Novel BTK Mutation in Patient with Late Diagnosis of X-Linked Agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a genetic disorder with mutation in Bruton's tyrosine kinase (BTK). Defects in B cell development and immunoglobulin production lead to recurrent infections following loss of maternal IgG at 6 months of age. A 55-year-old male with a longstanding common variable immunodeficiency diagnosis on infusion therapy presented to the clinic with cutaneous T-cell lymphoma, which inspired overall repeat evaluation. Immunoglobulin levels and lymphocyte markers, family history, and genetic testing prompted a true diagnosis of XLA and novel mutation in the BTK gene. Disease-associated mutations have been noted in all five domains of BTK, with missense variants most commonly cited among the 100s of reported genetic alterations. The BTK protein is expressed in hematopoietic lineages and plasma cells, with the exception of T lymphocytes. Disruption in the protein function or absence of BTK halts normal B cell development at the pre-B transitional cell stage and induces premature apoptosis. We present the first reported case of a novel hemizygous BTK c.1492C > G mutation in a patient causing XLA.

Augmentation of immune response to vaccinations through osteopathic manipulative treatment: a study of procedure.

CONTEXT: Anecdotal evidence suggested that osteopathic manipulative treatment (OMT) may have imparted survivability to patients in osteopathic hospitals during the 1918 influenza pandemic. In addition, previous OMT research publications throughout the past century have shown evidence of increased lymphatic movement, resulting in improved immunologic function qualitatively and quantitatively. OBJECTIVES: The following is a description of a proposed protocol to evaluate OMT effects on antibody generation in the peripheral circulation in response to a vaccine and its possible use in the augmentation of various vaccines. This protocol will serve as a template for OMT vaccination studies, and by adhering to the gold standard of randomized controlled trials (RCTs), future studies utilizing this outline may contribute to the much-needed advancement of the scientific literature in this field. METHODS: This manuscript intends to describe a protocol that will demonstrate increased antibody titers to a vaccine through OMT utilized in previous historical studies. Confirmation data will follow this manuscript validating the protocol. Study participants will be divided into groups with and without OMT with lymphatic pumps. Each group will receive the corresponding vaccine and have antibody titers measured against the specific vaccine pathogen drawn at determined intervals. RESULTS: These results will be statistically evaluated. Our demonstration of a rational scientific OMT vaccine antibody augmentation will serve as the standard for such investigation that will be reported in the future. These vaccines could include COVID-19 mRNA, influenza, shingles, rabies, and various others. The antibody response to vaccines is the resulting conclusion of its administration. Osteopathic manipulative medicine (OMM) lymphatic pumps have, in the past through anecdotal reports and smaller pilot studies, shown effectiveness on peripheral immune augmentation to vaccines. CONCLUSIONS: This described protocol will be the template for more extensive scientific studies supporting osteopathic medicine's benefit on vaccine response. The initial vaccine studies will include the COVID-19 mRNA, influenza, shingles, and rabies vaccines.

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.

Serial Convalescent Plasma Infusions for the Initial COVID-19 Infections in the Appalachian Region of West Virginia.

Purpose: The rapid spread of SARS-CoV-2, the virus that is responsible for causing COVID-19, has presented the medical community with another example of when convalescent plasma (CP) is still used today. The ability to standardize CP at the onset of a pandemic is unlikely to exist in a reliable and uniformly reproducible way. We hypothesized that CP of unknown strength given in a serial manner will promote health and reduce mortality in those inflicted with COVID-19. Methods: Participants were given up to 8 CP-units depending on their condition upon entry into the study and their response. Results: 102 out of 117 participants were given CP. The earlier a participant received CP corelated with survival (p = 0.0004). The number of CP-units given, throughout all the clinical severities, was not significant with outcomes, p = 0.3947. A higher number of CP-units given to the severe/critical participants (without biological immunosuppressants or restrictive lung disease) did correlate with survival p = 0.0116 (2.8 vs. 2 units). Lower platelets on admission corelated with mortality. Platelet levels increase correlated with CP infusions p < 0.0001. Conclusion: This study supports the serial use of CP of unknown strength based on clinical response for those infected with COVID-19. The use of 3-4 units of CP was found to be statistically significant for survival for severe and critical participants without restrictive lung disease and chronic biological immunosuppression. Increased platelet levels after CP infusions supports that CP is promoting overall health regardless of outcomes.

COVID-19 Infection in Patients with Humoral Immunodeficiency: A Case Series and Literature Review.

