Supplemental Digital Content for Tocilizumab and COVID-19 Study

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Supplemental Digital Content

Supplement to: Lewis TC, Adhikari S, Tatapudi V, et al. A propensity-matched cohort

study of tocilizumab in patients with Covid-19.

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Table of Contents

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NYU Langone Tocilizumab Study Team Members 3

Table S1. General tocilizumab criteria 4

Table S2. Summary of baseline study variables pre-matching, overall and stratified by tocilizumab status

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Table S3. Standardized mean difference to assess matching quality based on the variable patients were matched on

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Table S4. Summary of study outcomes pre-matching, overall and stratified by tocilizumab status

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Table S5. Hazard ratio from competing risks regression comparing time to inpatient discharge between tocilizumab and matched control group

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Figure S1: Competing risk regression comparing time to mortality with discharge as a competing event, and for time to discharge with mortality as a competing event, for those who did and did not receive steroids

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NYU Langone Tocilizumab Study Group Members

Institution Investigators

NYU Langone Health – Manhattan, NY Department of Pulmonary and Critical Care Medicine

Nancy Amoroso, MD Sam Parnia, MD John Munger, MD Department of Pharmacy Hongkai Bao, PharmD

Tania Ahuja, PharmD Serena Arnouk, PharmD Frank Cirrone, PharmD Cristian Merchan, PharmD John Papadopoulos, PharmD NYU Langone Transplant Institute Elaina Weldon, MSN, ACNP-BC

Bonnie Lonze, MD NYU Grossman School of Medicine Judith S. Hochman, MD NYU Winthrop Hospital – Mineola, NY

Department of Pulmonary and Critical Care Medicine

Peter Spiegler, MD Department of Infectious Diseases Martin Backer, MD

Diane Johnson, MD

Sigridh A. Munoz-Gomez, MD Adina Musta, MD

Daria Zainoullina, MD Dinuli Delpachitra, MD

Department of Internal Medicine Janette Hernandez-Torres, MD Rose Aye, MD

NYU Langone Hospital Brooklyn – Brooklyn, NY Department of Pulmonary and Critical

Care Medicine

Tshering Amdo, MD Jorge Mercado, MD Mark H. Adelman, MD Andrew DeMaio, MD Department of Pharmacy Ola Elnadoury, PharmD

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Table S1: General tocilizumab criteria

1. SARS-CoV-2 PCR positive

2. Within 72 hours of presentation to hospital

3. Significant oxygen requirement (4-6 L nasal cannula or higher) or rapidly increasing oxygen requirements

4. Elevated inflammatory markers

a) C-reactive protein > 100 mg/L b) Ferritin > 1,000 ng/mL

c) Lactate dehydrogenase > 220 U/L 5. Bilateral consolidations on chest radiography

aPCR=polymerase chain reaction.

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Table S2: Baseline study variables pre-matching, overall and stratified by tocilizumab status

Variable

Total (IQR/%)

On Tocilizumab

(IQR/%)

Not on Tocilizumab

(IQR/%)

p- value (n=3580) (n=497) (n=3083)

Age, Years, median (IQR)

64 (52,75) 61 (52,69) 64 (52,76)

<0.00 1 Gender, no. (%)

Female

1427 (39.86%) 145 (29.18%) 1282 (41.58%)

<0.00 1

Male 2153 (60.14%) 352 (70.82%) 1801 (58.42%)

Race, no. (%)

African-American 550 (15.36%) 73 (14.69%) 477 (15.47%) 0.778

Asian 242 (6.76%) 37 (7.44%) 205 (6.65%)

White 1552 (43.35%) 222 (44.67%) 1330 (43.14%)

Other/Unknown 1236 (34.53%) 165 (33.20%) 1071 (34.74%) Smoking Status, no. (%)

Current 61 (1.70%) 1 (0.20%) 60 (1.95%) 0.02

Former 707 (19.75%) 101 (20.32%) 606 (19.66%)

