Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Model-informed precision dosing (MIPD) software tools are used to optimize dosage regimens in individual patients, aiming to achieve drug exposure targets associated with desirable clinical outcomes. Over the last few decades, numerous MIPD software tools have been developed. However, they have still not been widely integrated into clinical practice. This study focuses on identifying the requirements for and evaluating the performance of the currently available MIPD software tools. First, a total of 22 experts in the field of precision dosing completed a web survey to assess the importance (from 0; do not agree at all, to 10; completely agree) of 103 pre-established software tool criteria organized in eight categories: user-friendliness and utilization, user support, computational aspects, population models, quality and validation, output generation, privacy and data security, and cost. Category mean ± pooled standard deviation importance scores ranged from 7.2 ± 2.1 (user-friendliness and utilization) to 8.5 ± 1.8 (privacy and data security). The relative importance score of each criterion within a category was used as a weighting factor in the subsequent evaluation of the software tools. Ten software tools were identified through literature and internet searches: four software tools were provided by companies (DoseMeRx, InsightRX Nova, MwPharm++, and PrecisePK) and six were provided by non-company owners (AutoKinetics, BestDose, ID-ODS, NextDose, TDMx, and Tucuxi). All software tools performed well in all categories, although there were differences in terms of in-built software features, user interface design, the number of drug modules and populations, user support, quality control, and cost. Therefore, the choice for a certain software tool should be made based on these differences and personal preferences. However, there are still improvements to be made in terms of electronic health record integration, standardization of software and model validation strategies, and prospective evidence for the software tools’ clinical and cost benefits.

Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn’s disease [CD]. Real-life data in CD patients receiving ustekinumab intravenously [IV] during induction, followed by subcutaneous [SC] maintenance, are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6 mg/kg IV induction, with 90 mg SC every 8 weeks thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD [SES-CD] at Week 24), endoscopic remission [SES-CD ≤2], and clinical remission [daily stool frequency ≤2.8 and abdominal pain score ≤1] were assessed at weeks 4,8,16, and 24. Further serial analyses included patient-reported outcomes [PRO2], faecal calprotectin [fCal], and ustekinumab serum levels. SES-CD decreased from 11.5 [8.0–18.0] at baseline to 9.0 [6.0–16.0] at week [w]24 [p = 0.0009], but proportions of patients achieving endoscopic response [20.5%] or endoscopic remission [7.1%] were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline [1242.9 μg/g] to w4 [529.0 μg/g] and w8 [372.2 μg/g], but increased again by w16 [537.4 μg/g] and w24 [749.0 μg/g]. A clear exposure-response relationship was observed, both during induction and during maintenance therapy, with different thresholds depending on the targeted outcome. In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.