SARS-CoV-2 and COVID-19 David H. Spach, MD - PowerPoint Presentation

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Slide1
SARS-CoV-2 and COVID-19
David H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington
Last Updated: December 7, 2020
Gretchen Snoeyenbos Newman, MDSenior FellowDivision of Infectious DiseasesUniversity of Washington
Treatment: Tocilizumab
Sarah A. McGuffin, MD MS
Senior Fellow
Division of Infectious Diseases
University of Washington
Slide2
Tocilizumab (
Actemra)
Slide3
Tocilizumab
Medication Class
: Interleukin-6 (IL-6) receptor blockerFDA Approved for: Cytokine release syndrome
Rheumatoid arthritis and other rheumatologic conditionsDose for Cytokine Release SyndromeWeight ≥30 kg: 8 mg/kg IV x 1 dose (max 800 mg)Weight ≤30 kg: 12 mg/kg IV x 1 dose (max 800 mg)Dose for COVID-19Range of doses used in studiesAdverse EffectsInjection site reactionsIncreases in ALT and/or AST levels
Slide4
Rationale for Use of Tocilizumab Persons with COVID-19
Source: Kellum JA, et al, Crit Care
Med. 2017 Mar; 45:438–45.Chen N, et al. Lancet
2020; 395(10223):507-13.Huang C, et al. Lancet 2020;395:497-506.Le RQ, et al. Oncologist. 2018;23:943-7.Elevated levels of inflammatory cytokines, including IL-6 have been associated with increased mortality from ARDS
Patients with COVID-19 have elevated levels of IL-6 and other inflammatory markers consistent with cytokine stormTocilizumab has been effective in treating the cytokine storm associated with CAR-T cell therapy
Slide5
Tocilizumab: Recombinant Humanized Anti-IL6 Receptor Monoclonal Antibody
Illustration: David H. Spach, MD
Mouse Monoclonal Antibody
Humanized Monoclonal Antibody
Mouse variable region
Mouse constant region
Human heavy chain
Human light chain
Complementary Determining Region
Slide6
Tocilizumab (
Actemra)Illustration: David H. Spach, MD
Humanized Murine Monoclonal Antibody IgG1 Subclass
Binds to:
- Soluble IL-6 receptor
- Membrane bound IL-6 receptor
Human heavy chain
Human light chain
Complementary Determining Region
Slide7
IL-6 Signaling via Membrane IL-6 Receptor:
Classic IL-6 Pathway
gp130
Signal Transduction
IL-6
gp130
Recruitment of gp130
gp130
Host Cell
Membrane
IL-6 Receptor
Slide8
Classic IL-6 Pathway – Image Series (1 of 3)
IL-6
gp130
Host Cell
Membrane
IL-6 Receptor
Slide9
IL-6
gp130
gp130
Host Cell
Membrane
IL-6 Receptor
Slide10
gp130
Signal Transduction
IL-6
gp130
gp130
Host Cell
Membrane
IL-6 Receptor
Slide11
Trans Signaling IL-6 Pathway
IL-6
ADAM-10
ADAM-17
gp130
Signal Transduction
Soluble
IL-6 Receptor
IL-6 and Soluble IL-6 Receptor Complex
gp130
Slide12
Trans Signaling IL-6 Pathway – Image Series (1 of 4)
ADAM-10
ADAM-17
Soluble
IL-6 Receptor
Slide13
IL-6
ADAM-10
ADAM-17
Soluble
IL-6 Receptor
Slide14
IL-6
ADAM-10
ADAM-17
Soluble
IL-6 Receptor
gp130
Slide15
IL-6
ADAM-10
ADAM-17
gp130
Signal Transduction
Soluble
IL-6 Receptor
gp130
Slide16
Tocilizumab Binds to Both Soluble and Membrane IL-6 Receptors
gp130
Soluble
IL-6 Receptor
Membrane
IL-6 Receptor
gp130
Tocilizumab
Slide17
Tocilizumab and Inhibition of IL-6 Signaling

