Clinical Circumstances

Based on the evidence to date, our recommendations are:

1. IL-6 inhibitors can be considered for off-label use in patients with severe COVID-19, particularly those requiring transfer to the ICU/ECMO or are at high risk of decompensating due to cytokine storm.

2. Elevated IL-6 levels may predict risk of decompensation due to hyper-inflammation and may guide IL-6 inhibitor therapy

Most published case series use IL-6 inhibitors prior to intubation but in severe cases. In Chinese studies, ‘severe’ is nationally standardized and is defined as SpO2 <93% on room air or RR>30 or PaO2/FiO2 <300. The same criteria, with addition of hypotension or end-organ failure, were used in the Alattar et al case series though the majority of their patients were intubated. In the Gritti et al case series, patient inclusion required a diagnosis of ARDS (but not necessarily invasive ventilation).

In addition, Herold et al provide pre-peer review evidence that IL-6 levels, CRP, and ferritin are predictive of development of subsequent hyper-inflammation and decompensation. They identify IL-6 >80 pg/mL as strongly predictive of worsening clinical outcomes within 1.5 days. Aziz et al conducted a meta-analysis of published case series and identified IL-6 level > 55 pg/mL as predictive of worsening outcomes. No paper to date have linked pre-treatment IL-6 levels with efficacy of IL-6 inhibitors

Off-label and non-study related use of this medication should be considered in consultation with Infectious Disease (ID) and/or a multidisciplinary panel of experts.

Medication Specific Considerations

Recommended dose:

1. For patients already on or about to be on ECMO or requiring intubation due to rapid decompensation, regardless of size: give 1x 800 mg IV. Trend vitals, labs (see below). Consider a repeat dose 2 days later. Max 2 doses.

2. For patients pre-intubation/ECMO but with risk for cytokine storm and demonstrating rapid decline who weigh ≥ 90kg: give one time 800 mg IV over 1 hr. Trend vitals, labs (see below). Consider a repeat dose 2 days later. Max 2 doses.

3. For patients pre-ICU but with risk for cytokine storm and demonstrating rapid decline who weigh < 90kg: give one time 400 mg IV over 1 hr. Trend vitals, labs (see below). Consider a repeat dose 2 days later. Max 2 doses.

This dosing strategy is based on poor-quality studies, resembles dosing used in as-yet unpublished clinical trials, and was chosen to help reduce waste of this restricted product and reduce potential side effects. There is no evidence at this time to indicate that a weight-based dose is any more or less safe or effective than a flat 400 mg or 800 mg dose. For very severe patients, a second dose of tocilizumab can be considered 2 days after the initial dose. However, as such severe patients often have upregulation of multiple, non-IL-6 dependent inflammatory pathways as part of cytokine storm, we recommend working with interdisciplinary teams to consider alternative therapeutic strategies.

Recommended monitoring:

1. Baseline labs (common across multiple therapies and guideline at University of Minnesota): CBC w/differential and reticulocyte count, Complete metabolic panel, CRP, ESR, Ferritin, DDimer, fibrinogen, LDH, PT/INR, PTT, CPK, troponin, HBV, HCV, EKG, IL-6

2. Highly recommended prior to IL-6 inhibitor (tocilizumab) administration: CRP, LDH, ferritin, IL-6

3. Monitoring labs: LDH once to twice daily; daily CRP, ferritin; blood culture (including candidal culture) every other day regardless of symptoms

Drug monitoring is required post administration. Because IL-6 inhibitors iatrogenically reduce CRP, ferritin, and fever, regardless of underlying disease activity, these may be unreliable markers of disease after administration. LDH is known to be a more reliable marker in other hyperinflammatory syndromes such as macrophage activation syndrome. In addition, the patient will not be able to mount a fever if infection occurs and the primary team should maintain a low threshold for sepsis evaluation and treatment. A case series published by Antinori et al (below) raises concern for late candidemia.

Availability: University of Minnesota/Fairview Health system is able to procure a limited supply of tocilizumab for off-label use. Drug shortages have occured before and will likely occur again.

Special Considerations:

• Pregnant women: tocilizumab can cross the placenta, particularly in the late second and third trimester. Limited data in pregnant rheumatology patients has not raised any red flags to date.

