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Chest Infections Original Research

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Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized COVID-19 Patients

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Survival and Clinical Outcomes

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Christina C. Price, MD; Frederick L. Altice, MD; Yu Shyr, PhD; Alan Koff, MBBS; Lauren Pischel, MD; George Goshua, MD; 67 68

Marwan M. Azar, MD; Dayna Mcmanus, PharmD; Sheau-Chiann Chen, PhD; Shana E. Gleeson, MD; 69 Clemente J. Britto, MD; Veronica Azmy, MD; Kelsey Kaman, MD; David C. Gaston, MD, PhD; Matthew Davis, PharmD; 70

Trisha Burrello, MS; Zachary Harris, MD; Merceditas S. Villanueva, MD; Lydia Aoun-Barakat, MD; Insoo Kang, MD;

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Stuart Seropian, MD; Geoffrey Chupp, MD; Richard Bucala, MD, PhD; Naftali Kaminski, MD; Alfred I. Lee, MD, PhD;

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Patricia Mucci LoRusso, DO, PhD; Jeffrey E. Topal, MD; Charles Dela Cruz, MD, PhD; and Maricar Malinis, MD

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Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syn-76 drome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. 77

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RESEARCH QUESTION:

BACKGROUND:

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The goal of this study was to determine if tocilizumab benefits patients 78 79 hospitalized with COVID-19.

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This observational study of consecutive COVID-19 patients hos- 81 pitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020,82 was conducted by chart review. Patients were treated with tocilizumab using an algorithm that83 targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and84 stratified according to disease severity designated at admission (severe, $ 3 L supplemental oxygen85 to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of86 clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were 87 88 conducted for race/ethnicity. STUDY DESIGN AND METHODS:

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Among the 239 patients, median age was 64 years; 36% and 19% were black and His90 panic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease 91 was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV92 (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P ¼ .003). Tocilizumab-treated 93 patients (n ¼ 153 [64%]) comprised 90% of those with severe disease; 44% of patients with 94 nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe 95 disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P 93%; 220 patients with critical disease (ie, requiring MV) were included in this

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group. As treatment experience evolved, clinicians increasingly prescribed tocilizumab to treat nonsevere patients with evolving CRS, manifested by increasing high-sensitivity C-reactive protein (hs-CRP) levels and oxygen requirements. Other recommendations for antiviral agents, hydroxychloroquine, and frequency of monitoring were also provided (e-Appendix 2). Patients admitted with severe disease could receive tocilizumab immediately; patients with nonsevere disease could receive it later if CRS evolved. Ultimately, treatment decisions were made by the provider based on clinical judgment. Tocilizumab was administered 8 mg/kg intravenously, not to exceed 800 mg; a second dose could be given if the patient had a markedly elevated BMI. Data Collection Structured chart review included time points such as symptom onset, hospitalization, MV, discharge, and death. Death was assessed either as occurring during hospitalization or following discharge and included a 21-day observation period. Definitions We included parameters recorded either upon admission, or for repeated measures, as once or twice daily as listed in e-Appendix 3. For analysis purposes, disease severity was designated at admission, recognizing that some patients with nonsevere disease would progress. Laboratory toxicity was scored according to guidelines set forth by the US Food and Drug Administration, ranging from 0 (no toxicity) to 4 (life-threatening). SpO2 was determined as the highest value measured for a 24-h period, irrespective of fluctuations. A 13-point scale was used to examine changes in oxygenation status over 14 days (eAppendix 4) following tocilizumab administration, reported as either worse (higher oxygen requirement) or improved (no change or improved). For the pre- and post-tocilizumab outcomes, all pretreatment values were those immediately prior to tocilizumab administration. If alive and hospitalized, patients’ posttreatment biomarkers and safety data were collected over 14 days; violin plots were deployed to show changes in the outcomes over the 14 days.

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Statistical Analysis

We hypothesized that patients treated for CRS, irrespective of disease 277 severity at the time of admission, would have improved outcomes 278 relative to other case series and that tocilizumab-treated patients 279 would have survival outcomes more like patients with less severe 280 disease. The primary outcome was 14-day survival. Secondary outcomes included MV days and post-tocilizumab CRS response. 281 Prespecified subgroup analyses were for those who received 282 tocilizumab and for those who required MV. Because there are no 283 data to guide response to tocilizumab use in COVID-19 patients, 284 pre/post assessments of oxygenation status, biomarkers, and adverse 285 consequences were made in tocilizumab-treated patients. Last, because of new reports of increased mortality in black and Hispanic 286 subjects,15 a post hoc age-adjusted survival analysis of race/ethnicity 287 was conducted. 288 We reported the mean and SD for nonskewed data and the median and 289 interquartile range for skewed data. Overall survival was estimated by 290 using the Kaplan-Meier estimator with 95% Greenwood CIs. The pre/ 291 post tocilizumab changes were examined by using either the McNemar 292 test or the Wilcoxon signed-rank test for categorical and continuous 293 variables, respectively. For severe and nonsevere subgroups, 2 difference between these two groups used either c or Wilcoxon 294 rank sum testing for categorical and continuous variables. The log- 295 rank test was used for survival data. No comparisons were made 296 between patients treated and not treated with tocilizumab due to the 297 nonrandomized study design. 298 Sample size justification used precision analysis in which computer 299 simulation was employed to estimate the half-width of the 300 95% Greenwood CIs for survival data. Assumptions for the survival 301 curve include exponential distribution with z10% attrition within 302 30 days. We simulated 2,000 times for each condition. With the proposed sample size (ie, 120-180), the half-width of the 303 95% Greenwood CI is # 10%. A two-sided P value < .05 was 304 considered statistically significant; all analyses were performed by 305 using R 3.6.3 (R Foundation for Statistical Computing). 306 307

