783482). Over a 12-month study period, 49 patients aged 3 to 70 years with a confirmed diagnosis of primary immunodeficiency received GC5107 at doses ranging from 319 to 881 mg/kg body weight every 21 or 28 days, according to their previous IVIG maintenance therapy. A total of 667 infusions of GC5107 were administered comprising a total of 45.86 patient-years of treatment. A single acute serious bacterial infection occurred during the study, resulting in an incidence of 0.02 events per patient-year (upper 99% one-sided confidence interval limit: 0.21), meeting the prespecified primary efficacy endpoint. The mean incidence of infections other than acute serious bacterial infections was 2.9 infections per patient-year. Efficacy was also demonstrated by the low mean annualized rate of hospitalizations due to infection (0.1 day) and the mean annualized duration of hospitalizations (0.1 day). The mean rate of intravenous and oral antibiotic use was 0.1 day and 13.2 days, respectively. There was a mean of 7.1 days of missed work, school, or daycare days. The proportion of infusions with temporally associated adverse events (TAAEs) occurring during or within 72 hours after GC5107 infusion was 0.24 (upper 95% one-sided confidence interval limit: 0.31), meeting the pre-specified primary safety endpoint. Overall, 149 of 667 infusions (22%) were associated with TAAEs. The most common TAAE was headache, reported by 49% of patients. More than 98% (731/743) of all adverse events that occurred throughout the 12-month study period were mild or moderate. More than 98% of infusions were completed without discontinuation, interruption or rate reduction. There were no treatment-emergent serious adverse events related to GC5107 or study discontinuations due to an adverse event. Overall, pharmacokinetic parameters for GC5107 were within the range of those reported in studies of other marketed IVIG products. Results of the present study demonstrate that GC5107 is an effective, safe and well-tolerated treatment for patients with primary immunodeficiency.

PMID:34305948 | PMC:PMC8297997 | DOI:10.3389/fimmu.2021.707463

Front Immunol. 2021 Jul 8;12:699126. doi: 10.3389/fimmu.2021.699126. eCollection 2021.

NO ABSTRACT

PMID:34305936 | PMC:PMC8296640 | DOI:10.3389/fimmu.2021.699126