Léonard de Vinci Kanda Kupa

Background: Patients with autoimmune rheumatic diseases (ARDs) are at an increased risk for herpes zoster (HZ). Vaccination is recommended for this population. Objective: The aim of this study was to evaluate the safety of vaccination with the recombinant zoster vaccine (Shingrix) in ARD patients, humoral immunogenicity (HI), cellular immunogenicity (CI), and the incidence of HZ. Methods: This randomized, double-blind, placebo-controlled phase 4 study involves 1180 ARD patients and a control group (CG) of 393 balanced healthy individuals, aged ≥50 years. ARD patients will be randomly assigned in a blinded manner (1:1 ratio) to 2 groups: vaccine or placebo (on days 0 and 42), administered intramuscularly. Outcomes will be assessed at baseline, 6 weeks, and 12 weeks after vaccination, including disease activity (using specific disease activity scores), HI, and CI. Adverse events will be assessed using a standardized questionnaire after each vaccine dose. Incident HZ cases will be monitored throughout the study. One year following the second dose, the persistence of HI and CI will be evaluated in both ARD patients and CG. HI and CI will be assessed using serum concentrations of anti-gE antibodies and the frequencies of gE-specific CD4+ T cells, respectively. Comparisons of anti-gE titers between ARD patients and CG at different time points will be analyzed using 2-way repeated-measures analysis of variance. Multiple regression analysis will be conducted, with a positive immune response as the dependent variable, and variables with p < 0.2 from univariate analysis as independent variables. Conclusions: This large trial addresses a critical gap by examining disease safety, efficacy, adverse effects, and immunogenicity, considering the impact of diverse therapies following recombinant zoster vaccine administration in ARD patients.

Introduction: Septic shock is one of the leading causes of death among critically ill patients in the Intensive Care Unit (ICU), including severely major burned patients. Rapid diagnosis and early initiation of effective antimicrobial therapy are the main challenges. The role of leukocytes as the neutrophil/lymphocyte ratio (NLR) and various systemic inflammatory indices, include serum levels of interleukin-6 (IL-6), procalcitonin (PCT) and c-reactive protein (c-RP) are the informative laboratory markers in this regard respect. Subject: Monitoring of serum levels of interleukin (IL6), procalcitonin (PCT) and C-reactive protein (C-RP), including among leukocytes the index neutrophil/lymphocyte ratio (NLR), proposed previously, investigated at the first septic shock of major burns undergoing meropenem therapy recommended in hospital, during the systemic inflammatory response syndrome (SIRS), after ICU admission. Fundamental aim of study was to investigate the relationship, and contribution of these biomarkers at the early versus late stage of septic shock, as well as to determine the diagnostic performance of them in major burn patients that could impact outcome. Methods: In this prospective open label study, a total of 30 major septic burn patients with renal function preserved, augmented or with acute kidney injury (AKI) was enrolled at the first septic shock after accident and ICU admission, based on systemic inflammatory response syndrome (SIRS) criteria. All patients had been selected from the ICU of Plastic Surgery and Burn Unit of tertiary public hospital of Medical School, University of Sao Paulo, SP, Brazil. Laboratory data with known clinicopathological parameters were recorded. Serum levels of IL6, PCT, c-RP and NLR from the blood count were evaluated. Inflammatory biomarkers such as c-RP, PCT and IL6 in serum were performed on the COBAS 8000 series (c-RP) or COBAS E411 series analyzer for PCT, IL6 (Roche, registered trademark), neutrophil to lymphocyte ratio (blood count) was measured using a Hematology Analyzer (SYSMEX brand). Therapeutic serum measurements of combined therapy with antibiotics (ATB) were done by comparison of coverage at the earlier versus late stage of septic shock. Results: A significant difference was found in NLR, IL6, PCT and c-RP in surviving patients (n=20) comparing data obtained in early stage versus late-stage SIRS (p<0.05) in major burns with positive bacteriological cultures. On the other hand, there was no significant difference between the NLR and IL6 periods, which occurred when comparing data in the early versus late stage of SIRS in non-survival patients, who died between 7 and 10 days of antimicrobial therapy. There was an increasing trend in serum levels of NLR and IL6, PCT and c-RP in large burns, dependent on the timing of septic shock stages, with diagnostic value as early appearance of biomarkers. On the other hand, we recorded that the association of NLR and IL6 produces better diagnostic value in predicting ICU mortality than PCT or c-RP. Conclusion: It was shown in this pilot study that elevated NLR and increasing serum levels of IL6, PCT, c-RP occurred during SIRS in septic patients’ major burns. So, the combined use of these biomarkers may play a potential role in the early diagnosis of septic shock for adequate initial therapy of these ICU patients. Combined biomarkers (NLR-IL6) can further predict ICU mortality of septic patients with acute kidney injury occurring during SIRS. Finally, a prospective multicenter study in a large cohort can be performed to confirm the data obtained in this investigation.

