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.

Corneal Ulcers with NOD2 Mutations Presenting with Mixed Syndromic Phenotype.

PURPOSE: To report a case of corneal ulcers in a patient with NOD2 mutations unique to but phenotypically resembling well-characterized syndromic phenotypes like Blau syndrome. OBSERVATION: A 25-year-old female with a medical history of type I diabetes mellitus, Asperger syndrome, and neuropathy presented with bilateral corneal ulcers. Her visual acuity was 20/200 OU. Macular edema was identified OS, and posterior synechiae OS suggested a history of anterior uveitis.Genetic testing confirmed NOD2 mutations, and her tear film was positive for matrix metallopeptidase 9. Recent intravenous immunoglobulin therapy improved her neuropathy, and an aggressive regimen of erythromycin ointment and lubrication has improved her ophthalmic symptoms. CONCLUSION AND IMPORTANCE: This case advances our understanding of NOD2's role in regulating inflammatory processes of the eye. In addition to precipitating uveitis, patients with these mutations may also be at increased risk of developing corneal pathology related to their reduced capacity to moderate inflammatory processes.

Evaluation and treatment of rhinosinusitis with primary antibody deficiency in adults: Evidence-based review with recommendations.

BACKGROUND: There is clear evidence that the prevalence of primary antibody deficiency (PAD) is higher in patients with recurrent and chronic rhinosinusitis (CRS) than in the general population. The purpose of this multi-institutional and multidisciplinary evidence-based review with recommendations (EBRR) is to thoroughly review the literature on rhinosinusitis with PAD, summarize the existing evidence, and provide recommendations on the evaluation and management of rhinosinusitis in patients with PAD. METHODS: The PubMed, EMBASE, and Cochrane databases were systematically reviewed from inception through August 2022. Studies on the evaluation and management of rhinosinusitis in PAD patients were included. An iterative review process was utilized in accordance with EBRR guidelines. Levels of evidence and recommendations on the evaluation and management principles for PAD were generated. RESULTS: A total of 42 studies were included in this evidence-based review. These studies were evaluated on incidence of PAD in rhinosinusitis patients, incidence of rhinosinusitis in PAD patients, and on the different treatment modalities used and their outcome. The aggregate quality of evidence was varied across reviewed domains. CONCLUSION: Based on the currently available evidence, PAD can occur in up to 50% of patients with recalcitrant CRS. Despite the presence of multiple studies addressing rhinosinusitis and PAD, the level of evidence supporting different treatment options continues to be lacking. Optimal management requires a multidisciplinary approach through collaboration with clinical immunology. There is need for higher-level studies that compare different treatments in patients with PAD and rhinosinusitis.

Outcome of Immunoglobulin Replacement Therapy in Adults With Rhinosinusitis.

OBJECTIVE: To evaluate the outcome of immunoglobulin (IG) replacement therapy in adults with rhinosinusitis and primary humoral immunodeficiency disorders (PID). STUDY DESIGN: Retrospective cohort study. METHODS: Retrospective chart review of adult (18 years and older) patients who were diagnosed with PID and had the diagnosis of recurrent acute rhinosinusitis (RARS) and chronic rhinosinusitis (CRS) and who are on IG replacement therapy. Demographic data, associated conditions, and duration of treatment were reviewed. Number of yearly sinus infections, sinus CT Lund-Mackay (LM) score, and need for functional endoscopic sinus surgery (FESS) were reviewed before and after starting IG therapy. RESULTS: Fifty-eight patients were included. Average age was 52 years (18-79 years). About 74% were female. Thirty patients (51.7%) had common variable immunodeficiency (CVID), 18 (31.1%) had hypogammaglobulinemia, and 10 (17.2%) had specific antibody deficiency (SAD). About 79% of patients had allergic rhinitis and 74% had asthma. Pretreatment LM score was 7.6 (±2.2, range of 0-24) compared to posttreatment score of 3.5 (±1.3, range of 0-16) (P = .01). Eleven patients (19%) had FESS pretreatment compared to only two patients (3.4%) requiring ESS after starting treatment on IG therapy (P = .004). Prior to starting IG therapy, five patients (8.6%) had more than 10 sinus infections per year, 33 patients (56.9%) had 5 to 10 infections, and 20 patients (34.5%) had 1 to 5 infections per year. After starting on IG, 34 patients (58.6%) had no infections reported anymore (P < .001), and 24 patients (41.4%) had only 1 to 5 infections reported per year CONCLUSION: IG therapy is a promising treatment option for recurrent rhinosinusitis in patients with PID. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:732-736, 2022.

A 14-Year-Old Female With Several-Week History of Rash, Worsening Diffuse Arthralgias, and Fevers.

