COVID02 - IL-6 serum levels predict severity and response to Tocilizumab in COVID-19: An observational study
1Rheumatology Service; 2Internal Medicine Service; 3Immunology Service; 4Pneumology Service; 5Intensive Care Unit; 6Emergency Service; 7Hematology Service. 8Hospital Pharmacy Service; 9Microbiology Service. Hospital Universitario de la Princesa. Autonomous University of Madrid. Princesa Health Research Institute (IIS-IP). Madrid.
Introduction: COVID-19 patients can develop a cytokine release syndrome leading to acute respiratory distress syndrome (ARDS) requiring invasive mechanical ventilation (IMV). Since interleukin-6 (IL-6) is a relevant cytokine in ARDS, its blockade with Tocilizumab (TCZ) could reduce mortality and/or morbidity in severe COVID-19.
Objectives: To determine whether baseline IL-6 serum levels can predict the need for IMV and the response to TCZ.
Methods: We performed a retrospective observational study including hospitalized patients diagnosed with COVID-19. Clinical information and laboratory findings, including IL-6 levels, were collected approximately 3 and 9 days after admission to be matched with pre-and post-administration of TCZ. Multivariable logistic and linear regression were used to analyze predictors of the need for IMV and evolution of the arterial oxygen tension/fraction of inspired oxygen ratio (PaO2/FiO2) respectively. Mortality was assessed through survival analysis and Cox proportional hazards modelling.
Results: 146 patients were studied, 66% were male with a median age of 63 years (table 1). 44 (30%) required IMV and 58 (40%) received TCZ, their main features are shown in tables 2 and 3 respectively. IL-6 levels showed a negative correlation with PaO2/FiO2 (r= -0.38; p < 0.001) and high levels (>30 pg/ml) discriminated patients requiring IMV with an AUC of 0.73. Furthermore, high IL-6 levels predicted the need for IMV [OR= 7.1 (95%CI 3.02 to 16.62)] (table 4) and early administration of TCZ (< 11 days from symptom onset) in these patients was associated with an improvement of the PaO2/FiO2 (p=0.048). Patients with high IL-6 and not treated with TCZ showed higher mortality [HR= 4.6 (1.7 to 12.7)], as well as those with low IL-6 treated with TCZ [HR= 3.6 (1.3 to 10.0)]. No serious adverse events were observed in the TCZ-treated group.
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Table 1. Baseline clinical characteristics and laboratory findings of the study population |
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Study Population (n = 146) |
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Age |
63 (54-71) |
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Male sex |
97 (66) |
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Comorbidities |
100 (69) |
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Duration of symptoms at admission (days) |
6 (4-7) |
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Baseline PaO2/FiO2 |
215 (112-310) |
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Treatment during hospitalization |
|
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Hydroxychloroquine |
137 (96) |
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Lopinavir/Ritonavir |
119 (83) |
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Azithromycin |
82 (57) |
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Interferon-β |
7 (5) |
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Glucocorticoids |
85 (59) |
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Methylprednisolone bolus |
61 (42) |
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Laboratory Findings |
|
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White Blood Count (103/mm3) |
7.64 (5.25–10.68) |
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Lymphocyte Count (103/mm3) |
0.83 (0.60–11.7) |
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Creatinine. mg/dl |
0.86 (0.70-1.10) |
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LDH (U/L) |
341 (256-461) |
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CK (U/L) |
72 (48-155) |
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Serum IL-6 (pg/ml) |
21.36 (7.53-54.21) |
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Ferritin (ng/ml) |
1,598 (830-2,305) |
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CRP (mg/dL) |
11.55 (5.16-22.53) |
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PCT (ng/ml) |
0.15 (0.10-0.35) |
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D-dimer (mg/ml) |
0.75 (0.48-1.48) |
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All categorical variables are expressed as number (%) and quantitative variables as median (p25-p75). PaO2/FiO2: arterial oxygen tension - fraction of inspired oxygen ratio; LDH: Lactate Dehydrogenase; IL-6: Interleukin-6; CRP: C-reactive protein; PCT: Procalcitonin. |
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Table 2. Baseline clinical characteristics of groups requiring vs not requiring Invasive Mechanical Ventilation |
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Invasive Mechanical Ventilation |
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Required (n = 44) |
Not-required (n = 102) |
P value |
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Age |
63.5 (56.5-72) |
62 (54-71) |
0.517 |
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Male sex |
32 (73) |
65 (64) |
0.291 |
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Comorbidities |
30 (68) |
70 (69) |
0.893 |
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Duration of symptoms at admission (days) |
5 (5-7) |
7 (4-8) |
0.265 |
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Baseline PaO2/FiO2 |
125.5 (75-207) |
247 (172-348) |
< 0.001 |
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Treatment during hospitalization |
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Hydroxychloroquine |
38 (86) |
99 (100) |
< 0.001 |
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Lopinavir/Ritonavir |
38 (86) |
81 (82) |
0.502 |
