Concurrence of familial Mediterranean fever and Behçet’s disease: a case report and review of the literature

Abstract Background Familial Mediterranean fever and Behçet’s disease are distinct disorders that are prevalent in the Mediterranean and Middle Eastern populations. They are characterized by unprovoked inflammatory episodes caused by overexpression of proinflammatory cytokines. Although reported previously, the overlapping presentation of familial Mediterranean fever and Behçet’s disease remains uncommon. Case presentation A 46-year-old Lebanese–Canadian man who presented with recurrent oral and genital ulcers, polyarticular synovitis, ocular swelling, recurrent infections, and fevers was later found to have heterozygous mutations of pathogenic MEFV c.2080A > G (p. Met 694Val) and c.2082G > A (p.Met694IIe) genes indicating familial Mediterranean fever. He was treated with prednisone, colchicine, and azathioprine, with inadequate symptoms control. Treatment was complicated by recurrent infections. Conclusions Our case contributes to the growing literature demonstrating the presentation of predominantly Behçet’s disease-like features in the setting of diagnosis of familial Mediterranean fever. These findings emphasize that clinicians should be aware that patients with familial Mediterranean fever may present with Behçet’s disease-like clinical manifestations

Shift in Epidemiology of Cryptococcal Infections in Ottawa with High Mortality in Non-HIV Immunocompromised Patients

Cryptococcus neoformans is a fungus that can cause life-threatening infections. While human immunodeficiency virus (HIV)-positive status historically had the highest risk for cryptococcal infection and was associated with high mortality rates, there have been changes in HIV treatment and the epidemiology of other acquired immunodeficiencies, such as hematological malignancies. We conducted a retrospective case series analysis of patients who had cryptococcal infections documented at the Ottawa Hospital from 2005 to 2017. The Ottawa Hospital is a tertiary care hospital and provides complex care such as chemotherapy and transplantations. There were 28 confirmed cryptococcal infections. The most common underlying condition associated with cryptococcal infection was hematological malignancy (n = 8.29%), followed by HIV (n = 5.18%) and solid organ transplantation (n = 4.14%). Furthermore, while there was a decrease in the number of cryptococcal infections in HIV patients after 2010 (four to one case), the number of cases in non-HIV immunocompromised patients increased from four in the years 2005–2010 to fourteen in 2011–2017. There were nine cryptococcal-attributable deaths. The case fatality rate was highest among patients with underlying hematological malignancies (63%), followed by solid organ transplant (50%) and HIV patients (20%). In conclusion, this study showed that there may be an epidemiological shift of cryptococcal infection in Ottawa. Additionally, infections may be associated with a worse prognosis in patients with a hematological malignancy and solid organ transplant than in patients with HIV infection in the modern era. Better prevention and/or treatment is warranted for high-risk populations

Monoclonal antibodies as COVID-19 prophylaxis therapy in immunocompromised patient populations

Objectives: The objective of this review was to examine the latest literature regarding the effectiveness of monoclonal antibodies as COVID-19 prophylaxis therapy for immunocompromised patient populations. Methods: Literature review of published real-world and randomized control trials (RCTs) from 2020 to May 2023. Results: COVID-19 is highly transmissible with potentially serious health outcomes, underscoring the need for effective prevention and treatment strategies. Vaccines are highly effective at preventing COVID-19 for the general population; however, efficacy is often impaired in immunocompromised patients given insufficient response to initial exposure and/or memory for secondary exposures. Some individuals may also have contraindications to vaccination. As such, additional protective measures are needed to bolster the immune response in these populations. Monoclonal antibodies have been effective at bolstering immune system responses to COVID-19 among immunocompromised patients; however, they are proving ineffective against the most recent Omicron strains (BA.4 and BA.5). Conclusion: Several studies have investigated the efficacy of monoclonal antibodies as pre- and post-prophylaxis for COVID-19. Historical evidence is promising; however, new variants of concern are proving challenging for currently available regimens

Cutaquig^® Is Well Tolerated in Immunodeficient Patients Who Did Not Tolerate Other Subcutaneous Immunoglobulin Products

Objective: Subcutaneous immunoglobulin (SCIG) treatment is generally tolerable, but some patients may experience adverse events to one or more SCIG products. We investigated whether 16.5% Cutaquig® treatment offered a tolerable and safe alternative treatment for immunodeficient patients. Methods: A one-year prospective cohort study was conducted at a single center in Ottawa, Canada. Adult immunodeficient patients who reported previous intolerability, adverse events, or other difficulty to other 20% SCIG product(s) were recruited to start on 16.5% Cutaquig®. Treatment tolerability, safety, and quality of life were observed and described. Results: Seven out of ten patients tolerated Cutaquig®. There were no serious or severe adverse events related to the treatment. Three moderate infections were reported (two urinary tract infections and one injection site infection). The mean serum IgG level at the end of the study was comparable to baseline levels recorded before the study: 9.6 ± 4.5 vs. 7.6 ± 4.3 g/L, p = 0.07. The overall health and health domain changes in the SF-36 and quality of life tests using the EQ visual analog scale improved by 21.5% (p = 0.38), 16.7% (p = 0.29), and 7.7% (p = 0.23), respectively. Conclusions: Cutaquig® may be used as an alternative treatment option for patients who did not tolerate 20% SCIG products

Differential immunomodulation of T-cells by immunoglobulin replacement therapy in primary and secondary antibody deficiency.