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Results Over the 21-day observation period, 239 consecutive COVID-19 patients were admitted, with 104 (44%) meeting admission criteria for severe disease (Table 1). Figure 1 shows the daily census for all COVID-19 patients hospitalized and for those on MV for the 21-day observation period plus the 21-day follow-up period. Total census increased markedly to 209 after three weeks and was 450 three weeks later, after accounting for discharges and deaths. MV census increased early but flattened and never exceeded 18% of hospital census. The demographic, clinical presentation, and concomitant treatment data are presented in Table 1, stratified according to disease severity; 64% of all patients received tocilizumab. Patients with severe and nonsevere disease did not differ by age, sex, race/ ethnicity, or type or number of comorbidities. Those with severe disease were, however, significantly more likely to have higher admission hs-CRP and IL-6 levels, abnormal chest radiographs, and to receive adjuvant

medications such as hydroxychloroquine, glucocorticoids, and tocilizumab. Relative to patients with nonsevere disease, those with severe disease were more likely to receive tocilizumab (90% vs 44%; P < .001) and have a shorter median time from admission to tocilizumab administration (2 vs 3 days; P < .001).

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Fourteen-day survival for the 239 patients was 86% and 316 was lower (78% vs 93%; P < .001) for patients with 317 severe disease (Fig 2). Overall, 53 patients (22%) 318 required MV, higher among patients with severe disease 319 (44 vs 5%; P < .001). Fourteen-day survival for patients 320 321 receiving MV was 72%. 322

Among tocilizumab-treated patients, no differences were 323 observed for age, sex, race/ethnicity, or medical 324 comorbidities when stratified according to disease 325 severity (Table 2). Patients with severe disease had 326 327 significantly higher admission hs-CRP levels and Q11 abnormal chest radiographs. Although median hs-CRP 328 levels were higher for patients with severe disease upon 329 admission (120 vs 71 mg/L; P ¼ .002), they were similar 330

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TABLE 1

) ] Baseline Characteristics of Patients, Stratified According to COVID-19 Disease Severity (N ¼ 239

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Variable

No.

344 345

388 389 390

b

64 (22-99)

62 (23-99)

65 (22-93)

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Sex

238

.

.

.

.09 a

392

113/238 (47%)

71/135 (53%)

42/103 (41%)

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393

125/238 (53%)

64/135 (47%)

61/103 (59%)

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394

.82 a

395

Male

343

387 P Value

239

339

342

Severe (n ¼ 104)

Age, median (range), y

Female

341

Nonsevere (n ¼ 135)

Patient characteristics

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Entire Sample (N ¼ 239)

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238

Race/ethnicity

238

391

African American

86/238 (36%)

48/134 (36%)

38/104 (37%)

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396

Hispanic

45/238 (19%)

28/134 (21%)

17/104 (16%)

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397

White

95/238 (40%)

51/134 (38%)

44/104 (42%)

.

Other

12/238 (5%)

7/134 (5.2%)

5/104 (4.8%)

.

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Days of symptoms prior to hospitalization, median (IQR)

233

5.0 (2.0, 8.0)

3.0 (2.0, 6.0)

6.0 (2.0, 8.0)

< .001 b

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Days hospitalized, median (IQR)

239

10 (7, 20)

10 (6, 19)

11 (8, 22)

.06 b

403

349

Hospitalized at day 14

239

94/239 (39%)

47/135 (35%)

47/104 (45%)

.13 a

404

350

Length of follow-up, median (IQR)

239

10 (7, 20)

10 (6, 19)

11 (8, 22)

.06 b

405

239

91/239 (38%)

46/135 (34%)

45/104 (43%)

.19 a

37/90 (41%)

18/45 (40%)

19/45 (42%)

> .99a

36/239 (15%)

19/135 (14%)

17/104 (16%)

.76 a a

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351 352 353 354 355 356 357

401 402

406 407

Medical comorbidities Diabetes mellitus Uncontrolled diabetes mellitus defined as glycosylated hemoglobin $ 8% Immunosuppressed

90

408 409 410

239

411 412

Chronic lung disease

239

91/239 (38%)

48/135 (36%)

43/104 (41%)

.44

Hypertension

237

142/237 (60%)

79/133 (59%)

63/104 (61%)

.96 a

Chronic heart disease

239

71/239 (30%)

42/135 (31%)

29/104 (28%)

.69 a

361

Obesity (BMI $ 30 kg/m2 )

231

112/231 (48%)

55/129 (43%)

57/102 (56%)

.06 a

416

362

No. of comorbidities

239

3.0 (2.0, 4.0)

3.0 (2.0, 4.0)

3.0 (2.0, 4.0)

.36 b

417

363

BMI, kg/m2 , median (IQR)

231

30 (25, 35)

29 (24, 32)

32 (27, 37)

< .001b

418

364

BMI, kg/m2

231

.