Unknown or Never 2812 (78.55%) 395 (79.48%) 2417 (78.40%) BMI (continuous), kg/m²,

median (IQR)

29.18 (25.79, 33.41)

30.14 (26.50, 33.90)

29.05 (25.7, 33.28)

0.002

BMI (categorical), kg/m², no. (%)

<30 1983 (55.39%) 245 (49.30%) 1738 (56.37%) 0.011

30-40 254 (7.09%) 37 (7.44%) 217 (7.04%)

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>40 1343 (37.51%) 215 (43.23%) 1128 (36.59%)

Diabetes, no. (%) 1035 (28.91%) 124 (24.95%) 911 (29.55%) 0.041 Heart disease, no. (%) 483 (13.49%) 52 (10.46%) 431 (13.98%) 0.039 Hypertension, no. (%)

1676 (46.82%) 194 (39.03%) 1482 (48.07%)

<0.00 1 Lung disease, no. (%)

726 (20.28%) 66 (13.28%) 660 (21.41%)

<0.00 1 Solid organ transplant, no.

(%)

33 (0.92%) 9 (1.81%) 24 (0.78%) 0.047

Leukemia/lymphoma, no. (%) 49 (1.37%) 5 (1.01%) 44 (1.43%) 0.588 Vasopressors (pre-Toci), no.

(%)

415 (11.59%) 28 (5.63%) 387 (12.55%)

<0.00 1 Steroid (at any point), no. (%)

731 (20.42%) 257 (51.71%) 474 (15.37%)

<0.00 1 NMB (pre-Toci), no. (%) 552 (15.42%) 78 (15.69%) 474 (15.37%) 0.908 ECMO (pre-Toci), no. (%) 14 (0.39%) 3 (0.60%) 11 (0.36%) 0.667 Days since admission

(baseline), median (IQR)

6 (3, 11) 3 (2, 5) 6 (3, 12)

<0.00 1 Hydroxychloroquine, no. (%)

2880 (80.45%) 470 (94.57%) 2410 (78.17%)

<0.00 1 Azithromycin, no. (%)

2673 (74.66%) 450 (90.54%) 2223 (72.11%)

<0.00 1 Nitazoxanide, no. (%) 241 (6.73%) 31 (6.24%) 210 (6.81%) 0.706 Lopinavir/ritonavir, no. (%) 292 (8.16%) 54 (10.87%) 238 (7.72%) 0.022 Time admitted in hospital, no. (%)

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Before April 1 1876 (52.40%) 230 (46.28%) 1646 (53.39%) 0.004 After April 1 1704 (47.60%) 267 (53.72%) 1437 (46.61%) 0.004 CRP (continuous), mg/L,

median (IQR)

94 (34.9, 193)

202.6 (143.17,

255.59)

60.95 (23.5, 136)

<0.00 1

CRP (categorical), mg/L, no. (%) 0-34

408 (11.40%) 6 (1.21%) 402 (13.04%)

<0.00 1

35-94 405 (11.31%) 34 (6.84%) 371 (12.03%)

95-192 402 (11.23%) 139 (27.97%) 263 (8.53%)

193+ 406 (11.34%) 225 (45.27%) 181 (5.87%)

Not measured 1959 (54.72%) 93 (18.71%) 1866 (60.53%) D-dimer (continuous), ng/mL,

median (IQR)

756 (344, 2208.5)

892 (474, 2540.5)

716 (313, 2151)

<0.00 1 D-dimer (categorical), ng/mL, no. (%)

0-343

301 (8.41%) 43 (8.65%) 258 (8.37%)

<0.00 1

344-752 303 (8.46%) 93 (18.71%) 210 (6.81%)

753-2207 304 (8.49%) 84 (16.90%) 220 (7.14%)

2207+ 304 (8.49%) 83 (16.70%) 221 (7.17%)

Not measured 2368 (66.15%) 194 (39.03%) 2174 (70.52%) Ferritin (continuous), ng/mL,

median (IQR)

989.5 (484, 1916.78)

1522 (995, 2635)

