A case series of bacillus Calmette-Guérin scar reactivation after administration of both mRNA and viral vector COVID-19 vaccines.

AIM: Reactivation of the scar resulting from intradermal injection of bacillus Calmette-Guérin (BCG) is a common specific reaction in Kawasaki's disease. It has also sporadically been associated with viral infections, multisystem inflammatory syndrome in children, influenza vaccination and mRNA COVID-19 vaccination. In this case series, characteristics of BCG scar reactivation after different COVID-19 vaccinations are presented and possible mechanisms are discussed. METHODS: Data were collected from the spontaneous reporting system of the Netherlands Pharmacovigilance Centre Lareb. Descriptives were made for the case reports in which a BCG scar reactivation was detected. RESULTS: Since the start of the COVID-19 vaccination campaign in January 2021, the Netherlands Pharmacovigilance Centre Lareb has received 22 case reports of BCG reactivation after vaccination with a COVID-19 vaccine. In 20 case reports, it concerned mRNA COVID-19 vaccines Moderna (14) and Pfizer (6). In two case reports, the viral vector COVID-19 vaccine AstraZeneca was administered. Erythema and pain were the most frequently reported symptoms and the size of the inflammation was between 1.5 and 5 cm. BCG scar reactivation occurred with a median time to onset of 2 days after the second or booster COVID-19 vaccination, whereas the median time to onset was 7 days after the first COVID-19 vaccination. None of the BCG scar reactivations were treated. CONCLUSIONS: The exact mechanism of the occurrence of BCG scar reactivation remains unknown, but involvement of heat shock protein 65 is suggested. BCG scar reactivation is a nonserious, self-limiting reaction that can occur after vaccination with both mRNA and viral vector COVID-19 vaccines.

Global Risk of Bacterial Skin Infections and Herpesviridae Infections with Ustekinumab, Secukinumab, and Tumour Necrosis Factor-alpha Inhibitors: Spontaneous Reports of Adverse Drug Reactions from the World Health Organization Pharmacovigilance Center.

Genetic defects in interleukin-12/23/17 immunity are associated with an increased risk of Staphylococcus aureus and herpesvirus skin infections. This study analysed spontaneous safety reports from the WHO Pharmacovigilance Center of bacterial skin or herpesvirus infections associated with secukinumab, ustekinumab and tumour necrosis factor-α inhibitors. Associations found in disproportionality analyses were expressed as reporting odds ratios (ROR). For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% confidence interval (95% CI) 5.44-6.81), and, among the tumour necrosis factor-α inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97-4.40). Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00-4.09). Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78-6.10). All biologics were equally associated with herpes zoster. Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08-6.31) and had the strongest association with Epstein-Barr virus infection (ROR 6.90; 95% CI 6.03-7.90). All biologics evaluated were positively associated with bacterial skin infections, herpes simplex, and herpes zoster, compared with all other drugs in the WHO database for which individual case safety reports were collected. The possibility of under-reporting, reporting bias and difference in causality assessment between countries and reporters must be taken into account when interpreting the results of disproportionality analyses.

Prevalence, risk and severity of SARS-CoV-2 infections in psoriasis patients receiving conventional systemic, biologic or topical treatment during the COVID-19 pandemic: a cross-sectional cohort study (PsoCOVID).

BACKGROUND: The risk of SARS-CoV-2 infection does not appear to be increased for psoriasis patients using biologics compared to those on other treatments, but evidence is still limited. OBJECTIVES: (1) to estimate the prevalence of SARS-CoV-2 infection in patients with psoriasis, (2) to compare SARS-CoV-2 infection rates for different psoriasis treatments groups (biologic vs. systemic conventional vs. topical therapy) corrected for confounders and (3) to describe patients with severe COVID-19 for all treatment groups. METHODS: In this cross-sectional cohort study all patients received a questionnaire to gather data on psoriasis treatment, SARS-CoV-2 infections and related risk factors. Simultaneously, they underwent a blood test to screen for antibodies to SARS-CoV-2 N-antigen. Prevalence of SARS-CoV-2 infections was calculated and logistic regression and Cox proportional-hazards models were performed to determine the association between treatment group and SARS-CoV-2 infection risk, corrected for confounders. Patients with severe COVID-19 disease were described and the mortality rate per treatment group was calculated for the target population. RESULTS: Patients were included between April 12 2021 and October 31 2021. Of 551 patients, 59 (10.7% (CI95% 8.3-13.6)) had experienced a SARS-CoV-2 infection, based on questionnaire data combined with serological data. In our study cohort, corrected for confounders, biologic or non-biologic systemic therapy users did not appear to have increased SARS-CoV-2 infection risk compared to patients using other treatment. Only 4 hospitalizations (0.7% (CI95% 0.2-1.0) were reported in our study population and no ICU admissions were reported. The rough mortality rate in the target cohort was 0.32% (CI95% 0.13-0.66) in all treatment groups. CONCLUSIONS: Corrected for risk-mitigating behavior and vaccination status, a higher SARS-CoV-2 incidence for biologics or non-biologics systemics compared to other treatments could not be proven. Severe cases were infrequent in all treatment groups. This finding further strengthens treatment recommendations that systemic therapies for patients with psoriasis do not require preventive cessation for reduction of SARS-CoV-2 infection risk.

