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.

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.

Successful Anti-SARS-CoV-2 Spike Protein Antibody Response to Vaccination in MAGT1 Deficiency.

BACKGROUND: Novel messenger RNA vaccines against severe acute respiratory syndrome coronavirus (SARS-CoV-2) have been vital in resolving the coronavirus disease-2019 (COVID-19) pandemic. Detection of neutralizing antibodies (NAbs) against the SARS-CoV-2 spike protein (S) confirms immunogenicity with high sensitivity and specificity. Few recent studies with primary and secondary immunodeficient cohorts present adequate or reduced antibody response. We describe the first reported successful response to anti-SARS-CoV-2 S antibody post-vaccination in magnesium transporter 1 (MAGT1) gene deficiency, more commonly recognized as x-linked immunodeficiency with magnesium defect, Epstein-Barr Virus infection, and neoplasia (XMEN). CASE PRESENTATION: We present a 30-year-old male with selective anti-polysaccharide antibody deficiency, peripheral blood CD5 + /CD19 + B-cell predominance (97%), MAGT1 mutation, and reduced CD16 + CD56 + natural killer- and/or CD8 + T-cell receptor, Group 2, Member D expression. His initial immunological evaluation revealed all seronegative post-vaccination antibody titers but clinically adequate response to protein antigens tetanus and diphtheria anti-toxoids.COVID-19 vaccination and associated serology antibody testing was recommended at this office visit. Anti-SARS-CoV-2 immunoglobulin (Ig)M and IgG antibodies before and after the first BNT162b2 mRNA COVID-19 vaccine doses, as well as nucleocapsid antibody, were negative. S protein total antibody was reactive after the second dose. DISCUSSION: Robust immunological sequelae post-COVID-19 vaccination in the general population are well-documented in the recent literature. Few studies have evaluated COVID-19 vaccination antibody response in immunodeficient patients. The majority positive anti-S antibody detection in most primary immunodeficient (PID) patients among the few studies in the literature, such as the present case, support the safety and efficacy of mRNA COVID-19 vaccination in immunodeficient patients, although larger scale studies are needed. CONCLUSION: We demonstrate successful vaccination in the PID MAGT1 deficiency in this first reported case of reactive anti-S antibody post-COVID-19 vaccination.

An Osteopathic Modular Approach to Asthma: A Narrative Review.

Asthma is among of the first ailments documented in the existing academic literature as being successfully managed with osteopathic manipulative treatment (OMT) techniques. Time-efficient and well-tolerated OMT techniques have been gradually added to the literature to manage this increasingly prevalent disease. In this narrative review, the authors discuss previously-published literature describing the history, diagnosis, and management of asthma related to osteopathic principles and practices and OMT application. They also present current and newly-approved medical managements, including biologics and inhaled corticosteroids. This article also includes supplemental videos showcasing OMT techniques for asthma management, which were developed by the authors based on recommendations indicated in the literature.

Expedited Desensitization to Canakinumab.

INTRODUCTION: Interleukin-1 (IL-1) antagonists have been successful in the management of monogenic auto-inflammatory diseases, notably classic hereditary fever syndromes, such as Familial Mediterranean Fever (FMF). Anakinra (Kineret®), a human recombinant IL-1 receptor antagonist (IL-1Ra), has been clinically effective in the management of persistent auto-inflammation, such as FMF. Few studies report anaphylaxis in response to anakinra, which were resolved with an anakinra desensitization or the anti-IL-1ß monoclonal antibody canakinumab (ILARIS®). We describe the first reported desensitization protocol to canakinumab. CASE REPORT: A 51-year-old man with a prior history of FMF presented with history of failed colchicine, nonsteroidal anti-inflammatory drug, and anakinra trials. Anakinra desensitization and canakinumab intradermal testing (IDT) resulted in anaphylactic and allergic symptoms, respectively. Expedited desensitization to canakinumab was successfully performed with 15-minute intervals between 13 doses of incremental increase to 150 mg. DISCUSSION: Biological agents are immune modulators that may evoke unanticipated hypersensitivity reactions, including anaphylaxis. These anaphylactic reactions to biologics have been infrequently reported, but the expanding market may increase the risk of IgE-mediated hypersensitivities and subsequent need for desensitization protocols. The current, expedited desensitization evaluated several published protocols involving anakinra desensitization to determine appropriate dosing for canakinumab. CONCLUSION: We report the gastrointestinal intolerance and continued FMF flares on colchicine, followed by anaphylactic responses to anakinra and allergic reaction to IDT of canakinumab, in the present case of FMF. Our novel, expedited canakinumab desensitization protocol serves as an effective and alternative therapy in cases when other appropriate biologic agents are not tolerated.