Patients with primary or secondary antibody deficiency (PAD or SAD) are at increased risk of recurrent infections that can be alleviated by immunoglobulin replacement therapy (IRT). In addition to replenishing antibody levels, IRT has been suggested to modulate immune response in patients with antibody deficiency. Although both commonly treated with IRT, the underlying causes of PAD and SAD vary greatly, suggesting differential modulation of T-cell function that may lead to different responses to IRT. To explore this, peripheral blood mononuclear cells (PBMCs) were sampled from 17 PAD and 14 SAD patients before and 2-10 months after initiation of IRT, and analyzed for changes in T-cell phenotype and function. Proportions of CD4, CD8, Treg, or memory T-cells did not significantly change post-IRT compared to pre-IRT. However, we report distinct modulation in T-cell function between PAD and SAD patients post-IRT. Upon α-CD3/CD28 stimulation, proportion of IFN-γ+ CD4 and CD8 T-cells increased in SAD (p = 0.005) but not PAD patients post-IRT compared to baseline. Interestingly, total T-cell proliferation was reduced post-IRT in both PAD and SAD patients, although the reduction in proliferation was primarily due to reduced CD4 T-cell proliferation in PAD (p = 0.025) in contrast to CD8 T-cells in SAD (p = 0.042). In summary, even though IRT provides patients with passive humoral immunity-mediated protection in PAD and SAD, our findings suggest that IRT immunomodulation of T-cells is different in T-cell subsets depending on underlying immunodeficiency

Incidence Rate of Post-Kidney Transplant Infection: A Retrospective Cohort Study Examining Infection Rates at a Large Canadian Multicenter Tertiary-Care Facility

Background: Reducing post-operative infections among kidney transplant patients is critical to improve long-term outcomes. With shifting disease demographics and implementation of new transplantation protocols, frequent evaluation of infection rate and type is necessary. Objective: Our objectives were to assess the incidence and types of post-operative infections in kidney transplant recipients at a large tertiary-care facility and determine sample sizes needed for future intervention trials. Design: Retrospective cohort study. Setting: The Ottawa Hospital, Ottawa, Ontario. Patients: Adult kidney transplant patients, N = 142. Measurements: Demographic data, transplant protocol, infections up to 2 years following transplantation. Methods: Infections within 2 years following transplantation in all kidney transplant recipients between January 2011 and December 2012 were reviewed. Sample sizes were determined using all-cause infection rates and infection-free survival data. Results: Of 142 patients, 44 (31.0%) had at least one infection. The incidence of infection was 36.2 per 100 patient-years by 2 years post-transplant. A total of 32 (22.5%) patients had 56 infection-related hospitalizations with 73.2% occurring in the first year. In the first 2 years, urinary tract infections had the highest incidence (18.1 per 100 patient-years) followed by skin (3.9 per 100 patient-years), cytomegalovirus (3.9 per 100 patient-years), and bacteremia (3.9 per 100 patient-years). Results indicate that 206 patients per study arm would be needed to show a 30% reduction in the 2-year incidence of infection post-transplantation. Limitations: Infection rates may be slightly underestimated due to the relatively short 2-year follow-up; however, the highest infection-risk period was captured within this time frame. Conclusions: Infections post-kidney transplant are still common, particularly urinary tract infections. They are associated with significant morbidity and hospitalization. Given the feasible sample sizes calculated in this study, intervention trials are indicated to further reduce infection rates within the first 2 years post-kidney transplantation

Simultaneous engineering of natural killer cells for CAR transgenesis and CRISPR-Cas9 knockout using retroviral particles

Natural killer (NK) cells are potent cytotoxic innate lymphocytes that can be used for cancer immunotherapy. Since the balance of signals from activating and inhibitory receptors determines the activity of NK cells, their anti-tumor activity can be potentiated by overexpressing activating receptors or knocking out inhibitory receptors via genome engineering, such as chimeric antigen receptor (CAR) transgenesis and CRISPR-Cas9-mediated gene editing, respectively. Here, we report the development of a one-step strategy for CRISPR-Cas9-mediated gene knockout and CAR transgenesis in NK cells using retroviral particles. We generated NK cells expressing anti-epidermal growth factor receptor (EGFR)-CAR with simultaneous TIGIT gene knockout using single transduction and evaluated the consequence of the genetic modifications in vitro and in vivo. Taken together, our results demonstrate that retroviral particle-mediated engineering provides a strategy readily applicable to simultaneous genetic modifications of NK cells for efficient immunotherapy