IL-6
Soluble
IL-6 Receptor
Signal Transduction
gp130
gp130
Membrane Bound IL-6 Receptor: Classic Pathway
Tocilizumab
Soluble IL-6 Receptor: Trans Signaling Pathway
Tocilizumab
Signal Transduction
gp130
Membrane
IL-6 Receptor
Slide18
Efficacy of Tocilizumab in Patients Hospitalized with Covid-19
Published Data
— Randomized Clinical Trial
Source: Stone JH, et al. N
Engl
J Med. 2020 Oct 21.
doi
: 10.1056/NEJMoa2028836. Online ahead of print
Slide19
Efficacy of Tocilizumab in Patients Hospitalized with COVID-19
Study DesignSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Study Design
Background
: Randomized, d
ouble-blind, placebo-controlled, multicenter trial conducted at 7 hospitals in Boston between April 20 and June 15, 2020 to evaluate the effectiveness of tocilizumab in patients with severe COVID-19 infection.
Location:
Boston, Massachusetts, USA
Inclusion
Criteria (n = 242)
-

SARS-CoV-2 infection confirmed by nasopharyngeal swab PCR or serum IgM antibody assay
- At least 2 of following: fever <72 hours,
pulmonary infiltrates, or need for supplemental oxygen
- At least 1 of following: CRP >50 mg/L, ferritin >500 ng/mL, D-dimer >1000 ng/mL, or LDH >250 U/L
- Age 19-85 years
Exclusion
Criteria
-
Supplemental oxygen at a rate >10 L/min, recent treatment with biologic agents or small molecule immunosuppressive therapy, if they were receiving other immunosuppressive therapy that the investigator believed placed them at higher risk for an infection, or if they had had diverticulitis. Randomization: 2:1Primary Endpoint- Intubation (or death for patients who died before intubation)
Slide20
Study Design*Source: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Tocilizumab
(single dose)
(8 mg per kilogram of body weight administered intravenously, not to exceed 800 mg)
Placebo
or
Treatment Groups*
Concomitant treatments allowed: Antiviral therapy, hydroxychloroquine, and glucocorticoids
2x
1x
Slide21
Baseline CharacteristicsSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Baseline Characteristics
Tocilizumab (n = 161)
Placebo (n = 82)
Median age (IQR) –
yr
61.6 (46.4–69.7)
56.5 (44.7–67.8)
Age >65 years – no. (%)
60 (37)
22 (27)
Male sex — no. (%)
96 (60)
45 (55)
Race or ethnic group – no. (%) †
American Indian or Alaska Native
1 (1)
0
Asian
7 (4)2 (2)Black24 (15)16 (20)Native Hawaiian or Pacific Islander01 (1)White71 (44)33 (40)
Other35 (22)15 (18)
Unknown
23 (14)15 (18)Hispanic or Latino ethnic group — no. (%)†Hispanic or Latino70 (43)39 (48)Hispanic or Latino84 (52)35 (43)Unknown7 (4)8 (10) † Race and ethnic group were reported by the patients.
Slide22
Tocilizumab (n = 161)
Placebo (n = 82)
Median BMI (IQR)
29.9 (26.0–34.2)
30.2 (25.7–33.8)
BMI ≥30 — no. (%)
80 (50))
42 (51)
Median time symptom onset to randomization (IQR) — days
9.0 (6.0–13.0)
10.0 (7.0–13.0)
Hypertension — no. (%)
80 (50)
38 (46)
Heart failure — no. (%)
17 (11)
7 (9)
Heart failure — no. (%)15 (9)6 (7)Chronic obstructive pulmonary disorder — no. (%)15 (9)7 (9)Asthma — no. (%)15 (9)7 (9)Smoking status — no. (%) Current smoker
7 (4) 0
Former smoker46 (29)
26 (32)Lifelong nonsmoker99 (61) 48 (59)Unknown9 (6) 8 (10)Diabetes— no. (%)45 (28)30 (37)Chronic kidney disease — no. (%)29 (18) 13 (16)History of cancer — no. (%) 22 (14) 8 (10)
Slide23
7-Point Ordinal Scale
1: Discharged (or "ready for discharge" as evidenced by normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or ≤ 2L supplemental oxygen)
2: Non-ICU hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
3:
Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
4:
ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
5:
ICU, requiring intubation and mechanical ventilation
6:
ICU, requiring ECMO or mechanical ventilation and additional organ support (e.g. vasopressors, renal replacement therapy)
7: Death
Slide24
Tocilizumab (n=161)
Placebo (n=82)
Ordinal scale score — no. (%)
2
23 (14)
15 (18)
3
133 (83)
61 (74)
4
5 (3)
5 (6)
5
0
1 (1)
Median laboratory values (IQR)
Absolute lymphocyte count — cells/mm
31040 (700–1400)1030 (680–1360)C-reactive protein level — mg/liter116.0 (67.1–190.6)
94.3 (58.4–142.0)Ferritin level — ng/ml
723 (413–1212)
686 (382–1228)d-Dimer level — ng/ml857 (536–1695)980 (500–1739)Lactate dehydrogenase level — U/liter351 (287–420)324 (290–395)Serum interleukin-6 level — pg/ml 23.6 (14.0–49.9)25.4 (14.6–40.3)Erythrocyte sedimentation rate — mm/hr61 (42–90)63 (42–87)Troponin level — ng/liter8 (6–22)9 (6–24)NT-proBNP level — pg/ml110 (50–438)93 (33–431)
Procalcitonin level — ng/ml
0.2 (0.1–0.4)
0.2 (0.1–0.3)
Slide25
Outcome
No. of Patients
with Event within
28 Days

