Rituximab-treated rheumatic patients: B cells predict seroconversion after COVID-19 boost or revaccination in initial vaccine non-responders.

OBJECTIVES: To investigate the effect of either a booster vaccine (one dose) or revaccination (two doses 3 weeks apart) on the antibody response to the COVID-19 mRNA vaccines in patients with rheumatic disease (RD) treated with rituximab (RTX) who had not produced vaccine-reactive antibodies after the initial two vaccine doses. Further, to examine if B cell levels in peripheral blood predicted seroconversion. METHODS: We included 91 RTX-treated RD patients previously vaccinated against COVID-19. Patients were offered revaccination or a single booster vaccination with an mRNA vaccine. Serum total antibodies against SARS-CoV-2 spike protein were measured before and 6 weeks after the last vaccine dose. B cells (CD19+CD45+) were measured by flow cytometry at inclusion. RESULTS: Of RD patients with undetectable SARS-CoV-2 antibody levels before inclusion, seroconversion was seen in 38% 6 weeks after the booster dose and 32% after revaccination. Patients receiving revaccination had significantly higher antibody levels than patients receiving a booster dose (P < 0.001). In both univariate and multivariate logistic regression analysis, only B cells higher than 10/µl before boost or revaccination were associated with seroconversion (P = 0.009 and P = 0.01, respectively). Seroconversion was independent of age, gender, diagnosis, cumulative RTX dose, RTX treatment time and time since last RTX treatment. CONCLUSION: Continuously impaired humoral response to mRNA vaccines was found in most RTX-treated patients after a booster dose or revaccination. Seroconversion was observed in approximately one-third of the patients. Measurable B cells before boosting or revaccination was the strongest predictor of antibody response after boost or revaccination.

SARS-CoV-2 Infection Rates Following Use of Regular Compared With Defective Respirators When Caring for COVID-19 Patients: A Retrospective Follow-up Study.

BACKGROUND: There is strong observational evidence that respirators are highly effective in protecting the users from being infected with Middle East respiratory syndrome and severe acute respiratory syndrome coronavirus (SARS-CoV), but the evidence for SARS-CoV-2 during daily work is limited. This study utilized a subset of healthcare workers' temporary use of a new brand respirator with frequent defects when caring for coronavirus disease 2019 (COVID-19) patients to assess the protective effect of regular respirators against SARS-CoV-2 infection. METHODS: We retrospectively followed 463 participants wearing a regular respirator and 168 wearing the new brand respirator day-by-day when caring for COVID-19 patients until testing polymerase chain reaction positive for SARS-CoV-2 between 27th December 2020 and 14th January 2021. RESULTS: We observed seven and eight incident SARS-CoV-2-infected cases. This corresponded with daily infection rates of 0.2 and 0.5%, an incidence rate ratio of 0.4 [95% confidence interval (CI) 0.1; 1.0], and an incidence rate difference of 0.3% (95% CI -0.1; 0.8) when comparing a regular with the new brand respirator. DISCUSSION: We regard the new brand respirator a sham intervention, and this study thus provides further evidence for the protective effect of respirators when exposed to SARS-CoV-2 virus.

Impaired Antibody Response to the BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine in Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis.

OBJECTIVE: With a vaccine effectiveness of 95% for preventing coronavirus disease 2019 (COVID-19), Pfizer-BioNTech BNT162b2 (BNT162b2) was the first vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to be approved. However, immunosuppressive therapy was an exclusion criterion in the phase 3 trial that led to approval. Thus, extrapolation of the trial results to patients with rheumatic diseases treated with immunosuppressive drugs warrants caution. METHODS: Patients with systemic lupus erythematosus (SLE; n = 61) and rheumatoid arthritis (RA; n = 73) were included from the COPANARD (Corona Pandemic Autoimmune Rheumatic Disease) cohort, followed since the beginning of the COVID-19 pandemic. Patients received the BNT162b2 vaccine between December 2020 and April 2021. All patients had total antibodies against SARS-CoV-2 measured before vaccination and 1 week after the second vaccination (VITROS Immunodiagnostic Products). RESULTS: Of 134 patients (median age, 70 years), 77% were able to mount a detectable serological response to the vaccine. Among patients treated with rituximab, only 24% had detectable anti-SARS-CoV-2 antibodies in their serum after vaccination. The time since the last rituximab treatment did not seem to influence the vaccine response. No significant difference was observed between patients with RA or SLE when adjusting for treatment, and no correlation between antibody levels and age was detected (r = -0.12; P = 0.18). CONCLUSION: Antibody measurements against SARS-CoV-2 in patients with RA and SLE after two doses of the BNT162b2 vaccine demonstrated that 23% of patients could not mount a detectable serological response to the vaccine. B cell-depleting therapy (BCDT) is of specific concern, and our findings call for particular attention to the patients receiving BCDT.