Something to Sweat About: Two Cases of Dupilumab-Induced Hyperhidrosis and Bromhidrosis.

INTRODUCTION: Atopic dermatitis (AD, eczema) is familial chronic inflammatory skin disease of complex etiology and increasing prevalence. Dupilumab is an IL-4 receptor subunit alpha (IL-4Rα) antagonist that is the first Food and Drug Administration-approved biological therapy for moderate-to-severe adult AD inadequately controlled with topical therapies. Adverse effects reported in the literature include injection site reactions, conjunctivitis, headache, and nasopharyngitis. OBJECTIVE: We report the first cases of hyperhidrosis and bromhidrosis as side effects from dupilumab (Dupixent®) for the treatment of AD. CASE REPORTS: Case 1 is a 20-year-old woman with controlled allergic rhinitis and severe AD reported axillary hyperhidrosis with bromhidrosis, comparable to sweat from high-intensity exercise, with no relief from several different over-the-counter antiperspirants. Case 2 is a 61-year-old woman with history of chronic asthma, allergic contact dermatitis, allergic rhinitis, and AD noticed markedly increased sweating with bromhidrosis that was reminiscent of her menopausal symptomology, about 3 months after initiating dupilimab. DISCUSSION: Traditional immunosuppressive agents and corticosteroids have limited efficacy, numerous side effects, and increased risk of infection. The safety profile and efficacy of the newly approved IL-4Rα antagonist dupilumab may be favorable to oral immunosuppressants, but its use remains limited to severe recalcitrant cases, due to financial implications and lack of long-term safety data and comparative head-to-head trials. CONCLUSION: We report improved outcomes with dupilumab, in addition to unpublished cases of bromhidrosis and hyperhidrosis in 2 patients with AD. This report of additional complications may inspire further clinical research and assist clinicians in considering the option of dupilumab for uncontrolled AD, despite aggressive traditional treatment.

A 27-year-old man with recurrent sinopulmonary and cutaneous infections.

The increasing availability of genetic testing for modern immunologists in the evaluation of immune diseases could provide a definite diagnosis in elusive cases. A 27-year-old white male patient presented to the clinic with recurrent sinopulmonary and cutaneous infections since childhood. The patient's mother had seronegative polyarthritis, and one of two sisters of the patient had chronic sinopulmonary infections. Serum immunoglobulins, immunoglobulin G (IgG) subclasses, lymphocyte subset markers, mannose-binding lectin, mitogen and antigen stimulation, bacteriophage study, and Streptococcus pneumoniae titers to 23 serotypes were all normal. B-cell phenotyping revealed a decrease in both nonswitched memory B cells (CD19+CD27+IgD+) and switched memory B-cells (CD19+CD27+IgD-). Genetic testing and the improvement of clinical symptoms after IgG replacement led to the final diagnosis.

Post Autologous Bone Marrow Transplant Associated With a Resultant Mixed Polyclonal/Monoclonal Hyper-IgG3.

There have been few studies illustrating the post immunological phenotype of patients receiving autologous bone marrow transplant (ABMT) for the treatment of diffuse large B-cell lymphoma. High-dose chemotherapy and autologous bone marrow transplantation have been shown to be the only potential curative treatment modalities for B-cell lymphoma. Autologous bone marrow transplantation, although widely utilized in patients with non-Hodgkin lymphoma recurrence, does have an association with immunologic side effects, although serologic changes where rarely reported unless accompanied by recurrent infections. We report the first case of a 62-year-old female patient who experienced recurrent infections, namely, sinusitis and pneumonia, after receiving an ABMT with subsequent hyper-IgG3 phenotype.

No Bull: A Case of Alpha-Gal Syndrome Associated With Buffalo Meat Sensitivity.

