Adipocytokine plasma concentrations reflect influence of inflammation but not body mass index (BMI) on clinical outcomes of COVID-19 patients: A prospective observational study from the Netherlands.

Obesity is recognized as a risk factor for adverse outcome in COVID-19, but the molecular mechanisms underlying this relationship remain unknown. Adipose tissue functions as an endocrine organ by secreting multiple pro-inflammatory and anti-inflammatory factors, known as adipocytokines, which could be involved in COVID-19 severity. We explored the role of adipocytokines in COVID-19 and its association with BMI, clinical outcome, and inflammation. This is an observational study in 195 hospitalized COVID-19 patients. Serial plasma concentrations of the adipocytokines leptin, adiponectin, resistin, and various inflammatory cytokines were assessed. Adipocytokines were compared between patients with normal weight (BMI: 18.5-24.9 kg/m2 ), overweight (BMI: 25.0-29.9 kg/m2 ), and obesity (BMI ≥ 30 kg/m2 ), between patients admitted to the ICU and to non-ICU clinical wards, and between survivors and non-survivors. Patients with overweight and obesity displayed higher leptin concentrations and lower adiponectin concentrations throughout hospital admission (p < .001), whereas resistin concentrations were not different from patients with normal weight (p = .12). Resistin concentrations correlated with inflammatory markers and were persistently higher in ICU patients and non-survivors compared to non-ICU patients and survivors, respectively (both p < .001), whereas no such relationships were found for the other adipocytokines. In conclusion, leptin and adiponectin are associated with BMI, but not with clinical outcomes and inflammation in COVID-19 patients. In contrast, resistin is not associated with BMI, but high concentrations are associated with worse clinical outcomes and more pronounced inflammation. Therefore, it is unlikely that BMI-related adipocytokines or differences in the inflammatory response underlie obesity as a risk factor for severe COVID-19.

Clinical sepsis phenotypes in critically ill COVID-19 patients.

BACKGROUND: A greater understanding of disease heterogeneity may facilitate precision medicine for coronavirus disease 2019 (COVID-19). Previous work identified four distinct clinical phenotypes associated with outcome and treatment responses in non-COVID-19 sepsis patients, but it is unknown if and how these phenotypes are recapitulated in COVID-19 sepsis patients. METHODS: We applied the four non-COVID-19 sepsis phenotypes to a total of 52,274 critically ill patients, comprising two cohorts of COVID-19 sepsis patients (admitted before and after the introduction of dexamethasone as standard treatment) and three non-COVID-19 sepsis cohorts (non-COVID-19 viral pneumonia sepsis, bacterial pneumonia sepsis, and bacterial sepsis of non-pulmonary origin). Differences in proportions of phenotypes and their associated mortality were determined across these cohorts. RESULTS: Phenotype distribution was highly similar between COVID-19 and non-COVID-19 viral pneumonia sepsis cohorts, whereas the proportion of patients with the δ-phenotype was greater in both bacterial sepsis cohorts compared to the viral sepsis cohorts. The introduction of dexamethasone treatment was associated with an increased proportion of patients with the δ-phenotype (6% vs. 11% in the pre- and post-dexamethasone COVID-19 cohorts, respectively, p < 0.001). Across the cohorts, the α-phenotype was associated with the most favorable outcome, while the δ-phenotype was associated with the highest mortality. Survival of the δ-phenotype was markedly higher following the introduction of dexamethasone (60% vs 41%, p < 0.001), whereas no relevant differences in survival were observed for the other phenotypes among COVID-19 patients. CONCLUSIONS: Classification of critically ill COVID-19 patients into clinical phenotypes may aid prognostication, prediction of treatment efficacy, and facilitation of personalized medicine.

Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients.