.

.

.02 a

419

< 30

119/231 (52%)

74/129 (57%)

45/102 (44%)

.

420

30.0-34.99

61/231 (26%)

36/129 (28%)

25/102 (25%)

.

421

35.0-39.99

30/231 (13%)

12/129 (9.3%)

18/102 (18%)

.

21/231 (9%)

7/129 (5.4%)

14/102 (14%)

.

424

38.25 (37.57, 38.80)

38.10 (37.40, 38.60)

38.50 (37.80, 39.32)

< .001b

425

68 (20, 134)

42 (11, 81)

110 (64, 182)

< .001b

427

< 100 mg/L

150/233 (64%)

104/129 (81%)

46/104 (44%)

< .001a

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$ 100 mg/L

83/233 (36%)

25/129 (19%)

58/104 (56%)

.

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.

< .001a

431

70/235 (30%)

53/132 (40%)

17/103 (17%)

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432

165/235 (70%)

79/132 (60%)

86/103 (83%)

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433

358 359 360

365 366 367 368 369 370 371 372 373 374 375 376

$ 40 Temperature at admission, median (IQR),  C hs-CRP at admission, mg/L, median (IQR)

Chest radiograph at baseline

377

Normal

378

Abnormal

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235

414 415

422 423

426

430

434

Hospital treatments, No. (%) Antiviral agents

237

237/237 (100)

135/135 (100)

102/102 (100)

> .99a

382

Days from admission to antivirals

115

2.0 (1.0, 2.0)

2.0 (1.0, 3.0)

2.0 (1.0, 2.0)

.06 b

383

Hydroxychloroquine

238

201/238 (84%)

106/134 (79%)

95/104 (91%)

.02 a

381

413

384

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(Continued)

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4 Original Research

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TABLE 1

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442 443

Variable

444

Glucocorticoids

445

Entire Sample (N ¼ 239)

No. 239

Nonsevere (n ¼ 135)

48/239 (20%)

497

Severe (n ¼ 104)

12/135 (8.9%)

36/104 (35%)

< .001

153/239 (64%)

59/135 (44%)

94/104 (90%)

< .001

447

Tocilizumab (second dose)

239

8/239 (3%)

5/135 (3.7%)

3/104 (2.9%)

> .99 a

448

Days to tocilizumab from onset of symptoms

135

7.0 (4.5, 10.0)

7.0 (4.0, 9.0)

6.5 (5.0, 10.0)

.36 b

Days to tocilizumab from admission

135

2.0 (2.0, 4.0)

4.0 (2.0, 6.5)

2.0 (1.0, 3.0)

< .001 b

450 451

500

a

239

449

499

a

Tocilizumab

446

498

P Value

501 502 503 504 505 506

Patient outcomes

452

507

Survivalc

453 454

.

.

.

.001d

508

86% (80%, 91%)

93% (88%, 99%)

78% (69%, 87%)

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509

239

53/239 (22%)

7/135 (5.2%)

46/104 (44%)

< .001a

510

53

4.5 (3.0, 7.5)

1.0 (0.5, 2.0)

5.5 (4.0, 7.9)

.003b

511

239

14-Day survival (95% CI)

455

Mechanical ventilation

456

Days mechanically ventilated

512

457 Data are expressed as median (interquartile range [IQR]), No. (%). Survival probability (95% CI). COVID-19 ¼ coronavirus disease 19; hs-CRP ¼ highsensitivity C-reactive protein. a Test used, Pearson c 2 test. b Test used, Wilcoxon signed-rank test. c Seven and 21-day survival available in e-Table 1. d Test used, log-rank test; N is the number of nonmissing values.

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513 514 515 516 517 518

463

when tocilizumab was administered (137.75 vs 131.9 mg/L; P ¼ .34). For tocilizumab-treated patients, unlike the overall sample, 14-day survival was 87% and did not differ (83% vs 91%; P ¼ .11) according to disease severity. Survival at 7 and 21 days is shown in e-Table 1. MV was used in 48 (31%) tocilizumab-treated patients; they spent a median of 5.5 days on the ventilator, and their survival was 75%.

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Figure 3 shows the 14-day trajectory following 519 tocilizumab administration. Oxygenation improved over 520 521 14 days but less so over the first 3 to 4 days. Temperat...