Existing Data Sources in Clinical Epidemiology: The Danish COVID-19 Cohort.

BACKGROUND: To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a prospective cohort of all Danish residents tested for SARS-CoV-2 in Denmark is established. DATA STRUCTURE: All Danish residents tested by reverse transcriptase polymerase chain reactions (RT-PCR) for SARS-CoV-2 in Denmark are included. The cohort is identified using the Danish Microbiology Database. Individual-level record linkage between administrative and health-care registries is facilitated by the Danish Civil Registration System. Information on outcomes related to SARS-CoV-2 infection includes hospital admission, intensive care unit admission, mechanical ventilation, and death and is retrieved from the five administrative Danish regions, the Danish National Patient Registry, and the Danish Register of Causes of Death. The Patient Registry further provides a complete hospital contact history of somatic and psychiatric conditions and procedures. Data on all prescriptions filled at community pharmacies are available from the Danish National Prescription Registry. Health-care authorization status is obtained from the Danish Register of Healthcare Professionals. Finally, selected laboratory values are obtained from the Register of Laboratory Results for Research. The cohort is governed by a steering committee with representatives from the Danish Medicines Agency, Statens Serum Institut, the Danish Health Authority, the Danish Health Data Authority, Danish Patients, the Faculties of Health Sciences at the Danish universities, and Danish regions. The steering committee welcomes suggestions for research studies and collaborations. Research proposals will be prioritized based on timeliness and potential clinical and public health implications. All research protocols assessing specific hypotheses for medicines will be made publicly available using the European Union electronic Register of Post-Authorisation Studies. CONCLUSION: The Danish COVID-19 cohort includes all Danish residents with an RT-PCR test for SARS-CoV-2. Through individual-level linkage with existing Danish health and administrative registries, this is a valuable data source for epidemiological research on SARS-CoV-2.

Penicillin G Treatment in Infective Endocarditis Patients - Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin-susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined penicillin G plasma concentration [p-penicillin] once weekly in 46 IE patients. The aim was to evaluate whether penicillin G 3 g every 6 hr (q6 h) resulted in therapeutic concentrations and to analyse potential factors that influence inter- and intra-individual variability, using linear regression and a random coefficient model. [P-penicillin] at 3 hr and at 6 hr was compared with the minimal inhibitory concentration (MIC) of the bacteria isolated from blood cultures to evaluate the following PK/PD targets: 50% fT > MIC and 100% fT > MIC. [P-penicillin] varied notably between patients and was associated with age, weight, p-creatinine and estimated creatinine clearance (eCLcr). Additionally, an increase in [p-penicillin] during the treatment period showed strong correlation with age, a low eCLcr, a low weight and a low p-albumin. Of the 46 patients, 96% had [p-penicillin] that resulted in 50% fT > MIC, while 71% had [p-penicillin] resulting in 100% fT > MIC. The majority of patients not achieving the 100% fT > MIC target were infected with enterococci. Streptococci and staphylococci isolated from blood cultures were highly susceptible to penicillin G. Our results suggest that penicillin G 3 g q6 h is suitable to treat IE caused by streptococci and penicillin-susceptible staphylococci, but caution must be taken when the infection is caused by enterococci. When treating enterococci, therapeutic drug monitoring should be applied to optimize penicillin G dosing and exposure.

Moxifloxacin pharmacokinetic profile and efficacy evaluation in empiric treatment of community-acquired pneumonia.

When antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0-24) values predicted for each patient were evaluated against epidemiological cutoff MIC values for Streptococcus pneumoniae, Haemophilus influenzae, and Legionella pneumophila. PK-PD targets adopted were a Cmax/MIC of ≥12.2 for all pathogens, an fAUC0-24/MIC of >34 for S. pneumoniae, and an fAUC0-24/MIC of >75 for H. influenzae and L. pneumophila. Individual predicted estimates for Cmax/MIC and fAUC0-24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable for S. pneumoniae and H. influenzae but not for L. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused by L. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.).

Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort.

BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage. METHODS: Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression. RESULTS: Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p ≤ 0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (OR(CD,adj): 0.38, 95% CI: 0.21-0.67, p = 0.03; OR(IBD,adj) 0.43, 95% CI: 0.28-0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (OR(CD,unadj) 0.54, 95% CI: 0.41-0.72, p = 7*10-4; OR(IBD,unadj): 0.61, 95% CI: 0.48-0.77, p = 0.001) were associated with reduced risk of CD. CONCLUSION: The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.