Probiotics: are they beneficial?

There are wide-ranging probiotic choices in Australasia. We reviewed the efficacy of probiotics for the management of gastrointestinal (GI) conditions in adults and assessed relevance to clinical practice. The benefits of probiotics were inconsistent, with a strong consensus reached for only a few of the indications. As different species/strains and combinations differ in efficacy, results cannot be extrapolated from one to another. This review endorses specific probiotics for limited indications. Efficacy of most marketed probiotic formulations remains unstudied and unproven, warranting further research.

A single-center experience of COVID-19 infection in patients with primary immunodeficiency.

Background: Reported outcomes in patients with primary immunodeficiency (PID) infected by coronavirus disease 2019 (COVID-19) have been variable owing to a combination of viral strain heterogeneity, differences in patient populations and health systems, and local availability of vaccination and specific COVID-19 therapies. There are few reports on the experience of Australian patients with PID during the pandemic. Objectives: In this retrospective study, we describe the baseline characteristics and short-term outcomes of patients with PID who were infected by COVID-19 and known to the Royal Melbourne Hospital, a major tertiary center in Victoria, Australia. Methods: Between April 2021 and April 2022, a total of 31 of 138 patients with PID were affected by COVID-19. More than half of them had 3 vaccine doses at the time of infection (which at the time was considered being fully vaccinated) and received COVID-19-targeted treatment. Results: All of the infected patients had ambulatory disease, with no cases of morbidity or mortality. In line with the current literature, the PID subtypes described did not appear to independently predict worse outcomes. Conclusions: Some protective factors include this cohort's relatively younger average age and its high uptake of vaccination and COVID-19 therapies.

Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial.

Importance: Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling. Objective: To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy. Design, Setting, and Participants: This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies. Interventions: Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm). Main Outcome and Measure: The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp). Results: A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, -0.45 pp; 95% CI, -4.87 to 3.96 pp). No serious adverse events occurred. Conclusions and Relevance: In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label. Trial Registration: ClinicalTrials.gov Identifier: NCT04454229.

Case Report: Cytomegalovirus Disease Is an Under-Recognized Contributor to Morbidity and Mortality in Common Variable Immunodeficiency.

BACKGROUND: Common Variable Immunodeficiency (CVID) is classified as a 'Predominantly Antibody Deficiency' (PAD), but there is emerging evidence of cellular immunodeficiency in a subset of patients. This evidence includes CVID patients diagnosed with cytomegalovirus (CMV) infection, a hallmark of 'combined immunodeficiency'. CMV infection also has the potential to drive immune dysregulation contributing to significant morbidity and mortality in CVID. We aim to determine the extent of cellular immune dysfunction in CVID patients, and whether this correlates with CMV infection status. METHODS: We conducted a single-center retrospective cohort study of individuals with CVID at the Royal Melbourne Hospital, and identified patients with and without CMV disease or viraemia. We then isolated T-cells from patient and healthy donor blood samples and examined T-cell proliferation and function. RESULTS: Six patients (7.6%, 6/79) had either CMV disease (pneumonitis or gastrointestinal disease), or symptomatic CMV viraemia. A high mortality rate in the cohort of patients with CVID and CMV disease was observed, with 4 deaths in the period of analysis (66.6%, 4/6). Individuals with CMV infection showed reduced T-cell division in response to T-cell receptor (TCR) stimulation when compared with CMV-negative patients. DISCUSSION: This study demonstrates the morbidity and mortality associated with CMV in CVID, and highlights the need for focused interventions for patients with CVID at risk of CMV disease.

Cytomegalovirus in primary immunodeficiency.