Immunological Effects of Anti‒IL-17/12/23 Therapy in Patients with Psoriasis Complicated by Candida Infections.

Biologics that block the T helper (Th) 17 pathway are very effective in the treatment of psoriasis and other inflammatory diseases. However, IL-17 is also crucial for antifungal host defense, and clinical trial data suggest an increase in the incidence of Candida infections during IL-17 inhibitor (IL-17i) therapy. We investigated the innate and adaptive immune responses of patients with psoriasis with a history of skin and/or mucosal candidiasis during IL-17i or IL-12/23 inhibitor therapy, comparing those responses with those of healthy controls. Patients with psoriasis with IL-17i showed significantly lower CD4+Th1-like (CCR6‒CXCR3+CCR4‒) and Th1 Th17-like (CD4+CCR6+CXCR3+CCR4‒) cell percentages. Patient cells stimulated with Candida albicans produced significantly lower IL-6 in the IL-12/23 inhibitor group and IL-1ß in the IL-17i group, whereas the release of TNF-α and ROS was similar between patients and controls. IFN-γ and IL-10 production in response to several stimuli after 7 days was particularly decreased in patients receiving IL-17i therapy. Finally, after stimulation with the polarizing cytokines IL-1ß and IL-23, the Th17 cytokine response was significantly lower in the IL-17i patient group. These innate and adaptive immune response defects can diminish antifungal host immune response and thereby increase susceptibility to candidiasis in patients treated with IL-17i or IL-12/23 inhibitor.

Risk of candidiasis associated with interleukin-17 inhibitors: A real-world observational study of multiple independent sources.

BACKGROUND: Biologics directed against the T-helper (Th)-17 pathway have been approved for several inflammatory diseases. Interleukin (IL)-17 is involved in anti- Candida host defense, and clinical trials suggested increased candidiasis incidence during IL-17 inhibitor therapy. We describe the worldwide epidemiology of candidiasis during Th17 inhibitor therapy, and immunological mechanisms involved in candidiasis susceptibility. METHODS: A comprehensive analysis of multiple independent sources reporting Candida adverse events during biologics inhibiting the Th17 pathway was performed. Association between Th17 inhibitors and candidiasis was assessed using safety reports of (1) WHO and (2) EMA, (3) a population-based prescriptions registry, and (4) a psoriasis cohort. In a cohort of psoriasis patients experiencing candidiasis during Th17 inhibitors, Candida killing by immune cells and serum inflammatory proteome were analyzed. FINDINGS: A strong association between IL-17 inhibitors and candidiasis (ROR 10·20) was found in the WHO database, particularly for cutaneous (ROR 12·28), oropharyngeal (ROR 19·18), and esophageal candidiasis (ROR 21·20). Risk was higher relative to TNF-α inhibitors (4-10-fold, depending on candidiasis type), confirmed by EMA reports (16-33-fold), prescriptions registry (2-42-fold), and a psoriasis cohort (3-25-fold). After start of IL-17 inhibitors, patients' risk of candidiasis requiring antifungals increased 2-16 fold. In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis. In Th17 inhibitor recipients, proteins involved in anti- Candida immunity and Candida killing by mononuclear leukocytes were impaired. INTERPRETATION: IL-17 inhibitors are associated with an increased risk of oropharyngeal, esophageal, and cutaneous candidiasis, posing a significant disease burden for IL-17 inhibitor recipients. FUNDING: RadboudUMC.

Mitochondrial Respiration Correlates with Prognostic Markers in Chronic Lymphocytic Leukemia and Is Normalized by Ibrutinib Treatment.

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70+), cluster of differentiation 38 (CD38+), and elevated ß2-microglobulin (ß2-M) predicted increased maximal respiration rates. ZAP-70+ CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70- CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70+ predicted increased maximal respiration. ZAP-70+ is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton's tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells.

Patient Susceptibility to Candidiasis-A Potential for Adjunctive Immunotherapy.

Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30-50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy.

Letters.

IRRIGATION OF WOUNDS OEDEMA AND LEG ULCERS PREPARING WOUND SAMPLES FOR ANALYSIS EDUCATION NEEDED.