Incidence of idiopathic nephrotic syndrome during the Covid-19 pandemic in the Paris area (France) and in the Netherlands.

BACKGROUND: The aetiology of idiopathic nephrotic syndrome (INS) remains partially unknown. Viral infections have been associated with INS onset. Since we observed fewer first onset INS cases during the Covid-19 pandemic, we hypothesised that lower INS incidence was the result of lockdown measures. Therefore, the aim of this study was to evaluate the incidence of childhood INS before and during the COVID-19 pandemic in two independent European INS cohorts. METHODS: Children with new INS in the Netherlands (2018-2021) and Paris area (2018-2021) were included. We estimated incidences using census data for each region. Incidences were compared using two proportion Z-tests. RESULTS: A total of 128 and 324 cases of first onset INS were reported in the Netherlands and Paris area, respectively, corresponding to an annual incidence of 1.21 and 2.58 per 100,000 children/year. Boys and young children (< 7 years) were more frequently affected. Incidence before and during the pandemic did not differ. When schools were closed, incidence was lower in both regions: 0.53 vs. 1.31 (p = 0.017) in the Netherlands and 0.94 vs. 2.63 (p = 0.049) in the Paris area. During peaks of hospital admissions for Covid-19, no cases were reported in the Netherlands or Paris area. CONCLUSIONS: Incidence of INS before and during the Covid-19 pandemic was not different, but when schools were closed during lockdown, incidence was significantly lower. Interestingly, incidences of other respiratory viral infections were also reduced as was air pollution. Together, these results argue for a link between INS onset and viral infections and/or environmental factors. A higher resolution version of the Graphical abstract is available as Supplementary information.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients.

INTRODUCTION: Imatinib reduced 90-day mortality in hospitalised COVID-19 patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19, and what baseline biological profile moderates the effect of imatinib. METHODS: Secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed-effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the above-described method. RESULTS: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin 2 to 1 ratio, E-selectin, tumour necrosis factor (TNF)α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers.Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (HR 0.29, 95%-CI: 0.10-0.92). CONCLUSIONS: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.

Real-world Evidence of the Effects of Novel Treatments for COVID-19 on Mortality: A Nationwide Comparative Cohort Study of Hospitalized Patients in the First, Second, Third, and Fourth Waves in the Netherlands.

Background: Large clinical trials on drugs for hospitalized coronavirus disease 2019 (COVID-19) patients have shown significant effects on mortality. There may be a discrepancy with the observed real-world effect. We describe the clinical characteristics and outcomes of hospitalized COVID-19 patients in the Netherlands during 4 pandemic waves and analyze the association of the newly introduced treatments with mortality, intensive care unit (ICU) admission, and discharge alive. Methods: We conducted a nationwide retrospective analysis of hospitalized COVID-19 patients between February 27, 2020, and December 31, 2021. Patients were categorized into waves and into treatment groups (hydroxychloroquine, remdesivir, neutralizing severe acute respiratory syndrome coronavirus 2 monoclonal antibodies, corticosteroids, and interleukin [IL]-6 antagonists). Four types of Cox regression analyses were used: unadjusted, adjusted, propensity matched, and propensity weighted. Results: Among 5643 patients from 11 hospitals, we observed a changing epidemiology during 4 pandemic waves, with a decrease in median age (67-64 years; P < .001), in in-hospital mortality on the ward (21%-15%; P < .001), and a trend in the ICU (24%-16%; P = .148). In ward patients, hydroxychloroquine was associated with increased mortality (1.54; 95% CI, 1.22-1.96), and remdesivir was associated with a higher rate of discharge alive within 29 days (1.16; 95% CI, 1.03-1.31). Corticosteroids were associated with a decrease in mortality (0.82; 95% CI, 0.69-0.96); the results of IL-6 antagonists were inconclusive. In patients directly admitted to the ICU, hydroxychloroquine, corticosteroids, and IL-6 antagonists were not associated with decreased mortality. Conclusions: Both remdesivir and corticosteroids were associated with better outcomes in ward patients with COVID-19. Continuous evaluation of real-world treatment effects is needed.

