All Patients with Severe Respiratory Failure Caused by SARS-CoV-2 Have Immune Dysregulation or MAS
We assessed the differences of immune activation and dysregulation between SARS-CoV-2 and other known severe infections in three patient cohorts: 104 patients with sepsis caused by bacterial CAP; 21 historical patients with 2009 H1N1 influenza; and 54 patients with CAP caused by SARS-CoV-2. Patients with bacterial CAP were screened for participation in a large-scale randomized clinical trial with the acronym PROVIDE (ClinicalTrials.gov NCT03332225). Patients with 2009 H1N1 influenza have been described in previous publications of our group (Giamarellos-Bourboulis et al., 2009, Raftogiannis et al., 2010). The clinical characteristics of patients with bacterial CAP and CAP caused by COVID-19 are described in Table 1 . Each cohort (bacterial sepsis and COVID-19) is split into patients who developed SRF and required MV and those who did not. Three main features need to be outlined: (1) patients with COVID-19 and SRF are less severe than those with severe bacterial CAP, on the basis of the traditional severity scores of sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II; (2) this leads to the conclusion that COVID-19 patients undergo an acute immune dysregulation with deterioration into SRF before the overall state of severity is advanced; and (3) although the burden of co-morbidities of patients with COVID-19, as expressed by the Charlson’s co-morbidity index, is higher among patients with SRF than among patients without SRF, it remains remarkably lower that traditional bacterial CAP and sepsis. It was also notable that the admission values of Glasgow Coma Scale scores of patients with bacterial CAP were 8.80 ± 4.76, and that of patients with COVID-19 was 14.71 ± 0.20 (p < 0.0001). This finding is fully compatible with clinical descriptions of severe COVID-19: patients are admitted at a relatively good clinical state and suddenly deteriorate.
Table 1 Baseline Clinical and Laboratory Characteristics of the Cohorts of Bacterial CAP and of Pneumonia Caused by SARS-CoV-2
No respiratory failure Severe respiratory failure
Bacterial SARS-CoV-2 p value Bacterial SARS-CoV-2 p value
Number of patients 48 26 56 28
Age (years, mean ± SD) 74.8 ± 16.8 59.2 ± 10.3 <0.0001 74.0 ± 12.6∗ 67.8 ± 10.8# <0.0001
Male gender (n, %) 25 (52.1) 15 (57.7) 0.807 27 (48.2)∗ 25 (89.3)∗∗ 0.0003
APACHE II score (mean ± SD) 18.50 ± 8.19 5.88 ± 3.40 <0.0001 26.63 ± 8.52∗∗ 10.17 ± 3.64## <0.0001
SOFA score (mean ± SD) 7.87 ± 3.81 1.50 ± 0.82 <0.0001 11.46 ± 3.15∗∗ 5.71 ± 2.19## <0.0001
CCI (mean ± SD) 5.53 ± 2.13 2.16 ± 1.46 <0.0001 5.57 ± 2.20∗ 3.39 ± 2.16## <0.0001
PSI (mean ± SD) 146.5 ± 43.2 80.0 ± 30.7 <0.0001 177.4 ± 40.4∗∗∗ 121.2 ± 28.3## <0.0001
Laboratory values (mean ± SD)
 Total white blood cell count (/mm3) 13,852.7 ± 7279.3 6379.6 ± 1993.9 <0.0001 17,666.9 ± 12,799.9∗ 9447.8 ± 3308.6## <0.0001
 Absolute platelet count (x103 /mm3) 201.3 ± 124.8 243.8 ± 109.1 0.141 224.3 ± 111.0∗ 213.9 ± 71.8∗ 0.654
 INR 1.28 ± 0.64 1.11 ± 0.15 0.187 1.33 ± 0.45∗ 1.17 ± 0.20∗ 0.077
 aPTT (secs) 37.19 ± 12.95 33.40 ± 6.22 0.165 38.42 ± 23.00∗ 37.52 ± 9.88∗ 0.844
 Fibrinogen (mg/dl) 475.6 ± 196.3 528.9 ± 152.5 0.234 495.3 ± 290.5∗ 693.5 ± 188.6# 0.002
 D-dimers (g/dl) 7.66 ± 13.9 2.76 ± 2.02 0.079 1.46 ± 1.62∗∗ 5.43 ± 6.41∗ <0.0001
 Creatinine (mg/dl) 1.55 ± 1.00 0.85 ± 0.19 0.001 1.71 ± 0.90∗ 1.11 ± 0.43# 0.001
 Total bilirubin (mg/dl) 1.43 ± 1.92 0.67 ± 0.50 0.052 1.17 ± 1.88∗ 0.97 ± 0.68∗ 0.588
 AST (U/l) 155.1 ± 308.1 39.9 ± 28.5 0.062 311.7 ± 748.2∗ 76.6 ± 59.2# 0.102
 ALT (U/l) 234.6 ± 764.3 40.2 ± 24.9 0.200 175.8 ± 378.0∗ 64.3 ± 62.2∗ 0.126
Main comorbidities (n, %)
 Type 2 diabetes mellitus 13 (27.1) 4 (15.4) 0.386 21 (37.5)∗ 6 (21.4)∗ 0.214
 Chronic heart failure 8 (16.7) 3 (11.5) 0.737 18 (32.1)∗ 4 (14.3)∗ 0.114
 Coronary heart disease 7 (14.6) 2 (7.7) 0.479 10 (17.9) 5 (17.9)∗ 1.0
Comparisons with the respective groups without respiratory failure by the Student’s t test: ∗p-non-significant; ∗∗p < 0.05; #p < 0.001; ##p < 0.0001. Abbreviations are as follows: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; APACHE, acute physiology and chronic health evaluation; CCI, Charlson’s comorbidity index; INR, international normalized ratio; PSI, pneumonia severity index; SD, standard deviation; SOFA, sequential organ failure assessment
Immune classification of patients with SARS-CoV-2 was performed by using the tools suggested for bacterial sepsis, i.e., ferritin more than 4,420 ng/mL for MAS (Kyriazopoulou et al., 2017), and HLA-DR molecules on CD14 monocytes lower than 5,000, in the absence of elevated ferritin, for the immune dysregulation phenotype (Lukaszewicz et al., 2009). It was found that contrary to the patients with bacterial CAP and SRF, all patients with SRF and SARS-CoV-2 had either immune dysregulation or MAS (Table 2 ).
Table 2 Association between Severe Respiratory Failure and Immune Classification among Patients with COVID-19 and Patients with Sepsis Caused by Bacterial CAP
Number of patients with SRF/total patients [%, (−95% CI, +95% CI)] p value∗
Bacterial CAP COVID-19
Intermediate 21/40 [52.5 (27.5-67.1)] 0/26 [0 (0-12.9)] <0.0001
Immunoparalysis (for bacterial CAP) and immune dysregulation (for COVID-19) or MAS 35/64 [54.7 (42.6-66.3)] 28/28 [100 (87.9-100)] <0.0001
∗comparisons by the Fisher exact test. Abbreviation is as follows: CI, confidence interval.