Research

J Clin Immunol. 2023 May 5. doi: 10.1007/s10875-023-01507-6. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Subcutaneous immunoglobulin (SCIG) home infusion is widely used as an alternative to intravenous immunoglobulin (IVIG). This study aimed to determine the quality of life (QoL) of patients with primary immunodeficiency (PID) after switching to home-based SCIG.

METHODS: In this prospective open-label single-center study, QoL was determined using the validated Arabic version of the Child Health Questionnaire at baseline and 3 and 6 months after switching from IVIG to SCIG.

RESULTS: Twenty-four patients were recruited from July 2018 to August 2021, including 14 females and 10 males. The median age of the patients was 5 years (range, 0-14 years). The patients’ diagnoses included severe combined immunodeficiency, combined immunodeficiency, agammaglobulinemia, Omenn syndrome, immunodysregulation, hyper-IgE syndrome, common variable immunodeficiency, and bare lymphocyte syndrome. The median duration on IVIG before inclusion was 40 months (range, 5-125 months). The QoL score showed a significant improvement in the patients’ global health at 3 and 6 months compared with those at baseline and a significant improvement in the patients’ general health at 3 and 6 months compared with that at baseline. The mean baseline serum IgG trough level was 8.8 ± 2.1 g/L. The mean serum IgG level was significantly higher on SCIG at both 3 and 6 months (11.7 ± 2.3 and 11.7 ± 2.5 g/L, respectively).

CONCLUSIONS: This is the first study involving an Arab population to show improvement in the QoL of patients with PID after switching from hospital-based IVIG to home-based 20% SCIG.

PMID:37145392 | DOI:10.1007/s10875-023-01507-6

Bull World Health Organ. 2023 May 1;101(5):346-354. doi: 10.2471/BLT.22.289066.

ABSTRACT

Individuals with primary immunodeficiencies who are infected with vaccine-derived polioviruses may continue to shed poliovirus for months and go undetected by surveillance programmes of acute flaccid paralysis. These patients therefore pose a risk of initiating poliovirus outbreaks that jeopardize efforts towards global polio eradication. To identify these individuals, we designed a study protocol for the establishment of a network for surveillance of immunodeficiency-related vaccine-derived poliovirus in India. In the first step we identified recognized centres in India that could diagnose and enrol patients with primary immunodeficiency disorder into the study. Stool sample collection from study sites, culture, isolation, characterization of enteroviruses and reporting to study sites was carried out at the National Institute of Virology Mumbai Unit, as per the WHO national polio surveillance project protocol. In the first phase of the study from January 2020 to December 2021, we implemented the protocol at seven study sites at different medical institutes to determine the proportion of poliovirus infections in primary immunodeficiency disorder patients of India. We later expanded the study by including an additional 14 medical institutes across the country in the second phase running from January 2022 to December 2023. We believe this study protocol will help other countries to initiate immunodeficiency-related vaccine-derived poliovirus surveillance to identify and follow up patients who are long-term excretors of vaccine-derived poliovirus. Integration of immunodeficiency-related poliovirus surveillance with acute flaccid paralysis surveillance of the existing poliovirus network will enhance continuous screening of patients with primary immunodeficiency disorder in the future.

PMID:37131936 | PMC:PMC10140681 | DOI:10.2471/BLT.22.289066

N Engl J Med. 2023 May 4;388(18):1680-1691. doi: 10.1056/NEJMoa2202348.

ABSTRACT

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations.

METHODS: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality.

RESULTS: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher.

CONCLUSIONS: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).

PMID:37133586 | DOI:10.1056/NEJMoa2202348

Allergy Asthma Clin Immunol. 2023 May 2;19(1):36. doi: 10.1186/s13223-023-00786-3.

ABSTRACT

BACKGROUND: Primary immunodeficiency disorders (PID) are rare disorders with heterogeneous manifestations, overlapping with other diseases such as autoimmunity, malignancy, and infections. This makes the diagnosis very challenging and delays management. Leucocyte adhesion defects (LAD) are a group of PIDs in which patients lack adhesion molecules on leukocytes needed for their emigration through blood vessels to the site of infection. Patients with LAD can present with diverse clinical features including severe and life-threatening infections, early in life, and the absence of pus formation around infection or inflammation. There is often delayed umbilical cord separation, omphalitis, late wound healing, and a high white blood cell count. If not recognized and managed early, can lead to life-threatening complications and death.

CASE PRESENTATION: LAD 1 is characterized by homozygous pathogenic variants in the integrin subunit beta 2 (ITGB2) gene. We report two cases of LAD1 with unusual presentations (post-circumcision excessive bleeding and chronic inflammation of the right eye) which were confirmed by flow cytometric analysis and genetic testing. We found two disease-causing ITGB2 pathogenic variants in both cases.

CONCLUSIONS: These cases highlight the importance of a multidisciplinary approach to recognizing clues in patients with uncommon manifestations of a rare disease. This approach initiates a proper diagnostic workup of primary immunodeficiency disorder leading to a better understanding of the disease, and appropriate patient counseling, and helps clinicians to be better equipped to deal with complications.

PMID:37131167 | DOI:10.1186/s13223-023-00786-3

J Med Case Rep. 2023 May 2;17(1):175. doi: 10.1186/s13256-023-03907-z.

ABSTRACT

BACKGROUND: Hepatic masses are relatively common findings, and the diagnostic approach often begins by identifying patient and mass characteristics that are risk factors for malignancy. Chronic immunosuppression is a known risk factor for various malignancies, and azathioprine in particular has been reported in association with solid and hematologic malignancies, including diffuse large B-cell lymphoma.