PURPOSE OF REVIEW: Cytomegalovirus (CMV) infection and disease are well described in the setting of secondary immunodeficiency. Less is known about CMV in the context of primary immunodeficiencies (PIDs), where inborn errors in one or more arms of the immune system result in variable degrees of CMV susceptibility. RECENT FINDINGS: PID presents unique challenges in the diagnosis and management of CMV disease. The clinical presentation of CMV in PID is often severe, accelerated by underlying immune dysregulation and iatrogenic immunosuppression. Here we describe the clinical significance of CMV infection in PID, the key components of immune defence against CMV and how these are affected in specific PIDs. CMV disease is under-recognized as a complication of common variable immunodeficiency (CVID). High rates of CMV end-organ disease, mortality, development of CMV resistance and prolonged antiviral use have been observed in individuals with CVID. SUMMARY: We recommend that clinicians tailor their approach to the individual based on their underlying immune deficit and maintain a high index of suspicion and low threshold for treatment. More research is required to improve stratification of CMV risk in PID, develop new diagnostic tools and manage end-organ disease in this cohort.

Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching.

OBJECTIVE: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS: Use of aspirin was associated with a 7% (95% CI, 2-12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis.

Clinical associations of IL-10 and IL-37 in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the development of autoantibodies to nuclear antigens and inflammatory responses mediated by multiple cytokines. Although previous studies have determined clinical associations between SLE and the anti-inflammatory cytokines IL-10 and IL-37, their role in the disease, or their potential as biomarkers, remains unclear. We examined serum levels of IL-10 and IL-37 in a large cohort of SLE patients, with detailed longitudinal clinical data. We demonstrate a statistically significant association of serum IL-10 with disease activity, with higher levels in active compared to inactive disease. High first visit IL-10 was predictive of high subsequent disease activity; patients with IL-10 in highest quartile at first visit were 3.6 times more likely to have active disease in subsequent visits. Serum IL-37 was also higher in SLE patients compared to control, and was strongly associated with Asian ethnicity. However, IL-37 was not statistically significantly associated with disease activity. IL-37 was significantly reduced in patients with organ damage but this association was attenuated in multivariable analysis. The data suggest that IL-10, but not IL-37, may have potential as a biomarker predictive for disease activity in SLE.

Brief Report: Interleukin-38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus.

OBJECTIVE: Knowledge of interleukin-38 (IL-38), formerly IL-1 family member 10, is sparse, but Il1f10 polymorphisms are associated with inflammatory diseases, and recombinant IL-38 inhibits inflammatory responses similar to those reported in the context of systemic lupus erythematosus (SLE). We undertook this study to explore the function of endogenous IL-38 in human peripheral blood mononuclear cells (PBMCs) as well as its abundance in serum in a well-characterized cohort of SLE patients. METHODS: Serum IL-38 and IL-10 levels were quantified by enzyme-linked immunosorbent assay in 142 SLE patients at ≤3 consecutive visits and in 28 healthy volunteers. To assess IL-38 function, we silenced IL-38 in PBMCs from healthy donors using IL-38 small interfering RNA (siRNA). RESULTS: IL-38 (63-5,928 pg/ml) was detectable in 16% of 372 serum samples. IL-38 abundance was significantly higher in samples from SLE patients than in samples from healthy controls (P = 0.004) and 11-fold higher in patients with active disease (SLE Disease Activity Index 2000 [SLEDAI-2K] score of ≥4) than in those with inactive disease (SLEDAI-2K score of <4) (P = 0.044). Importantly, IL-38 detection was associated with increased risk of renal lupus (relative risk [RR] 1.6, P = 0.027) and central nervous system lupus (RR 2.3, P = 0.034), and detectable baseline IL-38 entailed a 1.6-fold increased risk of subsequently meeting criteria for persistently active disease (P = 0.0097). Longitudinal time-adjusted mean IL-38 concentration was also 6-fold higher in patients with persistently active disease than in those without (P = 0.023). Remarkably, PBMCs treated with IL-38 siRNA produced up to 28-fold more of the proinflammatory mediators IL-6, CCL2, and APRIL than did control siRNA-transfected cells upon stimulation with Toll-like receptor agonists. Similarly, in SLE patients, the antiinflammatory cytokine IL-10 was 5-fold more abundant when IL-38 was detectable. CONCLUSION: This is the first study of the function of endogenous IL-38, and the data suggest that IL-38 may be protective in SLE. A strong association between IL-38 and SLE severity suggests that IL-38 expression is driven by processes linked to SLE pathogenesis. Exploitation of the regulatory effects of IL-38 may represent a promising therapeutic strategy in SLE.