Percentage of Patients
with Event (95% CI)†
Hazard Ratio
(95% CI)
Log-Rank
P Value‡
Day 14
Day 28
Primary outcome: mechanical ventilation or death
Tocilizumab
17
9.9 (6.2–15.7)
10.6 (6.7–16.6)
0.83 (0.38–1.81)
0.64
Placebo
10
10.0 (5.1–18.9)
12.5 (6.9–22.0)Secondary outcome: clinical worsening on ordinal scale§Tocilizumab3118.0 (12.9–24.9) 19.3 (14.0–26.2)1.11 (0.59–2.10) 0.73Placebo1414.9 (8.7–24.7)17.4 (10.7–27.7)Tertiary outcome: mechanical ventilation
Tocilizumab11
6.8 (3.6–11.4) 6.8 (3.6–11.4)
0.65 (0.26–1.62)-
Placebo
8
10.0 (4.6–17.7)
10.0 (4.6–17.7)
Tertiary outcome: death
-
Tocilizumab
9
4.4 (2.1–8.9)
5.6 (3.0–10.5)
1.52 (0.41–5.61)
Placebo
3
1.3 (0.2–8.7)
3.8 (1.2–11.3)
Outcomes
Engl
J Med. 2020 Oct 21.
doi
: 10.1056/NEJMoa2028836. Online ahead of print† Percentages were estimated from the Kaplan–Meier curve. ‡ P values are not reported for tertiary outcomes.
§ Def
ined as an increase in score by at least 1 point if receiving supplemental oxygen at baseline or at least 2 points otherwise
Slide26
OutcomesPrimary Outcome: Mechanical Ventilation or DeathSource: Stone JH, et al. N
Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Slide27
OutcomesSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Outcome
No. of Patients
with Event within
28 Days