BACKGROUND: Procalcitonin (PCT) and C-reactive protein (CRP) were previously shown to have value for the detection of secondary infections in critically ill COVID-19 patients. However, since the introduction of immunomodulatory therapy, the value of these biomarkers is unclear. We investigated PCT and CRP kinetics in critically ill COVID-19 patients treated with dexamethasone with or without tocilizumab, and assessed the value of these biomarkers to detect secondary bacterial infections. METHODS: In this prospective study, 190 critically ill COVID-19 patients were divided into three treatment groups: no dexamethasone, no tocilizumab (D-T-), dexamethasone, no tocilizumab (D+T-), and dexamethasone and tocilizumab (D+T+). Serial data of PCT and CRP were aligned on the last day of dexamethasone treatment, and kinetics of these biomarkers were analyzed between 6 days prior to cessation of dexamethasone and 10 days afterwards. Furthermore, the D+T- and D+T+ groups were subdivided into secondary infection and no-secondary infection groups to analyze differences in PCT and CRP kinetics and calculate detection accuracy of these biomarkers for the occurrence of a secondary infection. RESULTS: Following cessation of dexamethasone, there was a rebound in PCT and CRP levels, most pronounced in the D+T- group. Upon occurrence of a secondary infection, no significant increase in PCT and CRP levels was observed in the D+T- group (p = 0.052 and p = 0.08, respectively). Although PCT levels increased significantly in patients of the D+T+ group who developed a secondary infection (p = 0.0003), this rise was only apparent from day 2 post-infection onwards. CRP levels remained suppressed in the D+T+ group. Receiver operating curve analysis of PCT and CRP levels yielded area under the curves of 0.52 and 0.55, respectively, which are both markedly lower than those found in the group of COVID-19 patients not treated with immunomodulatory drugs (0.80 and 0.76, respectively, with p values for differences between groups of 0.001 and 0.02, respectively). CONCLUSIONS: Cessation of dexamethasone in critically ill COVID-19 patients results in a rebound increase in PCT and CRP levels unrelated to the occurrence of secondary bacterial infections. Furthermore, immunomodulatory treatment with dexamethasone and tocilizumab considerably reduces the value of PCT and CRP for detection of secondary infections in COVID-19 patients.

Effects of dalteparin on anti-Xa activities cannot be predicted in critically ill COVID-19 patients.

Critically ill COVID-19 patients are at high risk of thromboembolic events despite routine-dosed low-molecular-weight heparin thromboprophylaxis. However, in recent randomized trials increased-intensity thromboprophylaxis seemed futile and possibly even harmful. In this explorative pharmacokinetic (PK) study we measured anti-Xa activities on frequent timepoints in 15 critically ill COVID-19 patients receiving dalteparin and performed PK analysis by nonlinear mixed-effect modelling. A linear one-compartment model with first-order kinetics provided a good fit. However, wide interindividual variation in dalteparin absorption (variance 78%) and clearance (variance 34%) was observed, unexplained by routine clinical covariates. Using the final PK model for Monte Carlo simulations, we predicted increased-intensity dalteparin to result in anti-Xa activities well over prophylactic targets (0.2-0.4 IU/mL) in the majority of patients. Therapeutic-intensity dalteparin results in supratherapeutic anti-Xa levels (target 0.6-1.0 IU/mL) in 19% of patients and subtherapeutic levels in 22%. Therefore, anti-Xa measurements should guide high-intensity dalteparin in critically ill COVID-19 patients.

Interferon gamma immunotherapy in five critically ill COVID-19 patients with impaired cellular immunity: A case series.

BACKGROUND: Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shedding has been described in immunocompromised coronavirus disease 2019 (COVID-19) patients, resulting in protracted disease and poor outcome. Specific therapy to improve viral clearance and outcome for this group of patients is currently unavailable. METHODS: Five critically ill COVID-19 patients with severe defects in cellular immune responses, high SARS-CoV-2 viral RNA loads, and no respiratory improvement were treated with interferon gamma, 100 µg subcutaneously, thrice weekly. Bronchial secretion was collected every 48 h for routine diagnostic SARS-CoV-2 RT-PCR and viral culture. FINDINGS: Interferon gamma administration was followed by a rapid decline in SARS-CoV-2 load and a positive-to-negative viral culture conversion. Four patients recovered, and no signs of hyperinflammation were observed. CONCLUSIONS: Interferon gamma may be considered as adjuvant immunotherapy in a subset of immunocompromised COVID-19 patients. FUNDING: A.v.L. and R.v.C. are supported by National Institutes of Health (R01AI145781). G.J.O. and R.P.v.R. are supported by a VICI grant (016.VICI.170.090) from the Dutch Research Council (NWO). W.F.A. is supported by a clinical fellowship grant (9071561) of Netherlands Organization for Health Research and Development. M.G.N. is supported by an ERC advanced grant (833247) and a Spinoza grant of the Netherlands Organization for Scientific Research.

Body Mass Index and Mortality in Coronavirus Disease 2019 and Other Diseases: A Cohort Study in 35,506 ICU Patients.

