Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

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.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Heart rate time series characteristics for early detection of infections in critically ill patients.

It is difficult to make a distinction between inflammation and infection. Therefore, new strategies are required to allow accurate detection of infection. Here, we hypothesize that we can distinguish infected from non-infected ICU patients based on dynamic features of serum cytokine concentrations and heart rate time series. Serum cytokine profiles and heart rate time series of 39 patients were available for this study. The serum concentration of ten cytokines were measured using blood sampled every 10 min between 2100 and 0600 hours. Heart rate was recorded every minute. Ten metrics were used to extract features from these time series to obtain an accurate classification of infected patients. The predictive power of the metrics derived from the heart rate time series was investigated using decision tree analysis. Finally, logistic regression methods were used to examine whether classification performance improved with inclusion of features derived from the cytokine time series. The AUC of a decision tree based on two heart rate features was 0.88. The model had good calibration with 0.09 Hosmer-Lemeshow p value. There was no significant additional value of adding static cytokine levels or cytokine time series information to the generated decision tree model. The results suggest that heart rate is a better marker for infection than information captured by cytokine time series when the exact stage of infection is not known. The predictive value of (expensive) biomarkers should always be weighed against the routinely monitored data, and such biomarkers have to demonstrate added value.

Clinical and radiological factors associated with erosive radiographic progression in hand osteoarthritis.

OBJECTIVE: To identify prognostic factors of erosive progression in hand osteoarthritis (OA). METHOD: One hundred and fifty-four patients with hand OA were selected from an earlier cohort. X-rays, clinical and demographic data at baseline were present. All patients were seen for a follow-up between January and March 2014. Interphalangeal (IP) finger joints were scored on both radiographs using the anatomical scoring system. Radiographic progression was defined as a joint progressing from at least one anatomical phase, excluding the progression from a 'Normal' to 'Stationary' phase. Odds ratios (OR) and 95% confidence intervals (95% CI) of potential clinical and radiographic prognostic factors were calculated on joint, hand and patient level with a generalized estimating equation (GEE) model. RESULTS: Radiographic progression, including progression from 'N' to 'S' phase, was present in 1014 of 2750 joints (36.9%) after a mean follow-up of 5.8 years. On joint level, the following clinical factors were associated with radiographic progression (OR [95% CI]): presence of pain (1.48 [1.01-2.15]), tenderness (2.18 [1.56-3.05]), and soft tissue swelling (2.56 [1.54-4.24]). The following radiographic variables were significantly associated with erosive progression: presence of 'J' (16.74 [9.09-30.83]) and 'E' phase (76.34 [42.17-138.23]). On hand and patient level, soft tissue swelling, 'J' and 'E' phase were retained as prognostic factors. CONCLUSION: Pain, tenderness, soft tissue swelling, 'J' and 'E' phase were significantly associated with erosive progression in hand OA. These prognostic factors should be confirmed in further studies and considered when selecting patients for therapeutic trials with potential disease-modifying osteoarthritis drugs (DMODs).

Invasive Aspergillus niger complex infections in a Belgian tertiary care hospital.

The incidence of invasive infections caused by the Aspergillus niger species complex was 0.043 cases/10 000 patient-days in a Belgian university hospital (2005-2011). Molecular typing was performed on six available A. niger complex isolates involved in invasive disease from 2010 to 2011, revealing A. tubingensis, which has higher triazole minimal inhibitory concentrations, in five out of six cases.

Repetitive episodes of cryptogenic septicaemia in a patient with cirrhosis: a case of "heavy metal".

Endotipsitis or primary infection of a TIPS-stent, is an uncommon but possible life- threatening condition by its potential evolution to sepsis and death. Diagnosis should be suspected in patients with a TIPS-stent presenting with stent-dysfunction associated with fever or relapsing episodes of bacteremia/sepsis without any other alternative focus. A certain diagnosis is made by post-factum histopathological and/or microbiological examination of the TIPS-stent which is only possible after liver transplantation or at autopsy, whereas it can be highly suspected in case of repetitive positive blood-cultures without any other focus in a patient with a TIPS-stent. The microorganisms responsible for endotipsitis are most frequently of Gram-negative enteric origin. The regimen and duration of the treatment should be individualized and depends on multiple factors like the antibiotic sensitivity of the organism and the patients condition. In case of a fungal infection, longer treatment is recommended.