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.

Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).

BACKGROUND: Primary antibody deficiencies (PADs) are the most frequent primary immunodeficiencies in human subjects. The genetic causes of PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum membrane. SEC61A1 is a target gene of spliced X-box binding protein 1 and strongly induced during plasma cell (PC) differentiation. OBJECTIVE: We identified a novel genetic defect and studied its pathologic mechanism in 11 patients from 2 unrelated families with PADs. METHODS: Whole-exome and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B-cell differentiation and survival. RESULTS: We investigated 2 families with patients with hypogammaglobulinemia, severe recurrent respiratory tract infections, and normal peripheral B- and T-cell subpopulations. On in vitro stimulation, B cells showed an intrinsic deficiency to develop into PCs. Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in cotranslational protein translocation, and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response in multiple myeloma cell lines. CONCLUSION: We describe a monogenic defect leading to a specific PC deficiency in human subjects, expanding our knowledge about the pathogenesis of antibody deficiencies.

Association between α1-antitrypsin and bronchiectasis in patients with humoral immunodeficiency receiving gammaglobulin infusions.

BACKGROUND: In patients with humoral immunodeficiency, the progression of bronchiectasis has been known to occur despite adequate gammaglobulin therapy and in the absence of recurrent infections. This observation suggests that factors other than gammaglobulin replacement might play a part in the prevention of lung damage in this population. α1-Antitrypsin deficiency can be associated with bronchiectasis, a chronic inflammatory lung disease. The protective levels of α1-antitrypsin and phenotype in preventing bronchiectasis have not been thoroughly studied in the immunodeficient population. We hypothesized that patients with humoral immunodeficiencies on gammaglobulin infusions and bronchiectasis have lower median levels, but not necessary "classically" deficient levels, of α1-antitrypsin compared with those without bronchiectasis. OBJECTIVE: To compare levels of α1-antitrypsin in subjects with immunodeficiency with and without bronchiectasis. METHODS: One hundred ninety-two subjects with humoral immunodeficiencies requiring gammaglobulin therapy had their α1-antitrypsin levels and phenotype screened. High-resolution computed tomograms of the chest of participants were obtained and compared with α1-antitrypsin levels and phenotype. RESULTS: Participants without bronchiectasis were found to have higher median levels of α1-antitrypsin than those with bronchiectasis (P = .003). Furthermore, subjects with improving or resolved bronchiectasis since initiating gammaglobulin therapy had higher median levels of α1-antitrypsin than those with worsening bronchiectasis (P = .004). The prevalence of the α1-antitrypsin PiZZ mutation was higher than in the general public (P < .0001). CONCLUSION: Median α1-antitrypsin levels and phenotype in subjects were associated with humoral immunodeficiency and their bronchiectasis status. Prospective studies might be necessary to determine possible benefits of augmentation therapy. This study supports the idea that what is considered a "normal or protective" α1-antitrypsin range might need to be refined for patients with humoral immunodeficiency on gammaglobulin therapy.

Successful hematopoietic cell transplantation in a patient with X-linked agammaglobulinemia and acute myeloid leukemia.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19(+) B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient's leukemia.

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.

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.

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.

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.

Daily Integrated Care Conferences to Reduce Length of Hospital Stay for Patients With Chronic Obstructive Pulmonary Disease.

CONTEXT: Inefficiencies in care coordination-specifically, the lack of an effective method of communication among multiple health care professionals-often leads to an unnecessary increase in length of hospital stay. OBJECTIVE: To determine whether daily integrated care conferences (ICCs) would significantly reduce the length of stay for patients with chronic obstructive pulmonary disease (COPD) exacerbation. METHOD: Patients with COPD exacerbation were selected for the study using electronic medical records from 2 osteopathic community hospitals located in northeastern Ohio. One hospital used daily ICCs and the other hospital did not use daily ICCs. The average length of stay for patients at each hospital was retrospectively investigated. RESULTS: A total of 1683 patients with COPD exacerbation were selected. The mean (SD) length of stay in the hospital with daily ICCs was 3.37 (2.89) days compared with 5.55 (3.99) days in the hospital without daily ICCs (P<.0001). At the hospital with daily ICCs, patients aged 40 to 69 years had a 67% shorter hospital stay and patients aged 70 to 99 years or older had a 36% shorter length of stay compared with patients at the hospital without daily ICCs. CONCLUSION: Daily integrated care conferences significantly reduced the length of stay for patients with COPD exacerbation at an osteopathic community-based hospital. Implementing daily ICCs may make current health care services and coordinated care more efficient, resulting in decreased costs and length of stay for patients with COPD exacerbation.

Fenugreek Anaphylaxis in a Pediatric Patient.

Fenugreek (Trigonella foenum-graecum) is a food product that belongs to the Leguminosae family along with other legumes. It has been used in India, Greece, and Egypt for culinary and medical purposes since ancient times, and today, fenugreek is used for flavoring foods, dyes, and drugs throughout the world. Many members of the Leguminosae family have been associated with allergies including soybean, green pea, and peanut. Fenugreek is also included in this family and may result in allergic reactions. Two cases of anaphylaxis have been described in children after ingestion of curry and pastes that contain fenugreek, although the true nature of the causative agent was unclear. We report the first case of fenugreek anaphylaxis in a pediatric patient defined by skin testing, immunoglobulin E ImmunoCAP assays, and clear ingestion.

Stratification of peanut allergic murine model into anaphylaxis severity risk groups using thermography.

Murine models are readily used to investigate mechanisms potentially involved in anaphylaxis. Determining successful sensitization with current methods remain potentially lethal, invasive, expensive and/or cumbersome. Here we describe the use of thermography to read intradermal testing to detect peanut allergic sensitization in the murine model and as a first time sensitive tool for anaphylaxis stratification. The relative wheal size in the thermal image can be used to stratify anaphylaxis severity risk groups prior to a challenge. This screening method is nonlethal, inexpensive, minimally invasive and can be carried out expeditiously.

Type 1 Kounis syndrome in a patient with idiopathic anaphylaxis.

Anaphylactic insults that cause cardiovascular signs and symptoms have been defined as Kounis syndrome, which has been associated with specific triggered anaphylactic reactions. Kounis syndrome has not been described in patients with no evidence of coronary artery disease (type I Kounis) in a scenario of idiopathic anaphylaxis. We reported a case of a 65-year-old white woman with no evidence of coronary artery disease who experienced two myocardial infarctions on separate occasions attributable to idiopathic anaphylaxis.