Introduction: Faced with the growing challenge to the use of antimicrobials for the adequate and effective therapy of nosocomial infections, international health agencies have reinforced that combating bacterial resistance and preventing the development of multidrug-resistant (MDR) strains are urgent, since a significant increase based on minimum inhibitory concentration (MIC) for therapeutic agents were reported by the committee of hospitals infection. Meropenem, a carbapenem agent, is widely prescribed for therapy of septic shock caused by susceptible Gram-negative bacteria. In general, the prolonged 3-hrs-infusion has been widely applied in these patients over the past 10 years providing coverage only against susceptible Gram-negative pathogens (MIC 2 mg/L), extended also to intermediate susceptible strains up to MIC 4 mg/L, according to Clinical Laboratory Standard Institute (CLSI database). However, new strategies have been recommended to combat the development of resistance to pathogens isolated from cultures to increase the coverage of this carbapenem agent up to MIC 8 mg/L, to avoid mutant selection with death in ICU. Subject: Clinical protocol was carried out to investigate the efficacy & safety of meropenem at the dose regimen recommended 1g q8h by prolonged infusion, based on serum levels and on cultures monitoring of isolates. Aim of protocol was to assess pharmacodynamics (PD) based on changes of pharmacokinetics (PK), which could affect the coverage of meropenem in septic burns patients with increased or decreased renal function. Pharmacokinetic-pharmacodynamics (PK/PD) tools were applied to investigate efficacy & safety. Methods-clinical protocol: Forty-eight major septic burn patients with high variability on renal function in ICU were included. Cultures were collected before meropenem therapy starts; all of them had nosocomial infection caused by Gram-negative pathogens isolated. Patients undergoing meropenem therapy at the initial stage of septic shock from day-0 to day-8 (D0-D8) and at the late stage of septic shock from day 8 to day 14 (D-8 to D-14) were investigated according to dose requirements based on creatinine clearance, drug serum levels (TDM), and coverage up to MIC 8 mg/L, dose dependent on renal function. Results: Coverage occurred for all patients of both groups after the extended infusion against susceptible Gram-negative strains up to MIC 2 mg/L (minimum inhibitory concentration), and up to MIC 4 mg/L, strains of intermediate susceptibility, according to Clinical Laboratory Standards Institute (CLSI, database) of our hospital. It was demonstrated in patients with renal function augmented by vasopressors, the superiority on coverage by trice that occurred in 24/27 patients (89%) after 4 hrs.-infusion at TDM3 against strains MIC 8 mg/L by comparison with coverage registered in 12/39 patients (30%) after 3 hrs.-infusion at TDM2. On the other hand, meropenem dose regimen must be adjusted to 1g q24h in patients with AKI to guarantee effectiveness & safety in those patients. In addition, after continuous venovenous haemodialysis-filtration (CVVHDF) installed in those patients, meropenem PK/PD target was attained up to MIC 8 mg/L in patients with the empirical dose regimen recommended of 1g q8h, 3hrs.-infusion. Conclusion: Precision medicine guarantees meropenem serum levels combined with cultures monitoring; consequently, must be applied routinely to guarantee coverage against Gram-negative nosocomial pathogens susceptible including strains of intermediate susceptibility (MIC 4-8 mg/L) to avoid mutant selection. Therefore, effective, and safe antimicrobial therapy for patients in septic shock, combined with a continuous monitoring of inflammatory biomarkers, should guide clinical management to ensure cure with early ICU discharge.