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Azithromycin |
24 (55) |
58 (59) |
0.652 |
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Interferon-β |
3 (7) |
4 (4) |
0.676 |
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Glucocorticoids |
27 (61) |
58 (59) |
0.755 |
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Methylprednisolone bolus |
21 (48) |
40 (40) |
0.414 |
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Laboratory Findings |
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White Blood Count (103/mm3) |
9.39 (6.59-13.31) |
6.93 (5.13-8.78) |
< 0.001 |
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Lymphocyte Count (103/mm3) |
0.74 (0.58-1.08) |
0.87 (0.62-1.26) |
0.029 |
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Creatinine (mg/dl) |
0.99 (0.71-1.20) |
0.85 (0.72-1.1) |
0.398 |
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LDH (U/L) |
413 (315-496) |
302 (224-443) |
0.001 |
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CK (U/L) |
67 (39.50-167.50) |
94 (59-140) |
0.617 |
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Serum IL-6 (pg/ml) |
49.20 (17.28-103.57) |
16.08 (6.09-42.03) |
< 0.001 |
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Ferritin (ng/ml) |
1,665 (602-2,765) |
1,573 (1,012-2,300) |
0.832 |
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CRP (mg/dL) |
17.09 (7.69-28.98) |
10.13 (4.83-18.48) |
0.003 |
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PCT (ng/ml) |
0.29 (0.14-0.46) |
0.13 (0.08-0.26) |
0.001 |
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D-dimer (mg/ml) |
0.92 (0.56-2.31) |
0.71 (0.48-1.19) |
0.058 |
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All categorical variables are expressed as number (%) and quantitative variables as median (p25-p75). PaO2/FiO2: arterial oxygen tension - fraction of inspired oxygen ratio; LDH: Lactate Dehydrogenase; IL-6: Interleukin-6; CRP: C-reactive protein; PCT: Procalcitonin. |
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Table 3. Baseline clinical characteristics of groups treated vs not treated with Tocilizumab |
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Tocilizumab |
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Treated (n = 58) |
Not treated (n = 88) |
P value |
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Age |
61 (54-70) |
64 (54-72) |
0.288 |
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Male sex |
40 (69) |
57 (65) |
0.600 |
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Comorbidities |
35 (61) |
64 (73) |
0.124 |
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Duration of symptoms at admission (days) |
6 (5-7) |
7 (4-8) |
0.612 |
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Baseline PaO2/FiO2 |
137 (88-232) |
248 (183-348) |
< 0.001 |
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Treatment during hospitalization |
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Hydroxychloroquine |
53 (93) |
84 (98) |
0.171 |
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Lopinavir/Ritonavir |
51 (89) |
68 (79) |
0.103 |
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Azithromycin |
33 (58) |
49 (57) |
0.913 |
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Interferon-β |
2 (4) |
5 (6) |
0.532 |
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Glucocorticoids |
38 (67) |
47 (55) |
0.152 |
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Methylprednisolone bolus |
31 (54) |
30 (35) |
0.018 |
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Laboratory Findings |
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White Blood Count (103/mm3) |
7.99 (5.17-11.85) |
7.52 (5.4-10.36) |
0.527 |
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Lymphocyte Count (103/mm3) |
0.74 (0.52-0.997) |
0.93 (0.66-1.47) |
0.001 |
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Creatinine (mg/dl) |
0.83 (0.70-1.05) |
0.90 (0.72-1.14) |
0.177 |
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LDH (U/L) |
425 (302-510) |
293.5 (221-388) |
< 0.001 |
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CK (U/L) |
69 (38-270) |
75.5 (49-125) |
0.785 |
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Serum IL-6 (pg/ml) |
41.85 (12.37-71.95) |
16.25 (6.27-44.95) |
0.007 |
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Ferritin (ng/ml) |
1,888 (1,152-2,844) |
1,461 (471-1,861) |
0.038 |
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CRP (mg/dL) |
13.73 (8.75-27.08) |
9.09 (4.78-19.31) |
0.005 |
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PCT (ng/ml) |
0.25 (0.13-0.36) |
0.14 (0.1-0.3) |
0.045 |
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D-dimer (mg/ml) |
0.75 (0.48-1.48) |
0.71 (0.53-1.22) |
0.491 |
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All categorical variables are expressed as number (%) and quantitative variables as median (p25-p75). PaO2/FiO2: arterial oxygen tension - fraction of inspired oxygen ratio; LDH: Lactate Dehydrogenase; IL-6: Interleukin-6; CRP: C-reactive protein; PCT: Procalcitonin. |
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Table 4. Logistic regression model for invasive mechanical ventilation |
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OR |
p |
95%CI |
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COPD |
5.41 |
0.030 |
1.17 to 24.94 |
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White Blood Count (103) |
1.05 |
0.116 |
0.99 to 1.12 |
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High baseline IL-6 levels* |
7.09 |
< 0.001 |
3.02 to 16.62 |
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OR: Odds Ratio; 95%CI: 95% Confidence Interval; COPD: Chronic Obstructive Pulmonary Disease; IL-6: interleukin 6. *High IL-6 was considered if >30 pg/ml. |
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Conclusions: High baseline IL-6 levels predicts IMV requirement in patients with COVID-19 as well as the response to treatment with TCZ. These findings can be of help in guiding clinicians for an early and adequate indication for IL-6 blockade.