Macrophage activation syndrome (MAS) as the initial presentation of systemic juvenile idiopathic arthritis (sJIA) is an uncommon and difficult diagnosis to ascertain. However, it remains critical to establish the diagnosis since MAS is a potentially life-threatening systemic inflammatory condition. Prompt recognition can lead to early initiation of treatment with corticosteroids and overall improved outcomes. Here, we present a case of a 14-year-old female with MAS as the initial manifestation of sJIA.

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 Recurrence Without Seroconversion in a Patient With Mannose-Binding Lectin Deficiency.

INTRODUCTION: The SARS-CoV-2 virus has infected more than 63,000,000 people worldwide after emerging from Wuhan, China in December 2019. This outbreak was declared a Public Health Emergency in January 2020, and a pandemic in March. While rare, reinfection with the virus has been reported on multiple occasions. CASE PRESENTATION: We present a case report of an individual with mannose binding lectin deficiency who tested positive on two separate occasions, months apart, and did not develop IgG antibodies to SARS-CoV-2. This patient Is a 30- year-old female healthcare worker with a past medical history of ITP, pancreatitis, GERD, anxiety and recurrent pneumonia. She presented in March 2020 with fever, nasal congestion, and dry cough. She was diagnosed with COVID-19 in March 2020, via PCR through employee health. She was treated with a course azithromycin and hydroxychloroquine. Symptoms resolved, however in June 2020, SARS-CoV-2 IgG antibodies were negative. Seven months later in October, she once again developed symptoms which were milder. She was found to have a decreased level of mannose binding lectin, normal immunoglobulin levels, and normal streptococcus pneumonia IgG antibodies. On immune work-up after recovery, she was found to have a decreased level of mannose binding lectin (<50 ng/mL), normal immunoglobulin levels, and protective Streptococcus pneumoniae IgG antibodies with appropriate vaccine response. Her SARS-CoV-2 IgG returned back as positive 8 weeks after her second infection. DISCUSSION: This case illustrates that patients with mannose binding lectin deficiency may be at greater risk of re-infection than the general population.

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.

A case series: Association of anaphylaxis with a significant decrease in platelet levels and possible secondary risk of thrombosis.

INTRODUCTION: Anaphylaxis is a life threatening systemic inflammatory process that share mediators involved in the coagulation cascade. Platelet activating factor, known to increase platelet aggregation, has also been implicated as an important mediator of anaphylaxis. Although other inflammatory reactions are associated with an increased risk of thrombosis, anaphylaxis is currently not reported as one of them. Furthermore the role platelets may have in the perianaphylaxis period is not well understood. We here in present a retrospective case series of three patients that had platelet aberrations suggestive of PAF involvement and clinically significant thrombosis in close relationship with anaphylaxis. OBJECTIVE: To investigate platelet response before and after anaphylaxis and indirect observation evidence of platelet activating factors involvement with possible increased risk of thrombosis. METHODS: A retrospective investigation into medical records including medication administrations times, laboratory, and radiology results. Platelet levels pre- and post- anaphylaxis were statistically analyzed. RESULTS: Case 1, a 44 year old man had an anaphylactic reaction shortly after envenomation and subsequently suffered an acute infarction with thrombus in a cerebral artery. Case 2 is a 49 year old man with idiopathic anaphylaxis who developed a deep vein thrombosis after a protracted anaphylaxis event. Case 3 involved an 18 year old female with acute myeloid leukemia was found to have a thrombus in the celiac trunk following anaphylaxis. A paired two-tailed Wilcoxon test on the subjects pre and post anaphylactic platelet levels resulted in a overall P < 0.0001. CONCLUSIONS AND CLINICAL RELEVANCE: These three cases illustrate the potential role platelets may have in anaphylaxis and possible increased secondary risk for the development of thrombosis. Larger studies are required to determine incidence and risk factors for blood clots following anaphylaxis in order to provide management or screening recommendations.

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.

Fetal response to intramuscular epinephrine for anaphylaxis during maternal penicillin desensitization for secondary syphilis.

Penicillin desensitization is indicated in pregnant patients with severe allergies to penicillin with syphilis. The immediate effects of intramuscular epinephrine on the fetus during desensitization remain unreported. We describe a pregnant patient with secondary syphilis and penicillin allergy who developed anaphylaxis during penicillin desensitization. Anaphylaxis resolved after administration of intramuscular epinephrine. Throughout the procedure, continuous electronic fetal monitoring showed a stable fetus without a decrease in variability, tachycardia, decelerations, or signs of fetal distress. This case showed that intramuscular epinephrine is effective in treatment of anaphylaxis in a pregnant patient with little to no immediate effects on the fetus.

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.