SARS-COV-2 infections in inborn errors of immunity: A single center study.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). One of the main topics of conversation in these past months in the world of immunology has been the issue of how patients with immune defects will fare if they contract this infection. To date there has been limited data on larger cohorts of patients with Inborn Errors of Immunity (IEI) diagnosed with COVID-19. Here, we review the data of COVID-19 infections in a single center cohort of 113 patients from the Mount Sinai Immunodeficiency program, who had 132 infections between January 2020 and June 2022. This included 56 males and 57 females, age range 2 - 84 (median 42). The mortality rate was 3%. Comparison between admitted patients revealed a significantly increased risk of hospitalization amongst the unvaccinated patients, 4% vaccinated vs 40% unvaccinated; odds ratio 15.0 (95% CI 4.2 - 53.4; p <0.00001). Additionally, COVID anti-spike antibody levels, determined in 36 of these patients post vaccination and before infection, were highly variable.

Patient perspectives on penicillin allergy and testing.

Background: Most patients who report penicillin allergy are found to tolerate penicillin later in life. Few studies have examined patients' understanding and beliefs about penicillin allergy and testing. Evaluating patients' perspectives may help identify ways to improve patient education and increase testing to de-label those who can tolerate penicillin. Objective: To better understand patient perspectives on penicillin allergy testing and to identify whether patient characteristics and beliefs impact completion of testing. Methods: Patients who were visiting our allergy clinics and had documentation of a penicillin allergy in the electronic medical record (EMR) were approached to complete a survey with regard to their reaction history and knowledge and/or perspectives about penicillin allergy and testing. Eighty-eight patients completed the survey, and their medical records were reviewed to collect results of penicillin testing. Results: Fewer than half of the patients (45.5%) who had EMR-documented penicillin allergy reported awareness that testing for penicillin allergy is available. Awareness of penicillin allergy testing was significantly associated with completion of testing, whereas other patient characteristics, such as education, income, and distance to the hospital, were not. Patients who scheduled a return visit for testing at the time of their initial visit were significantly more likely to follow through with testing. Most patients were interested in penicillin testing. For patients who were not interested, the most frequently cited reason was fear of adverse effects of testing. Conclusion: Among the patients who carried a penicillin allergy label, those who were aware of penicillin allergy testing were more likely to complete testing, and ease of scheduling contributed to higher rates of testing completion. Fear about adverse effects from testing was the most reported barrier. Our findings emphasized the importance of increasing awareness of the availability and safety of penicillin testing through patient education and collaboration with other specialties.

Overcoming challenges to removing inappropriate penicillin allergy labels: A quality improvement report.

Over 3 months, we provided monthly education to internal medicine residents and distributed resources regarding penicillin-allergy history taking. Allergy information in the electronic record was updated more often during the intervention compared to the period before the intervention (16.1% vs 10.9%; P = .02). Education and interdepartmental collaboration have the potential to affect provider behavior.

Autoimmunity in common variable immunodeficiency.

OBJECTIVE: Common variable immunodeficiency (CVID) is a primary immunodeficiency that is clinically heterogeneous, characterized by both infectious and noninfectious complications. Although the hallmark of disease presentation is commonly a history of recurrent sinopulmonary infections, autoimmunity and noninfectious inflammatory conditions are increasingly associated with CVID. DATA SOURCES: A comprehensive literature search using PubMed of basic science and clinical articles was performed. STUDY SELECTIONS: Articles discussing the association of autoimmunity with primary immunodeficiency, specifically CVID, were selected. RESULTS: The most common autoimmune conditions are cytopenias, including immune thrombocytopenia purpura and hemolytic anemia, but organ-specific autoimmune/inflammatory complications involving the gastrointestinal, skin, joints, connective tissue, and respiratory tract. In most cases, immunoglobulin replacement therapy does not ameliorate or treat these inflammatory complications, and additional immunomodulatory treatments are needed. CONCLUSION: Mechanisms producing these conditions are poorly understood but include cytokine and cellular inflammatory pathways, and loss of tolerance to self-antigens through the multiple signaling molecules and pathways common to tolerance and immune deficiency.

Gastrointestinal Manifestations and Complications of Primary Immunodeficiency Disorders.

Gastrointestinal (GI) involvement can be the presenting disease manifestation in patients with primary immunodeficiency disorders (PIDs). Infections and noninfectious diarrhea are frequent manifestations; however, malignancy and inflammatory and autoimmune-related GI diseases are also described. GI symptoms and disease seen in association with PIDs can mimic other diseases but are often resistant to conventional treatments owing to alternate disease mechanisms. Despite the advances in treatments for these conditions, therapy for immunodeficiency-related GI disease is often empiric.

Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma.

The immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide (IMiDs) are an important component of myeloma treatment; one of six available drug classes for this incurable disease. Rash is a frequent side effect of IMiDs, particularly lenalidomide, often leading to treatment discontinuation. We retrospectively reviewed 52 patients (7.2% of patients seen during that time) with IMiD associated at a median of 3 weeks after exposure. Nearly all rashes were morbilliform, and 45% of evaluable rashes were grade 3-4 by NCI-CTCAE criteria. IMiDs were initially held in 33 patients (62%), and 25% received a short course of higher dose steroids. Seventy-nine percent of patients were reexposed to the same IMiD, often with dose reduction, and 57% were switched from weekly dexamethasone to thrice-weekly prednisone. Ninety-three percent of patients reexposed to the same IMiD with these interventions were able to tolerate and continue treatment, and only 14% had rash with reexposure, predominantly grade 1-2.

High-dose infliximab therapy in Crohn's disease: clinical experience, safety, and efficacy.

BACKGROUND: Inadequate response to infliximab [IFX] therapy in Crohn's disease [CD] may necessitate dose intensification. We evaluated safety and efficacy of high-dose IFX [HD IFX] [greater than 10mg/kg every 8 weeks] in CD and characterized predictors of response to HD IFX intensification. METHODS: Electronic medical records were queried for CD patients between 2010 and 2012 who received HD IFX and were reviewed for history, medications, laboratory data, efficacy, and safety. RESULTS: In all, 86 patients received HD IFX for CD at doses between 10 and 22.5mg/kg every 4 to 7 weeks. In early HD IFX therapy [week 1-16], 25.8% and 59.1% experienced full and partial response, respectively. In later HD IFX therapy [week 38-100], 27.9% and 34.4% experienced full and partial response, respectively. Median serum IFX levels increased from 1.7 to 7.3 µ/mL [p = 0.017], and median C-reactive protein [CRP] values decreased from 20.5 at baseline to 4.7 mg/L after 16 weeks [p < 0.001]. Baseline CRP values were significantly elevated in the group that responded at 1-16 weeks compared with nonresponders [22.0 vs 3.5mg/L, p < 0.01]. HD IFX therapy was discontinued in 26% and 7.3% of patients for inadequate response and adverse events, respectively. Eleven cases of infection required hospitalization for a serious infection rate of 7.41 events per 100 patient-years. CONCLUSIONS: HD IFX therapy may benefit CD patients who have failed standard doses of IFX. HD IFX therapy may be associated with more serious adverse events compared with standard dosing. Baseline CRP value may predict clinical response to HD IFX.

Prevalence and characteristics of reported penicillin allergy in an urban outpatient adult population.

Penicillin allergy remains the most common drug allergy, with a reported prevalence of 10% in the United States. Epidemiology of penicillin allergy in outpatient populations is relatively scarce. This study sought to determine the prevalence and characteristics of reported penicillin allergy in an urban outpatient population and to identify trends in clinical evaluation and management from a tertiary center serving a large inner-city population. A retrospective review of electronic medical records was performed of adult patients seen in the Internal Medicine Associates Clinic of Mount Sinai Hospital between January 31, 2012, and July 31, 2012. Medical records were selected based on the documentation of penicillin in patient's allergy section. Of the 11,761 patients seen in the clinic, 1348 patients (11.5%) reported a history of penicillin allergy. The most common allergic reactions were rash (37%), unknown/undocumented (20.2%), hives (18.9%), swelling/angioedema (11.8%), and anaphylaxis (6.8%). There was an increased prevalence of penicillin allergy in female patients compared with male patients (odds ratio [OR] = 1.82; 95% CI = 1.60, 2.08; p < 0.0001), and there were significantly fewer Asians with penicillin allergy compared with Caucasians (OR = 0.51; 95% CI = 0.32, 0.83; p = 0.007). However, only 78 (6%) of the patients reporting penicillin allergy had a referral to an allergy specialist. Overall, improved referral to an allergist will help to identify patients who have penicillin allergy requiring avoidance.

Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency.

Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists therefore must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency.

Normal response to vaccines in inflammatory bowel disease patients treated with thiopurines.

BACKGROUND: Thiopurines are considered immunosuppressive agents and may be associated with an increased risk for infections. However, few inflammatory bowel disease (IBD) patients are appropriately vaccinated, and data on their ability to mount an immune response are vague. We evaluated the effects of the thiopurines, azathioprine (AZA) and 6-mercaptopurine (6-MP), on cellular and humoral immune responses in IBD patients. METHODS: A prospective clinical investigation was conducted on IBD patients referred for thiopurine treatment. Immune competence was evaluated by assessing lymphocyte counts and phenotype, response to mitogen and antigen stimulation, immunoglobulin levels, and response to pneumococcal and tetanus vaccines (before treatment, week 0), and to Haemophilus influenza type b vaccine (at week 24). RESULTS: Thirty-one Crohn's disease and 12 ulcerative colitis patients who completed at least 24 weeks of therapy were included. The posttherapy average 6-MP dose was 1.05 ± 0.30 mg/kg, and white blood cell counts had decreased significantly from baseline values (P < 0.002). The posttreatment response to mitogens and antigens and the immunoglobulin levels were unchanged. Responses to vaccines were normal both in thiopurine-naïve and thiopurine-treated patients, suggesting that these patients were immunologically intact while on thiopurine therapy and capable of generating normal immune responses in vivo. CONCLUSIONS: There is no evidence for any intrinsic systemic immunodeficiency in IBD patients. Thiopurines at the doses used for treating IBD showed no significant suppressive effect on the systemic cellular and humoral immune responses evaluated. Thiopurine-treated IBD patients can be safely and efficiently vaccinated.