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.

Predictors of Nonseroconversion to SARS-CoV-2 Vaccination in Kidney Transplant Recipients

Background. Kidney transplant recipients (KTRs) are still at risk of severe COVID-19 disease after SARS‑CoV‑2 vaccination, especially when they have limited antibody formation. Our aim was to understand the factors that may limit their humoral response. Methods. Our data are derived from KTRs who were enrolled in the Dutch Renal Patients COVID-19 Vaccination consortium, using a discovery cohort and 2 external validation cohorts. Included in the discovery (N = 1804) and first validation (N = 288) cohorts were participants who received 2 doses of the mRNA-1273 vaccine. The second validation cohort consisted of KTRs who subsequently received a third dose of any SARS-CoV-2 vaccine (N = 1401). All participants had no history of SARS-CoV-2 infection. A multivariable logistic prediction model was built using stepwise backward regression analysis with nonseroconversion as the outcome. Results. The discovery cohort comprised 836 (46.3%) KTRs, the first validation cohort 124 (43.1%) KTRs, and the second validation cohort 358 (25.6%) KTRs who did not seroconvert. In the final multivariable model‚ 12 factors remained predictive for nonseroconversion: use of mycophenolate mofetil/mycophenolic acid (MMF/MPA);chronic lung disease, heart failure, and diabetes;increased age;shorter time after transplantation;lower body mass index;lower kidney function;no alcohol consumption;≥2 transplantations;and no use of mammalian target of rapamycin inhibitors or calcineurin inhibitors. The area under the curve was 0.77 (95% confidence interval [CI], 0.74-0.79) in the discovery cohort after adjustment for optimism, 0.81 (95% CI, 0.76-0.86) in the first validation cohort, and 0.67 (95% CI, 0.64-0.71) in the second validation cohort. The strongest predictor was the use of MMF/MPA, with a dose-dependent unfavorable effect, which remained after 3 vaccinations. Conclusions. In a large sample of KTRs, we identify a selection of KTRs at high risk of nonseroconversion after SARS-CoV-2 vaccination. Modulation of MMF/MPA treatment before vaccination may help to optimize vaccine response in these KTRs. This model contributes to future considerations on alternative vaccination strategies.

Immunomodulation and endothelial barrier protection mediate the association between oral imatinib and mortality in hospitalised COVID-19 patients

Introduction Imatinib reduced 90-day mortality in hospitalised COVID-19 patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19, and what baseline biological profile moderates the effect of imatinib. Methods Secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed-effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the above-described method. Results 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin 2 to 1 ratio, E-selectin, tumour necrosis factor (TNF)α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (HR 0.29, 95%-CI: 0.10–0.92). Conclusions The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.

Mortality and readmission rates among hospitalized COVID-19 patients with varying stages of chronic kidney disease: a multicenter retrospective cohort.

Chronic kidney disease (CKD) has been recognized as a highly prevalent risk factor for both the severity of coronavirus disease 2019 (COVID-19) and COVID-19 associated adverse outcomes. In this multicenter observational cohort study, we aim to determine mortality and readmission rates of patients hospitalized for COVID-19 across varying CKD stages. We performed a multicenter cohort study among COVID-19 patients included in the Dutch COVIDPredict cohort. The cohort consists of hospitalized patients from March 2020 until July 2021 with PCR-confirmed SARS-CoV-2 infection or a highly suspected CT scan-based infection with a CORADS score ≥ 4. A total of 4151 hospitalized COVID-19 patients were included of who 389 had a history of CKD before admission. After adjusting for all confounding covariables, in patients with CKD stage 3a, stage 3b, stage 4 and patients with KTX (kidney transplantation), odds ratios of death and readmission compared to patients without CKD ranged from 1.96 to 8.94. We demonstrate an evident increased 12-week mortality and readmission rate in patients with chronic kidney disease. Besides justified concerns for kidney transplant patients, clinicians should also be aware of more severe COVID-19 outcomes and increased vulnerability in CKD patients.