CASE PRESENTATION: A 46-year-old white woman presented to clinic with several weeks of gastrointestinal symptoms and was found to have a hepatic mass on imaging. Her history was notable for neuromyelitis optica spectrum disorder on chronic immunosuppression with azathioprine. It was initially thought to be an inflammatory adenoma. On 6-month follow-up imaging, the mass had grown rapidly in size and was surgically resected. Further workup determined the mass to be an iatrogenic immunodeficiency-associated Epstein-Barr virus-positive diffuse large B-cell lymphoma confined to the liver. Azathioprine was discontinued and the patient underwent treatment with rituximab with no evidence of recurrence 2 years after the initiation of treatment.

CONCLUSIONS: This case report describes the first time hepatic Epstein-Barr virus-positive diffuse large B-cell lymphoma has been reported with azathioprine, which highlights the unique sequelae of chronic immunosuppression, including atypical hematologic malignancies, and the importance of considering chronic immunosuppression in the diagnostic evaluation of a hepatic mass.

PMID:37127672 | DOI:10.1186/s13256-023-03907-z

J Allergy Clin Immunol Pract. 2023 Apr 27:S2213-2198(23)00458-0. doi: 10.1016/j.jaip.2023.04.018. Online ahead of print.

ABSTRACT

Autoimmunity may be a manifestation of inborn errors of immunity (IEI) specifically as part of the subgroup of primary immunodeficiency (PID) known as primary immune regulatory disorders (PIRD). However, while making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes and inheritance of autoimmunity associated with PIRD, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunological features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. Additionally, there will be a review of autoimmunity in non-genetically defined PID such as common variable immunodeficiency (CVID), and of instances where primary autoimmunity can result in clinical phenocopies of IEI.

PMID:37119983 | DOI:10.1016/j.jaip.2023.04.018

J Allergy Clin Immunol Pract. 2023 Apr 27:S2213-2198(23)00459-2. doi: 10.1016/j.jaip.2023.04.019. Online ahead of print.

ABSTRACT

Breakthroughs in sequencing technology, targeted immunotherapy, and immune reconstituting treatment have increased the pool of patients with inborn errors of immunity, requiring expertise from clinical immunologists. A growing category of immunodeficiency, presenting as primary immune regulatory disorder and secondary immunodeficiency due to targeted immune therapy for cancer and autoimmunity, has added to the growing burden of patients needing access to immune-supportive therapy. The confluence of a growing population of patients needing a clinical immunologist, complex payer structures, and inadequate health care representation will exacerbate current problems with access to therapy. Patients, health care providers, researchers, public and private payers, and industry must come together to find solutions to improve access to therapy. In this article, we reviewed the major topics regarding access to therapy for patients with immunodeficiency.

PMID:37119982 | DOI:10.1016/j.jaip.2023.04.019

Cell Rep. 2023 Apr 27;42(5):112446. doi: 10.1016/j.celrep.2023.112446. Online ahead of print.

ABSTRACT

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27^bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.

PMID:37119135 | DOI:10.1016/j.celrep.2023.112446

J Allergy Clin Immunol Pract. 2023 Apr 26:S2213-2198(23)00455-5. doi: 10.1016/j.jaip.2023.04.015. Online ahead of print.

ABSTRACT

Chronic mucocutaneous candidiasis (CMC) was recognized as a primary immunodeficiency in the early 1970’s. However, for almost 40 years, its genetic etiology remained unknown. The progressive molecular and cellular description of inborn errors of immunity (IEI) with syndromic CMC pointed toward a possible role of IL-17-mediated immunity in protecting against fungal infection and CMC. Since 2011, novel IEI affecting either the response to or production of IL-17A and IL-17F (IL-17A/F) in patients with isolated or syndromic CMC provided formal proof of the pivotal role of the IL-17 axis in mucocutaneous immunity to Candida spp. And, to a lesser extent, to Staphylococcus aureus in humans. In contrast, IL-17-mediated immunity seems largely redundant against other common microbes in humans. In this review, we outline the current knowledge of IEI associated with impaired IL-17A/F-mediated immunity, highlighting our current understanding of the role of IL-17A/F in human immunity.

PMID:37116791 | DOI:10.1016/j.jaip.2023.04.015

Int J Mol Sci. 2023 Apr 18;24(8):7449. doi: 10.3390/ijms24087449.

ABSTRACT

The congenital disorder of glycosylation type IIs (ATP6AP1-CDG; OMIM# 300972) is a rare X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Here, we examine the case of a 1-year-old male patient of Buryat origin, who presented with liver dysfunction. At the age of 3 months, he was hospitalized with jaundice and hepatosplenomegaly. Whole-exome sequencing identified the ATP6AP1 gene missense variant NM_001183.6:c.938A>G (p.Tyr313Cys) in the hemizygous state, which was previously reported in a patient with immunodeficiency type 47. At the age of 10 months, the patient successfully underwent orthotopic liver transplantation. After the transplantation, the use of Tacrolimus entailed severe adverse effect (colitis with perforation). Replacing Tacrolimus with Everolimus led to improvement. Previously reported patients demonstrated abnormal N- and O-glycosylation, but these data were collected without any specific treatment. In contrast, in our patient, isoelectric focusing (IEF) of serum transferrin was performed only after the liver transplant and showed a normal IEF pattern. Thus, liver transplantation could be a curative option for patients with ATP6AP1-CDG.

PMID:37108612 | DOI:10.3390/ijms24087449