790 (400.65,

1622.5)

<0.00 1

Ferritin (categorical), ng/mL, no. (%)

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0-483

381 (10.64%) 27 (5.43%) 354 (11.48%)

<0.00 1

484-990 380 (10.61%) 73 (14.69%) 307 (9.96%)

990-1917 380 (10.61%) 146 (29.38%) 234 (7.59%)

1917+ 381 (10.64%) 153 (30.78%) 228 (7.40%)

Not measured 2058 (57.49%) 98 (19.72%) 1960 (63.57%) IL-6 (continuous), pg/mL,

median (IQR)

21 (6,86) 29 (14,80) 11 (5,97) 0.003

IL-6 (categorical), pg/mL, no. (%) 0-6

63 (1.76%) 18 (3.62%) 45 (1.46%)

<0.00 1

7-21 58 (1.62%) 30 (6.04%) 28 (0.91%)

22-86 57 (1.59%) 45 (9.05%) 12 (0.39%)

87+ 59 (1.65%) 28 (5.63%) 31(1.01%)

Not measured 3343 (93.38%) 376 (75.65%) 2967 (96.24%) Oxygen Support, no. (%)

None (room air)

1702 (47.54%) 22 (4.43%) 1680 (54.49%)

<0.00 1 Nasal cannula or mask 1138 (31.79%) 273 (54.93%) 865 (28.06%)

High flow 490 (13.69%) 139 (27.97%) 351 (11.39%) Mechanical Ventilation 250 (6.98%) 63 (12.68%) 187 (6.07%)

*BMI=body mass index; CRP=C-reactive protein; ECMO=extracorporeal membrane oxygenation; IL-6=interleukin 6; NMB=neuromuscular blocker; Toci=tocilizumab.

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Table S3. Standardized mean difference to assess matching quality based on the variable patients were matched on

Matching variables

Control Pre Matching

Control Post Matching

On Tocilizumab

(n=497 )

Not on Tocilizumab

(n=3083 )

Std.

Mean Diff.

Not on Tocilizumab

(n=497)

Std.

Mean Diff.

Age, years 60.161 62.982

- 0.197

61.853 -0.118

Race, Reference Hispanic

African-American 73 (14.70%) 477 (15.50%) - 0.022

84 (16.90%) -0.062

Asian 37 (7.40%) 205 (6.60%) 0.03 33 (6.64%) 0.031

White

222 (44.70%)

1330 (43.10%)

0.031 211 (42.45%) 0.044

Other/ unknown

165 (33.20%)

1071 (34.70%)

- 0.033

169 (34.00%) -0.017

Male

352 (70.80%)

1801 (58.40%)

0.273 327 (65.79%) 0.111

Smoking status (Reference current smoker)

Former smoker

101 (20.30%)

606 (19.70%) 0.017 106 (21.33%) -0.025

Unknown or never smoker

395 (79.50%)

2417 (78.40%)

0.027 390 (78.47%) 0.025

BMI, kg/m² 30.867 30.019 0.135 30.427 0.07

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ECMO 3 (0.60%) 11 (0.36%) 0.032 5(1.01%) -0.052

Steroid (at any point)

257 (51.70%)

474 (15.37%) 0.726 125 (25.15%) 0.531

NMB at baseline

257 (15.70%)

474 (15.37%) 0.009 90 (18.11%) -0.066

Vasopressor at baseline

28 (5.60%) 387 (12.55%) -0.3 48 (9.66%) -0.174

Lopinavir/ritonavir 54 (10.90%) 238 (7.72%) 0.101 35 (7.04%) 0.123

Hydroxychloroquine

470 (94.60%)

2410 (78.17%)

0.723 456 (91.75%) 0.124

Azithromycin

450 (90.50%)

2223 (72.11%)

0.629 427 (85.92%) 0.158

Nitazoxanide 31 (6.20%) 210 (6.81%) - 0.024

38 (7.65%) -0.058

Hypertension

194 (39.00%)

1482 (48.07%)