Hydroxychloroquine (HCQ) has been used to treat Sjögren’s disease (SjD) patients. However, there are no studies evaluating drug adherence through HCQ blood levels, pharmacy refill (PR) and medication adherence questionnaires. The relationship of HCQ blood levels with glandular/extraglandular disease parameters was also poorly assessed. This cross-sectional observational study included 74 adult SjD patients, who were receiving a stable HCQ dose (4-5.5 mg/kg/day, actual weight) for at least 3 months before study inclusion. HCQ blood levels were quantified by high-performance liquid chromatography coupled to mass spectrometry. Adherence was assessed by PR and Medida de Adesão aos Tratamentos (MAT) questionnaire. The following parameters were evaluated: Xerostomia Inventory, Ocular Surface Disease Index, EULAR (European League Against Rheumatism) Sjögren’s Syndrome Disease Activity Index, EULAR Sjögren’s Syndrome Patient Reported Index, Schirmer’s I test and non-stimulated/stimulated salivary flow rates. HCQ blood levels were 775.3(25.0–2,568.6)ng/mL. Eleven patients (14.9%) had HCQ blood levels < 200ng/mL (non-adherent group); 11(14.9%), 200-499ng/mL (sub-therapeutic levels group); and 52(70.2%), ≥ 500ng/mL (adherent group). PR classified incorrectly all non-adherent/sub-therapeutic patients and 2/52(3.9%) adherent patients. Using MAT, the overall misclassification was 24/52(46.2%) in the adherent group, and were correctly identified 9/11(81.8%) patients in non-adherent and 7/11(63.6%) in sub-therapeutic groups. MAT sensitivity and specificity to identify non-adherent/sub-therapeutic patients were 72.7% and 53.9%, respectively. The three groups were comparable regarding glandular/extraglandular disease parameters (p > 0.05). The assessment of HCQ blood levels is a promising tool for evaluating drug adherence in SjD. This is particularly crucial as one-third of patients exhibited non-adherence/sub-therapeutic levels, and neither PR nor MAT reliably identified these patients.

Aim: To investigate the association between physical activity and immunogenicity among SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases prior to and following a 2-dose schedule of CoronaVac (Sinovac inactivated vaccine). Methods: This was a prospective cohort study within an open-label, single-arm, phase 4 vaccination trial conducted in Sao Paulo, Brazil. In this substudy, only SARS-CoV-2 seropositive patients were included. Immunogenicity was assessed by seroconversion rates of total anti-SARS-CoV-2 S1/S2 immunoglobulin G (IgG), geometric mean titers of anti-S1/S2 IgG, frequency of positive neutralizing antibodies, and neutralizing activity before and after vaccination. Physical activity was assessed through a questionnaire. Model-based analyses were performed controlling for age (2), and use of prednisone, immunosuppressants, and biologics. Results: A total of 180 seropositive autoimmune rheumatic disease patients were included. There was no association between physical activity and immunogenicity before and after vaccination. Conclusions: This study suggests that the positive association between physical activity and greater antibody responses seen in immunocompromised individuals following vaccination is overridden by previous SARS-CoV-2 infection, and does not extend to natural immunity.

Background: Physical activity associates with improved immunogenicity following a 2-dose schedule of CoronaVac (Sinovac’s inactivated SARS-CoV-2 vaccine) in patients with autoimmune rheumatic diseases (ARD). This study evaluates whether physical activity impacts vaccine-induced antibody responses to a booster dose in this population. Methods: This was a phase-4 trial conducted in São Paulo, Brazil. Patients with ARD underwent a 3-dose schedule of CoronaVac. One month after the booster, we assessed seroconversion rates of anti-SARS-CoV-2 S1/S2 IgG, geometric mean titers of anti-S1/S2 IgG, frequency of positive neutralizing antibodies, and neutralizing activity. Physical activity was assessed through questionnaire. Results: Physically active (n = 362) and inactive (n = 278) patients were comparable for most characteristics; however, physically active patients were younger (P < .01) and had a lower frequency of chronic inflammatory arthritis (P < .01). Adjusted models showed that physically active patients had ∼2 times odds of seroconversion rates (OR: 2.09; 95% confidence interval, 1.22 to 3.61), ∼22% greater geometric mean titers of anti-S1/S2 IgG (22.09%; 95% confidence interval, 3.91 to 65.60), and ∼7% greater neutralizing activity (6.76%; 95% confidence interval, 2.80 to 10.72) than inactive patients. Conclusions: Patients with ARD who are physically active have greater odds of experiencing better immunogenicity to a booster dose of CoronaVac. These results support the recommendation of physical activity to improve vaccination responses, particularly for immunocompromised individuals.

Aims: To validate an SPE-ultra-HPLC-MS/MS method for thalidomide (THD) measurement in dried plasma spot (DPS). Methods: Extraction included acetonitrile/water clean-up and online SPE. The LOD, LLOQ... Tweetable abstract Thalidomide measurement in dried plasma spot by ultra-HPLC-MS/MS combined with online SPE was successfully validated and applied in therapeutic drug monitoring. #thalidomide #DPS...

Objective: Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19. Methods: This prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed. Results: We included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age ( p=0.982) and sex ( p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG ( p=0.058) and IgM ( p=0.091); anti-beta-2 glycoprotein I (aβ2GPI) IgG ( p=0.513) and IgM ( p=0.468). Conclusion: We provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.