INTRODUCTION: Alpha (⍺)-gal syndrome (AGS) is an immunoglobulin E (IgE) antibody response against the glycoprotein carbohydrate galactose-⍺-1,3-galactose-ß-1-(3)4-N-acetylglucosamine-R (Gal⍺-1,3Galß1-(3)4GlcNAc-R or ⍺-gal) that is present in Ixodida (tick) saliva and noncatarrhine mammals as well as cetuximab, antivenom, and the zoster vaccine. The most frequently observed anaphylactic reactions in AGS are observed after beef, pork, lamb, and deer meat consumption. We present the first case of anaphylaxis to buffalo meat. CASE REPORT: A 55-year-old man presented with a history of recurrent urticaria that only developed approximately 7 hours after buffalo consumption. The patient denied history of Ixodidae bites but admitted to frequent hiking outdoors. Anti-⍺-1,3-gal IgE was positive (30.80 kU/L). The patient was advised to strictly avoid red meat. DISCUSSION: The prevalence of AGS has been increased in all continents in the past decade, and several Ixodidae species have been associated with this hypersensitivity. The list of IgE-mediated reactions to various types of meat has expanded to kangaroo, whale, seal, and crocodile, although these have not been associated with AGS. van Nunen only cautioned against consumption of exotic meats, such as buffalo, but no published case report describes AGS associated with anaphylaxis to this type of meat. CONCLUSION: AGS is a mammalian meat allergy that has been increasingly prevalent worldwide, especially in Ixodidae endemic regions of Australia and the United States. Multiple AGS case reports published in the past decade demonstrate rapidly increasing understanding of underlying mechanisms provoking ongoing sensitization to help devise management strategies and dietary information. We offer the first case report of delayed anaphylaxis to buffalo meat.

Familial Success in Allergen Desensitization.

INTRODUCTION: Allergic rhinitis (AR) is a widely prevalent immunoglobulin E-mediated inflammatory nasal condition resulting from reexposure to an allergen in a sensitized individual. The genetic associations behind AR and other allergic conditions have been studied. However, familial success with AR therapies, specifically allergen desensitization through subcutaneous immunotherapy (SCIT), has never been reported in the literature. Pharmocogenetics has been gradually applied to link heritable genetic variants with drug responses, such as intergenic region variants APOBEC3B and APOBEC3C and ß2-adrenergic receptor and glycoprotein ADAM33 polymorphisms as predictive biomarkers for biologic treatment response in asthma. We provide the first reported survey of familial success with SCIT. METHODS: We administered a month-long, institutional review board-approved (20190493) questionnaire to 200 adult patients receiving SCIT in a suburban allergy/immunology practice. The anonymous survey inquired about demographics, target allergens for their SCIT, current symptom improvement on SCIT, and family history of allergies and SCIT management. RESULTS: Twenty-six percent (52 of 200, 26%) SCIT patients reported familial success with the same allergy treatment modality. AR diagnosis and symptom improvement from SCIT was similar among previous/same (18 of 52, 38%; 26 of 52, 54%) and subsequent (10 of 52, 21%; 19 of 52, 40%) generations of family members. A combination of seasonal and perennial allergies was most prevalent (81%) among this population. CONCLUSION: In a subpopulation of SCIT patients, there appears to be a familial success rate with this allergen desensitization treatment. This is the first reported pharmocogenetic evidence of assessing hereditary influence on effective AR therapy. Understanding pharmacogenetic associations involved with SCIT may improve allergists' recommendations for this treatment option.

Radiologic Contrast Media Desensitization for Delayed Cardiac Catheterization.

This protocol for rapid desensitization to intravenous radiographic contrast material (RCM) improves the strategy first reported by Uppal et al. Desensitization is a validated preventative measure for medical emergencies, such as cardiac catheterization, when patients present with histories of anaphylactoid reactions to the allergen of concern. The patient required another catheterization that was modified to repeat the final dosage of 320 mg/mL of Visipaque®, accommodating cardiac catheterization postponement, contrary to readministration of doses 4 (0.625 mg/mL) and 8 (10 mg/mL) as reported in Uppal et al. Our risk score calculations suggested that the patient was at low risk of contrast-induced nephropathy (CIN) that did not necessitate reduced dosage. No complications were reported following catheterization. We propose repetition of the final RCM dosage as a more effective and efficient desensitization strategy, as long as the scoring system does not indicate high risk for CIN.