- 0.185

204 (41.05%) -0.041

Diabetes 124 (24.90%) 911 (29.55%) - 0.106

135 (27.16%) -0.051

Solid organ transplant

9 (1.80%)

24 (0.78%)

0.077 4 (0.80%) 0.075

Lung disease 66 (13.30%) 660 (21.41%) - 0.239

78 (15.69%) -0.071

Heart disease 52 (10.50%) 431 (13.98%) - 0.115

56 (11.27%) -0.026

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Treatment month,

after April 1

267 (53.70%)

1437 (46.61%)

0.142 262 (52.72%) 0.02

Days in hospital 3.817 8.527

- 1.385

5.429 -0.474

CRP at baseline, mg/L (Reference 0-34)

35 – 94 34 (6.80%) 371 (12.03%) - 0.205

52 (10.46%) -0.143

95 – 192

139 (27.97%)

263 (8.53%) 0.433 105 (21.13%) 0.152

193+ 225 (45.30%) 181 (5.87%) 0.791 115 (23.14%) 0.444

Unmeasured 93 (18.70%)

1866 (60.53%)

- 1.071

209 (42.05%) -0.598

D-dimer at baseline, ng/mL (Reference 0-343)

344-752 93 (18.70%) 210 (6.81%) 0.305 51 (10.26%) 0.216 753-2207 84 (16.90%) 220 (7.14%) 0.26 63 (12.68%) 0.113 2207+ 83 (16.70%) 221 (7.17%) 0.255 72 (14.49%) 0.059

Unmeasured 194 (39.00%)

2174 (70.52%)

- 0.645

279 (56.14%) -0.35

Oxygen support at baseline, Reference None/ Room air Nasal cannula or

mask

273 (54.93%) 865 (28.06%) 0.54 297 (59.76%) -0.097

High flow nasal cannula

139 (27.97%) 351 (11.39%) 0.369 112 (22.54%) 0.121

Mechanical ventilation

63 (12.68%) 187 (6.07%) 0.198 47 (9.46%) 0.097

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IL-6 at baseline, pg/mL (Reference 0-6)

7-21 30 (6.04%) 28 (0.91%) 0.215 13 (2.62%) 0.143

22-86 45 (9.05%) 12 (0.39%) 0.302 7 (1.41%) 0.266

87+ 28 (5.63%) 31 (1.01%) 0.201 21 (4.23%) 0.061

Unmeasured 376 (75.65%)

2967 (96.24%)

- 0.479

445 (89.54%) -0.323

Ferritin, ng/mL (Reference 0-483)

484-990 73 (14.69%) 307 (9.96%) 0.133 67 (13.48%) 0.034 991-1917 146 (29.38%) 234 (7.59%) 0.478 83 (16.70%) 0.278 1917+ 153 (30.78%) 228 (7.40%) 0.506 93 (18.71%) 0.261

Unmeasured 98 (19.72%)

1960 (63.57%)

- 1.101

226 (45.47%) -0.647

Mean distance 0.679 0.052 1.989 0.264 1.315

*BMI=body mass index; CRP=C-reactive protein; ECMO=extracorporeal membrane oxygenation; IL-=interleukin 6; NMB=neuromuscular blocker.

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Table S4: Study outcomes pre-matching, overall and stratified by tocilizumab status

Outcome

Total (IQR/%)

On Tocilizumab

(IQR/%)

Not on Tocilizumab

(IQR/%)

p-value

(n=3580) (n=497) (n=3083)

Death, no. (%) 855 (23.88%) 145 (29.18%) 710 (23.03%) 0.003

Discharged, no. (%)

2688

(75.08%) 332 (66.80%)

2356 (76.42%)

<0.001

Still hospitalized, no. (%) 37 (1.03%) 20 (4.02%) 17 (0.55%) <0.001 Secondary infection, no. (%) 604 (16.87%) 171 (34.41%) 433 (14.04%) <0.001 BSI, no. (%) 231 (6.45%) 69 (13.88%) 162 (5.25%) <0.001 PNA, no. (%) 313 (8.74%) 129 (25.96%) 184 (5.97%) <0.001 UTI, no. (%) 230 (6.42%) 40 (8.05%) 190 (6.16%) 0.136 Off ECMO (after Toci), no.