Background: The coronavirus 2019 disease (COVID-19) has infected many individuals worldwide and continues to pose a significant threat to those with weakened immune systems. The data evaluating the clinical outcomes of patients with humoral immunodeficiencies that contract COVID-19 is limited and conflicting. Objective: To describe the clinical outcomes of COVID-19 infections in patients with primary humoral immunodeficiency and compare results to current literature. Methods: We conducted a retrospective cohort review on 15 patients with a humoral immunodeficiency defined as Common Variable Immunodeficiency, Specific Antibody Deficiency, or unspecified hypogammaglobulinemia, who contracted COVID-19. Severity scores were determined to evaluate the clinical outcomes of these patients. Results: Of our 15-patient cohort, 33% of individuals with a humoral immunodeficiency infected with COVID-19 had moderate to severe disease, requiring hospitalization or resulting in death. COVID-19 mortality rate was found to be 7%. All 5 of our patients with severe COVID-19 infection had at least 1 comorbidity or risk factor. Conclusion: Within our cohort of humoral immunodeficient patients infected with COVID-19, we found a higher rate of moderate to severe COVID-19 infection and worse clinical outcomes, particularly in patients with comorbidities or risk factors.

Recurrent Bilateral Lime Disease in a Young Female- Case Report.

INTRODUCTION: Lime phytodermatitis, also known as margarita dermatitis, is a condition that results in a skin rash after sunlight exposure when handling certain plants. Misdiagnosis is common due to its resemblance to skin burns or allergic contact dermatitis. Detailed history and disease recognition is important to provide accurate treatment recommendations. CASE REPORT: A 32-year-old woman presented with a recurrent rash on her hands that would only occur in the summer months. She was previously misdiagnosed as allergic contact dermatitis. History revealed yearly vacations involving margaritas and squeezing lime into her drinks followed by exposure to sunlight. A presumptive diagnosis of lime phytodermatitis was made and she was advised to avoid contact with limes followed by exposure to direct sunlight. DISCUSSION: Lime phytodermatitis occurs after direct contact with lime and sunlight exposure. A phototoxic compound found in limes, Furocoumarin, has been implicated as a cause for lime disease. Detailed history is important in establishing a diagnosis of lime disease. Treatment is symptomatic with topical corticosteroids, avoidance of furocoumarin-containing objects, cold compresses, and subsequent UV exposure. CONCLUSION: We present the first case of recurrent, bilateral phytodermatitis in a 32-year-old woman following contact with limes and subsequent sunlight exposure in the summer months.

DNA-Binding domain mutations confer severe outcome at an early age among STAT1 gain-of-function patients.

BACKGROUND: STAT1 gain-of-function (GOF) is an immune dysregulatory disorder with poorly studied genotype-phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA-binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains. METHODS: Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non-DBD mutations. We subsequently re-analyzed mortality data from a large, previously-published 274-patient cohort by the International STAT1 GOF Study Group. RESULTS: While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non-DBD patients. Our re-evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations. CONCLUSION: We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early-onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.

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.

The Successful Vaccination of an IVIgG Naive CVID Patient with an mRNA COVID-19 Vaccine.

INTRODUCTION: Different subtypes of vaccines have been developed to help protect populations from COVID-19. Currently, three vaccines have been authorized by the United States Food and Drug Administration for emergency use to combat the COVID-19 pandemic. With COVID-19 vaccination rates increasing, it is important to know whether immunodeficient patients have the capacity to mount an immune response with the available vaccines. CASE REPORT: A 78-year-old female with Common Variable Immunodeficiency and anti-IgA antibodies who is naïve to IVIgG treatment responded positively to a COVID-19 mRNA vaccine. Successful seroconversion was proved by having positive COVID-19 spike protein IgG antibodies weeks after the vaccination. Her recent IgG, IgA, and IgM levels were all significantly reduced. Previously, she had no response to the polysaccharide pneumococcal vaccine, but did maintain titers afterTdap vaccination. DISCUSSION: Immunodeficient patients are a susceptible population during a pandemic. Unfortunately, there is a paucity of research on the infectivity, vaccination, and outcome of these patients during the COVID-19 outbreak. Our patient with CVID was able to respond to protein/toxoid vaccines, but did not respond to polysaccharide pneumococcal vaccine. After inoculation with an mRNA COVID-19 vaccine she was able to create COVID-19 spike protein IgG antibodies. CONCLUSION: We present a case of successful vaccination to COVID-19 by an mRNA vaccine in an IVIgG naïve CVID patient.

Two Cases of Well Controlled Chronic Spontaneous Urticaria Triggered by the Moderna COVID-19 Vaccine.

Chronic spontaneous urticaria (CSU, chronic idiopathic urticaria) is a clinical diagnosis characterized by recurrent urticaria of unknown origin, with or without angioedema, that occurs for six weeks or longer. Management of CSU includes a second-generation H1 antihistamine and/or elimination of exacerbating factors. If initial treatment is unsuccessful, trials of first generation H1 antihistamine, H2 blocking antihistamine, leukotriene-receptor antagonist, anti-inflammatory or immunosuppressive agents may be administered. Exacerbating factors include stress, environmental conditions, medications, physical stimuli, and infections. We report the first two cases of a COVID-19 vaccine triggered relapse of CSU that was previously well controlled on therapy.