Transitioning subcutaneous immunoglobulin 20% therapies in patients with primary and secondary immunodeficiencies: Canadian real-world study

Abstract Background Real-world data on transitioning to Immune Globulin Subcutaneous (Human) 20% solution (Ig20Gly) are limited. This study aimed to assess infusion parameters and experience of patients with primary (PID) or secondary immunodeficiencies (SID) transitioning to Ig20Gly in clinical practice in Canada. Methods Patients with PID or SID who received subcutaneous immunoglobulin (SCIG) for ≥ 3 months before transitioning to Ig20Gly were eligible for this multicenter (n = 6), phase 4, non-interventional, prospective, single-arm study. Ig20Gly infusion parameters, dosing, and adverse events were collected from patient medical records at Ig20Gly initiation and 3, 6, and 12 months post-initiation. Patient satisfaction and quality of life were assessed 12 months post-initiation using validated questionnaires. Results The study included 125 patients (PID, n = 60; SID, n = 64; PID + SID, n = 1). Median volume per infusion was 30.0 ml at initiation, and 40.0 ml at 6 and 12 months post-initiation. Most patients administered Ig20Gly weekly and used two infusion sites (primarily abdomen). At each time point, median infusion duration was ≤ 1 h. At 12 months, 61% of infusions were administered via a pump and 39% manually. Headache and infusion-site reactions were the most reported adverse events of interest. Patients expressed overall satisfaction with Ig20Gly at 12 months post-initiation, with all respondents indicating they would like to continue Ig20Gly. Conclusions This study provides a detailed description of Ig20Gly infusion parameters, tolerability, and quality of life in clinical practice among patients with PID or SID switching to Ig20Gly from another SCIG and confirms the feasibility of infusing Ig20Gly via pump or manual administration. Trial registration NCT03716700, Registered 31 August 2018, https://clinicaltrials.gov/ct2/show/NCT0371670

Correction : Transitioning subcutaneous immunoglobulin 20% therapies in patients with primary and secondary immunodeficiencies : Canadian real‑world study

Medicine, Faculty ofNon UBCMedicine, Department ofReviewedFacultyResearcherOthe

Complexity in clinical diagnoses of acute exacerbation of chronic obstructive pulmonary disease

Abstract Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a clinical syndrome with various causes. It is not uncommon that COPD patients presenting with dyspnea have multiple causes for their symptoms including AECOPD, pneumonia, or congestive heart failure occurring concurrently. Methods To identify clinical, radiographic, and laboratory characteristics that might help distinguish AECOPD from another dominant disease in patients with a history of COPD, we conducted a retrospective cohort study of hospitalized patients with admitting diagnosis of AECOPD who were screened for a prospective randomized controlled trial from Sep 2016 to Mar 2018. Clinical characteristics, course in hospital, and final diagnosis at discharge were reviewed and adjudicated by two authors. The final diagnosis of each patient was determined based on the synthesis of all presenting signs and symptoms, imaging, and laboratory results. We adhered to AECOPD diagnosis definitions based on the GOLD guidelines. Univariate and multivariate analyses were performed to identify any associated features of AECOPD with and without other acute processes contributing to dyspnea. Results Three hundred fifteen hospitalized patients with admitting diagnosis of AECOPD were included. Mean age was 72.5 (SD 10.6) years. Two thirds (65.4%) had spirometry defined COPD. The most common presenting symptom was dyspnea (96.5%), followed by cough (67.9%), and increased sputum (57.5%). One hundred and eighty (57.1%) had a final diagnosis of AECOPD alone whereas 87 (27.6%) had AECOPD with other conditions and 48 (15.2%) did not have AECOPD after adjudication. Increased sputum purulence (OR 3.35, 95%CI 1.68–6.69) and elevated venous pCO2 (OR 1.04, 95%CI 1.01 – 1.07) were associated with a diagnosis of AECOPD but these were not associated with AECOPD alone without concomitant conditions. Radiographic evidence of pleural effusion (OR 0.26, 95%CI 0.12 – 0.58) was negatively associated with AECOPD with or without other conditions while radiographic evidence of pulmonary edema (OR 0.31; 95%CI 0.11 – 0.91) and lobar pneumonia (OR 0.13, 95%CI 0.07 – 0.25) suggested against the diagnosis of AECOPD alone. Conclusion The study highlighted the complexity and difficulty of AECOPD diagnosis. A more specific clinical tool to diagnose AECOPD is needed