Percentage of Patients
with Event (95% CI)†
Median No. of Days to Event (95% CI)
Hazard Ratio
(95% CI)
Log-Rank
P Value‡
Day 14
Day 28
Secondary outcome: discontinuation of supplemental O
2
Tocilizumab
114
75.4 (67.9–82.2)
82.6 (75.9–88.4)
5.0 (3.8–7.6)0.94 (0.67–1.30)
0.69Placebo5678.8 (68.3–87.7)84.9 (75.2–92.2)4.9 (3.8–7.8)Tertiary outcome: clinical improvement on ordinal scale§Tocilizumab14786.3 (80.6–91.1)91.3 (86.3–95.1)6.0 (5.0–6.0)1.06 (0.80–1.41)Placebo7381.5 (72.4–89.0)88.9 (81.0–94.5)5.0 (4.0–7.0)
Tertiary outcome: initial discharge
Tocilizumab
147
86.3 (80.6–91.1)
91.3 (86.3–95.0)
6.0 (4.0–7.0)
1.08 (0.81–1.43)
Placebo
72
81.5 (72.4–89.0)
88.9 (81.0–94.5)
6.0 (5.0–6.0)
†Percentages were estimated from the Kaplan–Meier curve. ‡ P values are not reported for tertiary outcomes;
§
Def
ined as an increase in score by >2 points
Slide28
OutcomesSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
*Patients who did not receive supplemental oxygen were assigned a value of 0. Patients who died before discontinuation of supplemental oxygen were assigned a value equal to the number of days from when supplemental oxygen began until the end of the 28-day follow-up period.
† The median and IQR for duration of mechanical ventilation were estimated from Kaplan–Meier curves generated within patients who received mechanical ventilation (11 in the tocilizumab group and 8 in the placebo group). Data for patients who died without discontinuation of mechanical ventilation were censored at 28 days.
Outcome
Tocilizumab
(n = 161)
Placebo
(n = 81)
Relative Risk
Median duration of receipt of supplemental oxygen (IQR) — days*
4.0 (1.8–11.6)
3.9 (1.1–9.2)
-
Median duration of mechanical ventilation (IQR) — days†
15.0 (12.6–NR)
27.9 (16.3–NR)
-
Admission to ICU or death — %
15.9
15.80.97 (0.50-1.88)
Slide29
Adverse EffectsSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Event
Tocilizumab
(n = 161)
Placebo
(n = 81)
P value
Death, no. (%)
9 (5.6)
4 (4.9)†
0.81
Hypersensitivity reaction to infusion
2 (1.2)
2 (2.4)
0.52
Infection of grade ≥3
13 (8.1)
14 (17.1)
0.03
Grade 3Grade 4Myocardial infarction0
1 (1.2)
0.15Deep venous thrombosis
2 (1.2)3 (3.7)0.18Pulmonary embolism2 (1.2)2 (2.4)0.47Stroke 2 (1.2)00.31Seizure0 1 (1.2) 0.13Arterial ischemia1 (0.6)00.49Gastrointestinal perforation00-Demyelinating disorder
00-
Bleeding
01 (1.2)
0.15
† One patient who died was intubated before receiving placebo and was excluded from the modified intention-to-treat population but included in the safety population.
Slide30
Adverse EffectsSource: Stone JH, et al. N Engl J Med. 2020 Oct 21. doi: 10.1056/NEJMoa2028836. Online ahead of print
Event
Tocilizumab
(n = 161)
Placebo
(n = 81)
P value
Elevated liver-function values
ALT, grade ≥3
8 (5.0)
4 (4.9)
0.99
Grade 3
8 (5.0)
4 (4.9)
Grade 4
0
0
AST, grade ≥3
6 (3.7)3 (3.7)0.99Grade 36 (3.7)
2 (2.4)
Grade 40
1 (1.2)Neutropenia, grade ≥322 (13.7)1 (1.2)0.002Grade 321 (13.0)1 (1.2)Grade 41 (0.6)0Thrombocytopenia1 (0.6)00.51Grade 31 (0.6)0Grade 400Other
21 (13.0)
14 (17.1)0.15
Slide31
Authors’ Conclusions
Conclusions:
“
In this randomized, double-blind, placebo-controlled trial, we did not find any efficacy of interleukin-6 receptor blockade for the treatment of hospitalized patients with Covid-19.”
Engl
J Med. 2020 Oct 21.
doi
: 10.1056/NEJMoa2028836. Online ahead of print
Slide32
Tocilizumab Treatment of 15 Patients with COVID‐19:
A Single Center Experience (China)
Source: Luo P, et al. J Med
Virol
. 2020;92:814-8.
Published Data —
Retrospective Case Series
Slide33
Tocilizumab Treatment of 15 Patients with COVID‐19: Study Design
Study Design
Background
:
Retrospective case series study of 15 patients with variable severity of COVID-19 disease who received one or more doses of tocilizumab, with or without methylprednisolone during January 27– March 5, 2020 in China
Setting
: Wuhan, China
Inclusion
Criteria for Patients
-
Infected with SARS-CoV-2/COVID-19
- Received tocilizumab treatment
Treatment
- 1 or more doses of intravenous tocilizumab: 80-600 mg per dose*
- Option to receive methylprednisolone^
Source: Luo P, et al. J Med
Virol
. 2020;92:814-8.
*5 patients received >1 dose of tocilizumab (3 received 2 doses and 2 received 3 doses)
^8 of 15 received
methylprednisolone (range 4 to 7 days) of treatment
Slide34
Patient CharacteristicsSource: Luo P, et al. J Med Virol. 2020;92:814-8.
Baseline Characteristic
Patients
(n = 15)
Age (median, range), years
73 (62 – 80)
Male, Female
12, 3
Clinical Status*
Moderate
2
Severe
6
Critical
7
Comorbidities (HTN, CVD, DM)
10
Also received methylprednisolone
8
*Defined by guidance Diagnosis and Treatment of Pneumonia Infected by Novel Coronavirus issued by the National Health Commission of China
Slide35
ResultsSource: Luo P, et al. J Med Virol. 2020;92:814-8.3 of 7 critically ill patients progressed to death despite therapy
2 patients experienced worsening of their illnessCRP levels decreased in 14 of 15 patientsIL-6 levels remained persistently elevated in 1 seriously ill and 4 critically ill patients, including the 3 who died
IL-6 levels initially spiked after tocilizumab and then decreased in all patients experiencing clinical stabilization or improvement
Slide36
Tocilizumab Treatment of 15 Patients with COVID‐19: Study Design
: Authors’ Conclusions
Source: Luo P, et al. J Med Virol. 2020;92:814-8.
Conclusions
: “Tocilizumab appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL-6, repeated dose of the Tocilizumab is recommended.”
Slide37
Tocilizumab Treatment of 21 Patients with Severe COVID-19 (China)
Published Data —
Retrospective Analysis
Source: Xu X, et al. Proc Natl
Acad
Sci U S A. 2020:117:10970-5.
Slide38
Tocilizumab Treatment of 21 Patients with Severe COVID-19:
Design
Study Design
Background
:
Uncontrolled, observational study to evaluate the effectiveness of intravenous tocilizumab in patients with severe COVID-19 in Wuhan, China during February 5 – February 14, 2020.
Inclusion
Criteria (n = 21)
-
PCR-confirmed SARS-CoV-2
infection on throat swab
-
Severe COVID-19
(any of following):