OBJECTIVES: Obesity is a risk factor for severe coronavirus disease 2019 and might play a role in its pathophysiology. It is unknown whether body mass index is related to clinical outcome following ICU admission, as observed in various other categories of critically ill patients. We investigated the relationship between body mass index and inhospital mortality in critically ill coronavirus disease 2019 patients and in cohorts of ICU patients with non-severe acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and multiple trauma. DESIGN: Multicenter observational cohort study. SETTING: Eighty-two Dutch ICUs participating in the Dutch National Intensive Care Evaluation quality registry. PATIENTS: Thirty-five-thousand five-hundred six critically ill patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient characteristics and clinical outcomes were compared between four cohorts (coronavirus disease 2019, nonsevere acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and multiple trauma patients) and between body mass index categories within cohorts. Adjusted analyses of the relationship between body mass index and inhospital mortality within each cohort were performed using multivariable logistic regression. Coronavirus disease 2019 patients were more likely male, had a higher body mass index, lower Pao2/Fio2 ratio, and were more likely mechanically ventilated during the first 24 hours in the ICU compared with the other cohorts. Coronavirus disease 2019 patients had longer ICU and hospital length of stay, and higher inhospital mortality. Odds ratios for inhospital mortality for patients with body mass index greater than or equal to 35 kg/m2 compared with normal weight in the coronavirus disease 2019, nonsevere acute respiratory syndrome coronavirus 2 viral pneumonia, bacterial pneumonia, and trauma cohorts were 1.15 (0.79-1.67), 0.64 (0.43-0.95), 0.73 (0.61-0.87), and 0.81 (0.57-1.15), respectively. CONCLUSIONS: The obesity paradox, which is the inverse association between body mass index and mortality in critically ill patients, is not present in ICU patients with coronavirus disease 2019-related respiratory failure, in contrast to nonsevere acute respiratory syndrome coronavirus 2 viral and bacterial respiratory infections.

Increased sTREM-1 plasma concentrations are associated with poor clinical outcomes in patients with COVID-19.

Patients with sepsis display increased concentrations of sTREM-1 (soluble Triggering Receptor Expressed on Myeloid cells 1), and a phase II clinical trial focusing on TREM-1 modulation is ongoing. We investigated whether sTREM-1 circulating concentrations are associated with the outcome of patients with coronavirus disease 2019 (COVID-19) to assess the role of this pathway in COVID-19. This observational study was performed in two independent cohorts of patients with COVID-19. Plasma concentrations of sTREM-1 were assessed after ICU admission (pilot cohort) or after COVID-19 diagnosis (validation cohort). Routine laboratory and clinical parameters were collected from electronic patient files. Results showed sTREM-1 plasma concentrations were significantly elevated in patients with COVID-19 (161 [129-196] pg/ml) compared to healthy controls (104 [75-124] pg/ml; P<0.001). Patients with severe COVID-19 needing ICU admission displayed even higher sTREM-1 concentrations compared to less severely ill COVID-19 patients receiving clinical ward-based care (235 [176-319] pg/ml and 195 [139-283] pg/ml, respectively, P = 0.017). In addition, higher sTREM-1 plasma concentrations were observed in patients who did not survive the infection (326 [207-445] pg/ml) compared to survivors (199 [142-278] pg/ml, P<0.001). Survival analyses indicated that patients with higher sTREM-1 concentrations are at higher risk for death (hazard ratio = 3.3, 95%CI: 1.4-7.8). In conclusion, plasma sTREM-1 concentrations are elevated in patients with COVID-19, relate to disease severity, and discriminate between survivors and non-survivors. This suggests that the TREM-1 pathway is involved in the inflammatory reaction and the disease course of COVID-19, and therefore may be considered as a therapeutic target in severely ill patients with COVID-19.

A higher BMI is not associated with a different immune response and disease course in critically ill COVID-19 patients.

BACKGROUND/OBJECTIVES: Obesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients. SUBJECTS/METHODS: Sixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m2, n = 18, 72% class I obesity, 28% class II obesity) and non-obese (BMI < 30 kg/m2, n = 49) groups. Concentrations of circulating interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and IL-1 receptor antagonist (RA) were determined from ICU admission until 10 days afterward, and routine laboratory and clinical parameters were collected. RESULTS: BMI was 32.6 [31.2-34.5] and 26.0 [24.4-27.7] kg/m2 in the obese and non-obese group, respectively. Apart from temperature, which was significantly lower in obese patients (38.1 [36.9-38.9] vs. 38.7 [38.0 -39.5] °C, p = 0.02), there were no between-group differences on ICU admission. Plasma cytokine concentrations declined over time (p < 0.05 for all), but no differences between obese and non-obese patients were observed. Also, BMI did not correlate with the cytokine response (IL-6 r = 0.09, p = 0.61, TNF-α r = 0.03, p = 0.99, IP-10 r = 0.28, p = 0.11). The kinetics of clinical inflammatory parameters and respiratory mechanics were also similar in both groups. Finally, no differences in time on ventilator, ICU length of stay or 40-day mortality between obese and non-obese patients were apparent. CONCLUSIONS: In COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.

Anakinra treatment in critically ill COVID-19 patients: a prospective cohort study.

BACKGROUND: A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. METHODS: In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day - 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. RESULTS: Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) (p = 0.0002), ferritin (p = 0.009), and temperature (p = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature (p = 0.03), white blood cell counts (p = 0.02), and plasma levels of ferritin (p = 0.003), procalcitonin (p = 0.001), creatinine (p = 0.01), and bilirubin (p = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. CONCLUSIONS: Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.