• Lactation: limited data, no red flags to date

• Iatrogenically Immunosuppressed individuals: please consult with transplant or rheumatology services to evaluate safety of tocilizumab in conjunction with prior immunosuppression regimen

• Liver disease: consider adjustment for liver disease

Current Clinical Trials Underway

There are currently no IL-6 inhibitor trials at University of Minnesota/Fairview

1. 1. Tocilizumab trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=tocilizumab&cntry=&state=&city=&dist=

   2. Sarilumab trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=sarilumab&cntry=&state=&city=&dist=

   3. Siltuximab trials: https://clinicaltrials.gov/ct2/results?cond=COVID&term=siltuximab&cntry=&state=&city=&dist=&Search=Search

List of major peer-reviewed studies, and type of study (preclinical, human study, etc):

1. Luo et al. “Tociluzimab treatment in COVID-19: a single center experience” http://doi.org/10.1002/jmv.25801

   • Study design: retrospective observational study

   • Location: : jan 27 - Mar 5; Zhongfaxincheng campus of Tongji Hospital in Wuhan

   • N = 15

   • Patient inclusion criteria: COVID+, hospitalized

   • Exclusion criteria: none specified

   • Dosing: at least one and up to multiple doses of tocilizumab. Most patients received tociluzimab two or more times. Tociluzimab doses ranged from 80 mg to 600 mg per dose.

   • Clinical Outcomes:

     • Presenting symptoms not noted, definitions of mild/modeate/serious/critical are not described in this paper

     • Comorbidites not noted

     • Clinical outcomes for moderate and serious patients are not directly noted though it is implied that none progressed to critical

     • All 7 critical patients received tocilizumab. 3 (43% of critical) died regardless. 1 was noted not to respond in regards to CRP but unclear what the clinical outcome was.

   • Overall outcome: equivocal

2. Alattar R, Ibrahim TBH, Shaar SH, et al. Tocilizumab for the Treatment of Severe COVID-19 [published online ahead of print, 2020 May 5]. J Med Virol. 2020;10.1002/jmv.25964. doi:10.1002/jmv.25964

   • Study design: Retrospective case series from Qatar

   • Inclusion: severe COVID (RR>30, SpO2<93%RA, P/F<300, hypotensive, or with evidence of end-organ failure), admission to ICU (which occurred 0-4 days after hospital admission), and elevated CRP

   • Standard of Care included: multiple antivirals, plaquenil, azithromycin, IFNalpha

   • Tocilizumab dose: 1-3 doses over several days, median total dose is 5.7 mg/kg

   • Outcomes (days after initial toci dose):

     • %intubated: 84% -> 60% (d7) -> 28% (d14)

     • 3/25 patients died (12%)

     • 9/25 patients were discharged from ICU (36%)

     • 13/25 remained in ICU (52%)

     • 92% had an adverse event, most commonly secondary bacterial infection, candidal growth from respiratory cultures, anemia, elevated ALT, QT prolongation, and HSV reactivation. Cannot determine if these events were due to standard therapies or tocilizumab

   • Overall outcome: equivocal

3. Sciascia S, Aprà F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19 [published online ahead of print, 2020 May 1]. Clin Exp Rheumatol. 2020; PMID 32359035

   • Abstract only, very limited information

   • Study design: Open label, single arm, multicenter, 63 patients evaluated at baseline and d1,2,7,and14 days post tocilizumab administration

   • Unknown dose of tocilizumab, unknown inclusion criteria

   • PaO2/FiO2 improved from 152+/-53 at baseline to 283+/-116 day 7 to 302+/-126 day 14

   • D-dimer, but not IL-6, at baseline predicted mortality. 11% overall mortality.

   • Tocilizumab administration was barely associated with improved survival (HR 2.2 with 95% CI 1.3-6.7; p<0.05)

4. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab [published online ahead of print, 2020 Apr 29]. Proc Natl Acad Sci U S A. 2020;202005615. doi:10.1073/pnas.2005615117

   • Study design: prospective observation case series with historical control (no real propensity matching)

   • Inclusion: COVID+, severe (RR ≥30 or SpO2 ≤ 93% on RA or PaO2/FiO2 ≤ 300 mm Hg) and critical (intubation or shock or end organ failure or need for ICU).

   • Exclusion: active pulmonary TB or clear bacterial infection or fungal infection

   • All recieved SOC: lopinavir/ritonavir, aerosolized IFN-α, ribavirin, glucocorticoid equivalent of 1 to 2 mg/kg per day methylprednisolone, other symptom relievers and oxygen therapy.

   • IL-6 measurement: timing not specified. Method was by electrochemical luminescence method (Roche Diagnostics GmbH) in 18 patients or fluorescence-activated cell sorting analysis in 3 patients. Normal value <7pg/mL.

   • Treatment: first dose 4-8 mg/kg tocilizumab (400 - 800 mg total) with repeat dose at 12 hours if persistent fever. 2 doses max.

