key: cord-0976819-do33oyvb
authors: Kox, Matthijs; Frenzel, Tim; Schouten, Jeroen; van de Veerdonk, Frank L.; Koenen, Hans J. P. M.; Pickkers, Peter
title: COVID-19 patients exhibit less pronounced immune suppression compared with bacterial septic shock patients
date: 2020-05-26
journal: Crit Care
DOI: 10.1186/s13054-020-02896-5
sha: 168c68b51e9f9f64d8cca2dbc5e9436cb4df8dc9
doc_id: 976819
cord_uid: do33oyvb

nan

cluded in this prospective observational study. COVID-19 was confirmed by two positive RT-PCR tests for SARS-CoV-2 in throat swabs and by CT scan findings. Fourteen patients were transferred from other ICUs. The median ICU length of stay at the time of study inclusion was 3 days. The study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent in the Netherlands. All patients or legal representatives were informed about the study details and allowed to abstain from participation. Ethylenediaminetetraacetic acid (EDTA)-anticoagulated blood was stored at 4-8°C until mHLA-DR expression analysis (performed within 2 h after withdrawal). Expression levels were determined using the Anti-HLA-DR/Anti-Monocyte Quantibrite assay (BD Biosciences, San Jose, USA) on a Navios flow cytometer and software (Beckman Coulter, Brea, USA). Total number of antibodies bound per cell (mAb/cell) were quantified using a standard curve constructed with Quantibrite phycoerythrin beads (BD Biosciences). All other data were extracted from the electronic patient record. For patients who were transferred from other ICUs, patient characteristics were obtained at admission to our ICU. Data were analysed using SPSS Statistics v22 (IBM, Armonk, USA) and GraphPad Prism v8.3.0 (GraphPad Software, La Jolla, USA).

Patient characteristics are listed in Table 1 . In line with previous observations [3] , the majority of patients was male and many had comorbidities. The median time from onset of COVID-19 symptoms to ICU admission was 11 days. All patients were mechanically ventilated and exhibited increases in inflammatory parameters ( Table 1) . As of March 27, 2020, two patients died (at 3 and 4 days post-ICU admission, data of only one timepoint of these patients was recorded), and 22 patients were still in the ICU.

Although mHLA-DR expression levels in COVID-19 patients were lower than those observed in healthy subjects (15,000-45,000 mAb/cell [5] ), the extent of suppression was less pronounced than observed in bacterial septic shock patients (geometric mean [95% CI] of 11,860 [11,035-12,746] vs. 5211 [4904-5537] mAb/cell, respectively; p < 0.0001; Fig. 1a , sepsis data from [1] ). mHLA-DR expression kinetics revealed no change over time (Fig. 1b) . Circulating C-reactive protein concentrations declined over time (Fig. 1c) , whereas no significant changes in circulating procalcitonin, leukocytes, or ferritin levels were observed ( Fig. 1d-f) . None of the patients developed a secondary infection during the follow-up period (last recorded timepoint: 16-17 days post-ICU admission, see Fig. 1 ).

In conclusion, despite a pronounced inflammatory response in COVID-19 patients, our preliminary results indicate more moderate innate immune suppression compared with bacterial septic shock patients. These findings are in accordance with a low incidence of secondary infections in COVID-19 patients. Therefore, innate immune suppression as a negative feedback mechanism following pathogenassociated molecular pattern-induced inflammation appears less pronounced in COVID-19. Fig. 1 a mHLA-DR expression in patients with COVID-19 (n = 24, multiple timepoints) and bacterial septic shock (n = 241, days 1-2, 3-4, and/or 6-8 after onset of septic shock, obtained using the same methodology, data recently published [1] ). Horizontal line indicates geometric mean. The dotted lines indicate the reference range in healthy subjects [5] . p value calculated using unpaired t test on log-transformed data. b-f Kinetics of mHLA-DR expression, circulating C-reactive protein, procalcitonin, leukocyte numbers, and ferritin in COVID-19 patients (individual data are shown, n = 24). The transparent grey line represents mean (b, c, e) or geometric mean (c, e) values of the entire cohort. The transparent pink line in b represents data obtained from [1] (geometric mean ± 95% CI, please note that values obtained at days 1-2 (n = 203), 3-4 (n = 205), and 6-8 (n = 133) after onset of septic shock are plotted at days 1-3, 4-5, and 6-7, respectively). The dotted lines in b indicate the reference range in healthy subjects [5] . p values next to the transparent grey line represent changes over time in COVID-19 patients, calculated using mixed model analysis (on log-transformed data for d and f). Differences between COVID-19 and sepsis patients in b were analysed using unpaired t tests on log-transformed data (p < 0.0001 on days 1-3 and 4-5, and p = 0.0015 on days 6-7)

Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes

Hlh Across Speciality Collaboration UK. COVID-19: consider cytokine storm syndromes and immunosuppression

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Massive increase in monocyte HLA-DR expression can be used to discriminate between septic shock and hemophagocytic lymphohistiocytosis-induced shock

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Next to the authors of this letter, the RCI-COVID- 19 

Authors' contributions MK and PP designed the study. TF, JS, and FvdV were responsible for the data collection. HK performed the flow cytometric analysis. MK performed the statistical analysis and drafted the manuscript. TF, JS, FvdV, HK, and PP critically revised the manuscript. All authors read and approved the final manuscript.

The work was internally funded by the participating departments.

All data generated or analysed during this study are included in this published article.

The study was carried out in accordance with the applicable rules concerning the review of research ethics committees and informed consent in the Netherlands. All patients or legal representatives were informed about the study details and could abstain from participation.

Not applicable.

The authors declare that they have no competing interests.