COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.

CD5 B-Cell Predominant Primary Immunodeficiency: Part of the Spectrum of MAGT1 Deficiency.

Background: Selective anti-polysaccharide antibody deficiency (SPAD) with CD5 B-cell predominance and autoimmune phenomena was identified in a male cohort first reported by Antall et al in 1999. The phenotypically likewise and genotypically identical X-linked immunodeficiency with magnesium defect, Epstein-Barr Virus infection, and neoplasia (XMEN) disease was defined as a novel primary immunodeficiency (PID) in 2011. Recent studies of the magnesium transporter 1 (MAGT1) gene mutation reveal glycosylation defects contributing to more phenotypic variance than the "XMEN" title pathologies. The updated title, "X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect," was proposed in 2020. Objectives: To reflect the patient population more accurately, a prospective classification update may consider MAGT1 glycobiological errors contributing to phenotypic variance but also pre-genetic testing era reports with CD5 B-cell predominance. Methods: Patient 1 from Antall et al presented at 28 years of age for further immunological evaluation of his CD5/CD19 B-cell predominance diagnosed at 5 years old. Design: Immune re-evaluation done through flow cytometry and next-generation sequencing. Results: Flow cytometry B-cell phenotyping revealed persistent CD5+CD19+ (93%). Flow cytometric histogram quantified reduced activator CD16+CD56+ natural killer and CD8+ T-cell receptor, Group 2, Member D (NKG2D) glycoprotein expression. A c.923-1_934 deletion loss of function mutation was identified in the MAGT1 gene. Conclusion: We suggest the novel PID XMEN, based on its CD5 B-cell predominance, had been discovered and reported over a decade earlier as CD5+ PID based on the MAGT1 mutation found in the same. We encourage consideration of combining these labels and recent findings to offer the most accurate classification of this disease.

IgG3 Antibody Response to COVID-19 Vaccination in a Patient With a Large Heavy Chain Deletion.

Vaccinations for pathogenic organisms have been utilized for decades in both the protection and diagnosis of immunodeficiency patients. Some of these immunodeficient patients may not create an adequate response to vaccination, although some who have significant aberrancies in their immune system may surprisingly create antibodies to immunizations. We present a patient with a large Ig heavy chain deletion (severe deficiency of serum IgG1, IgG2, IgG4, and IgA1) that showed a considerable response (presumably through IgG3) after the Pfizer BioNTech COVID-19 vaccination. This finding in this unique immunodeficient patient warrants further research into alternate antibody response pathways against COVID-19.

IgM Deficiency Associated With Connexin Mutation in an 18-Year-old Male.

IgM deficiency is characterized by remarkably low serum levels of IgM with normal IgG and IgA levels. These patients clinically present with recurrent infections, autoimmune disorders, and malignancies. While unknown, the proposed mechanisms explain the pathophysiology as an issue due to impaired IgG antibody response. The connexin genes encode for gap junctional proteins where mutations can cause hearing deficits and immune dysregulation. We present a unique case of an 18-year-old patient with recurrent sinusitis, diagnosed connexin-26 mutation and an IgM deficiency. An 18-year-old male with chronic sinusitis, Marfanoid joint hypermobility syndrome, and sensorineural hearing loss due to connexin-26 deficiency with bilateral cochlear implants. This patient's mutation is a GJB2 deletion located on chromosome 13 which encodes for the connexin-26 protein. The patient experienced recurrent infections, and serum immunoglobulins showed a normal IgA (84 mg/dL; normal: 70-400 mg/dL), IgG (922 mg/dL; normal: 700-1600 mg/dL) and reduced IgM (26 mg/dL; normal: 40-230 mg/dL) levels. The patient was responsive to Mumps, Measles, Rubella, and Diphtheria vaccinations among others, consistent with SIGMD diagnoses. Antibody responses to polysaccharide antigens were absent. The leukocyte counts were within normal limits. His parents are connexin-26 deficient carriers, and his older brother was diagnosed with SIGMD. Connexin-26 has been identified with multiple immunological mechanisms. Although mutations of this gene have no direct tie to antibody formation in relation to IgM, the presence of these 2 pathologies in 1 patient is intriguing and may suggest a pathophysiologic connection. We describe the first case of connexin mutation with an IgM deficiency in an 18-year-old male.

Structural abnormalities and osteopathic considerations in primary immunodeficiencies.

Structural skeletal abnormalities are associated with primary immunodeficient (PID) patients. These abnormalities have not been well studied in PID with reference to osteopathic medicine tenets. Osteopathic structural examinations of PID patients with respect to these tenets and the diagnosis of somatic dysfunctions preventing the free flow of lymph fluids back into the circulation and the disruption of the skeletal microenvironment may have an impact on the status of the immune system in patients with a PID. A standardized evaluation was conducted in a patient with a phosphatidylinositol 3-kinase regulatory subunit 1 (PIK3R1) mutation who presented with skeletal abnormalities. A literature review was also conducted to determine the breadth of other PIDs with structural irregularities. Osteopathic structural clinical examinations (OSCEs) were performed by an osteopathic medical student, fellow, and attending after receiving informed consent from the patient. The findings were collected regionally noting severity, tissue texture changes, asymmetry, altered range of motion (ROM), and tenderness according to DO-Touch.NET physical examination and treatment form. A literature review was conducted utilizing various search engines and the textbook, Stiehm's Immune Deficiencies, 4th edition. The significant findings found from the patient were right sidebending rotation cranial strain pattern with decreased left temporal bone motion, temporomandibular joint crepitus, and right deviation upon mandibular opening. The thoracolumbar region revealed tissue tenderness and restricted psoas ROM. Bilateral sacroiliac joint tenderness, right superior sheering, and anterior innominate rotation, along with left-on-left sacral flexion, were associated with valgus knees. The literature search showed multiple other PIDs outside of PIK3R1 that have associated skeletal and structural abnormalities. Irregular skeletal features found in immunodeficient patients may have an additive defect on the immunological responses due to somatic dysfunction impinging on the lymphatic flow to the central circulation. Other different immunodeficient patients suffer from boney structural abnormalities, which may lead to further immune hindrance caused by impingement of flow as well as bone marrow microenvironment impact on the peripheral immunological output. We present the first osteopathic examination with detailed findings of somatic dysfunction in a patient with PID. Future studies on PID patients should require more attention to structure and function, as found by a thorough osteopathic examination in order to unrestrict preformed cellular and humoral components back into the peripheral circulation.