(%)

22 (0.61%) 19 (3.82%) 3 (0.10%) <0.001

ICU length of stay (days), median (IQR)

8.45 (2.64, 18.46)

13.8 (6.18, 23.2)

6.2 (1.82, 15.32)

<0.001

Time to death (days), median (IQR)

9 (5, 16.5) 16 (9, 26) 8 (5, 14) <0.001

Time to discharge (days), median (IQR)

6 (3, 11) 16 (11, 31) 5 (3, 9) <0.001

Time to any infection (days), median (IQR)

6 (1, 13) 10 (5, 15) 4 (1, 11) <0.001

Time to BSI (days), median (IQR)

7 (1, 15) 12 (7, 16) 4 (0, 12.75) <0.001

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Time to PNA (days), median

(IQR)

10 (5, 16) 12 (7, 17) 9 (4, 15) 0.001

Time to UTI (days), median (IQR)

3 (0.25, 13.75) 13.5 (2, 19.5) 1 (0, 10) <0.001

aAll comparisons are unadjusted. BSI=bloodstream infection; ECMO=extracorporeal membrane oxygenation; ICU=intensive care unit; PNA=pneumonia; Toci=tocilizumab; UTI=urinary tract infection.

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Table S5: Competing risk regression comparing time to inpatient discharge between

tocilizumab and matched control group

Unadjusted Adjusted

Hazard Ratio

95% CI

p- value

Hazard Ratio 95% CI p-value

Tocilizumab

0.86

(0.73, 1.01)

0.074 0.96 (0.78, 1.17) 0.67

Steroid use

0.4 (0.34, 0.48) 0 Pre-Toci

vasopressors

0.47 (0.30, 0.72) 0.001

Azithromycin 1.1 (0.82, 1.48) 0.52

Days in hospital 0.97 (0.95, 1) 0.048

CRP, mg/L

0-34 1.0 (Reference)

35-94 0.87 (0.52, 1.45) 0.59

95-192 0.54 (0.33, 0.9 ) 0.017

193+ 0.37 (0.22, 0.62) 0

Unmeasured 0.72 (0.41, 1.27) 0.26

D-dimer, ng/mL

0-343 1.0 (Reference)

344-752 0.71 (0.51, 0.97) 0.032

753-2207 0.4 (0.28, 0.57) 0

2207+ 0.29 (0.19, 0.43) 0

Unmeasured 0.57 (0.42, 0.78) 0

IL-6, pg/mL

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0-6 1.0 (Reference)

7-21 0.74 (0.44, 1.24) 0.25

22-86 0.51 (0.31, 0.84) 0.008

87+ 0.38 (0.21, 0.7) 0.002

Unmeasured 0.66 (0.45, 0.98) 0.041

Ferritin, ng/mL

0-483 1.0 (Reference)

484-990 1.05 (0.72, 1.53) 0.81

991-1917 0.98 (0.68, 1.41) 0.89

1917+ 0.76 (0.52, 1.1) 0.14

Unmeasured 0.74 (0.47, 1.17) 0.19

aCRP=C-reactive protein; IL-6=interleukin 6; Toci=tocilizumab

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Figure S1: Competing risk regression comparing time to mortality with discharge as a

competing event, and for time to discharge with mortality as a competing event, for those who did and did not receive steroids in the matched cohort

Death,

Days 0 20 40 60 80

Steroids, n events/

n at risk

0/497 134/363 50/313 7/306 2/304

No Steroids, n events/n at risk

2/495 158/337 2/335 1/334 0/334

Discharge,

Days 0 20 40 60 80

Steroids, n events/

n at risk

0/497 88/409 47/362 8/354 2/352

No Steroids, n events/

n at risk

2/495 204/291 5/286 0/286 0/286