Characterization of immunologic defects in patients with common variable immunodeficiency (CVID) with intestinal disease.

BACKGROUND: Common variable immunodeficiency (CVID) is a heterogeneous disorder commonly presenting with recurrent sinopulmonary infections. In all, 6%-10% of CVID patients develop an inflammatory bowel disease (IBD)-like disorder, making these patients a unique population to investigate immune-mediated gastrointestinal disease. This study examined whether defects in peripheral and/or intestinal lymphocytes are involved in disruption of the intestinal mucosa in CVID patients with inflammatory intestinal diseases. METHODS: Peripheral blood (PB) T cells from healthy controls; CD or UC; CVID; and CVID with IBD were stimulated for 48 hours with anti-CD3+CD28 or phytohemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA); cytokine production was measured by enzyme-linked immunosorbent assay (ELISA). Cytokine expression from unstimulated lamina propria lymphocytes (LPLs) was compared by real-time polymerase chain reaction (PCR). Immunohistochemistry of mucosal biopsies was performed. Cell populations were quantified by morphometry. RESULTS: CVID/IBD PB T cells stimulated by anti-CD3+CD28 had trends for reduced IL-2, IL-10, IFN-γ, and TNF-α compared to controls. These differences were not apparent following stimulation by PHA/PMA. Constitutive production of inflammatory cytokines by LPLs was not detected. Histologically, CVID patients had reduced/absent plasma cells with reductions in intestinal IgM and IgA. CVID patients with and without gastrointestinal (GI) disease exhibited increased CD3+ T cells, specifically CD8+, in the colon compared to normal and IBD controls, suggesting immune dysregulation. CONCLUSIONS: Intestinal inflammation in CVID patients with IBD-like disease may be mediated by abnormal cytokine production through a T-cell receptor-mediated pathway. However, the variability observed suggests multiple, rather than singular, mechanisms are involved. Histologic features such as reduced intestinal plasma cells and lack of intestinal immunoglobulins may be useful markers in diagnosing CVID in a patient with GI disease refractory to conventional therapies.

Innate and adaptive immunosenescence.

OBJECTIVE: To review the effect of increasing age on the immune system and some of its clinical implications. DATA SOURCES: MEDLINE and PubMed searches were performed cross-referencing the keywords immunosenescence, aging, and immunity. Articles were reviewed for additional citations. STUDY SELECTION: Articles were reviewed and selected based on relevance to subject matter. RESULTS: The study of immunosenescence is complex and not completely understood. Aging affects both the innate and adaptive arms of the immune response. With increased age, there may be a decrease in phagocytosis, alteration of cellular migration, changes in cell populations and numbers, and a decreased ability to produce specific antibodies. Clinically, these changes potentially increase morbidity and mortality in elderly individuals through an increased rate of infections, malignancy, and autoimmunity. CONCLUSIONS: The process of aging is accompanied by diverse changes in immunity. Several therapeutic approaches are under investigation, including cytokine therapy, hormonal replacement, antioxidant supplementation, and caloric restriction, to attenuate or potentially reverse immunosenescence.

Gastrointestinal manifestations in primary immune disorders.

The gastrointestinal tract is the largest lymphoid organ in the body containing T and B lymphocytes, macrophages, and dendritic cells. Despite the fact that these cells are constantly confronted with antigen primarily in the form of food and bacteria, immune responses in the gut are tightly regulated to maintain homeostasis. Without this balance of active immunity and tolerance, mucosal inflammation may ensue, and manifest as Crohn's disease, ulcerative colitis, pernicious anemia, or celiac sprue. Therefore, it is not unreasonable that inflammatory diseases of the gut are commonly encountered in patients with primary immune deficiencies. The exact pathogenesis of gastrointestinal diseases in the setting of primary immunodeficiency remains unknown, however, both humoral and cell-mediated immunity appear to play a role in preventing intestinal inflammation. Patients presenting with atypical gastrointestinal disease and/or failure to respond to conventional therapy should be evaluated for an underlying primary immune disorder in order to initiate appropriate treatment, such as immunoglobulin or in more severe cases bone marrow transplantation, to prevent long term complications.