RR ≥ 30/min
or

SpO
2
≤93% on room air or PaO2/FiO2 ≤300 mm Hg- Critical COVID-19 (any of following): Mechanical ventilation or shock or multiorgan failure plus ICU admitTreatment - Tocilizumab: 400 mg intravenous infusion x 1 plus- Standard of care at hospital: lopinavir, methylprednisolone, supportive careSource: Xu X, et al. Proc Natl Acad Sci U S A. 2020:117:10970-5.
Slide39
Baseline Characteristic*
Patients
(n = 21)
Age,

mean
± SD (range
)
56.8 ± 16.5 (25-88)
Male
, n
(%)
18 (85.7)
Comorbidity
Hypertension,
n
(%)
9 (42.9)
Diabetes, n (%)5 (23.8)Illness SeveritySevere, n (%)17 (81)Critical, n (%)4 (19)Mechanical ventilation2 (10)Pretreatment IL-6, mean ± SD* 132.38 ± 278.54 pg/mLSource: Xu X, et al. Proc Natl Acad Sci U S A. 2020:117:10970-5.
Slide40
Laboratory Markers of Inflammation Before
and After Tocilizumab (mean ± SD)
Before
Day 1 after Tocilizumab
Day 5 after Tocilizumab
WBC
(x 10
9
/L)
6.30 ± 2.77
8.05 ± 4.39
5.25 ± 2.11
Lymphocyte
percentage
15.52 ± 8.89
11.78 ± 11.36
22.62 ± 13.48
CRP
75.06 ± 66.80
38.13 ± 54.21
2.72 ±3.60
Procalcitonin, ng/mL0.33 ± 0.780.21 ± 0.35
0.12 ± 0.15
Interleukin-6,
pg
/mL
153.44 ± 296.63
129.18 ± 131.79
274.90 ± 414.08
Acad
Sci U S A. 2020:117:10970-5.
Slide41
Tocilizumab Treatment of 21 Patients with Severe COVID-19: Results
Fever in all patients resolved on day 1 after tocilizumab infusion21 of 21 (100%) experienced improvement in SpO2 and/or ventilator requirements15 of 20 (75%) had lower O2 intake <5 days after tocilizumab21 of 21 (100%) discharged from hospitalMean hospitalization time 15.1 ± 5.8 days after tocilizumab
Acad Sci U S A. 2020:117:10970-5.
Slide42
Tocilizumab Treatment of 21 Patients with Severe COVID-19 Infection:
Authors’ Conclusions
Conclusion
: “Preliminary data show that tocilizumab, which improved the clinical outcome immediately in severe and critical COVID-19 patients, is an effective treatment to reduce mortality.”
Acad
Sci U S A. 2020:117:10970-5.

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