   • Caveats: historical comparative population is not defined and comparative standard of care for such a “control” is not evaluated. Number of patients evaluated each day varies.

   • Outcomes (baseline -> d1 -> d3 -> d5):

     • WBC (109/L): 6.3±2.77 -> 8.05±4.39 -> 6.02±3.05 -> 5.25±2.11

     • %lymph: 15.5±8.9 -> 11.8±11.4 -> 16.9±13.6 -> 22.6±13.5

     • 81% were severe, 19% critical

     • A significant decrease in oxygen needs coupled with improving SpO2 was noted for all patients by day 5 (p<0.005)

     • All patients were discharged from hospital

   • Overall outcome: equivocal

5. Toniati P, Piva S, Cattalini M, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy [published online ahead of print, 2020 May 3]. Autoimmun Rev. 2020;102568. doi:10.1016/j.autrev.2020.102568

   • Study design: observational case series, single center, 100 patients total

   • Inclusion: BCRSS score 3-7 (standard italian scoring, Brescia COVID-19 Respiratory Severity Scale (BCRSS), a 9-category ordinal severity scale ranging from 0 (asymptomatic patient) to 8 (a critically ill patient with tracheal intubation, mechanical ventilation and advanced ICU management.)) which requires at minimum COVID+ PCR with dyspnea/staccato speech +/- RR>22 +/- PaO2 < 65 or SpO2 < 90% +/- worsening CXR. Also, eligibility required either IL-6 > 40 mg/dL or high acute phase reactants (CRP, d-dimer, fibrinogen)

   • Exclusion: none listed.

   • SOC: antiviral drugs, antibiotic prophylaxis (includes azithromycin), hydroxychloroquine, dexamethasone 20 mg/day

   • Treatment: 800 mg IV x2, given 12h apart. Some patients received a 3rd dose.

   • Caveats: usual caveats of case series.

   • Outcomes:

     • 69% of 100 patients overall felt to demonstrate improvement by BCRSS scoring, as well as oxygenation needs/extubation/transfer to general ward/discharge

     • 43 patients were in ICU to start, 32 (74%) improved of which 17 (40%) were extubated, 11 (26%) remained stable or worsened/died

     • 57 patients were on general ward, 37 (65%) improved and were able to come off non-invasive oxygen, 13 (23%) worsened or died

     • During 10 day follow up, 2 patients developed septic shock and 1 developed a GI perforation, all 3 died

   • Overall outcomes: most patients improved however there is no way to compare this to the natural history of disease. Equivocal

6. Campins L, Boixeda R, Perez-Cordon L, Aranega R, Lopera C, Force L. Early tocilizumab treatment could improve survival among COVID-19 patients. Clin Exp Rheumatol. 2020;38(3):578.

   • Study design: observational case series, single center, 58 patients total

   • Inclusion: COVID+

   • Exclusion: none listed.

   • SOC: not provided

   • Treatment: doses not provided. All got 1 dose of tocilizumab. 57 of 58 received pulsed steroids for 3-5 days.

   • Caveats: usual caveats of case series plus very limited details on patient selection, tocilizumab dose, high risk of bias in how pulsed steroids were used

   • Outcomes:

     • Outcomes per ICU v. non-ICU not evaluated

     • 8 of 43 (14%) died. Those that died had significantly higher LDH and d-dimer but no difference in remainder of inflammatory markers including IL-6 level

     • Patients who received pulsed steroids before tocilizumab had lower mortality rate. No actual statistical comparison done.

     • Overall outcomes: most patients improved however there is no way to compare this to the natural history of disease. equivocal

7. Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients [published online ahead of print, 2020 May 6]. Med Mal Infect. doi:10.1016/j.medmal.2020.05.001

   • Study design: retrospective case-control, combined primary endpoint

   • Inclusion: COVID+, failure of standard treatment, time to symptom onset ˃7 days, oxygen therapy ≥5 liters/min, >25% of lung damages on CT, and ≥2 parameters of inflammation or biological markers of mortality (with a high level) such as ferritin, CRP, D-dimers, lymphopenia, and lactate dehydrogenase.

   • Exclusion: no contraindication to TCZ. for control group, excluded from the control group patients with moderate disease and those that received treatments not provided at this hospital (remdesivir, immunoglobulins)

   • SOC: hydroxychloroquine or lopinavir-ritonavir therapy and antibiotics, and less commonly corticosteroids

   • Treatment: Patients received 1-2 doses of unspecified amount of tocilizumab

   • Caveats: baseline differences between groups though patients receiving tocilizumab seemed more severe and had more comorbidities which would not favor tocilizumab group

   • Outcomes:

     • No statistical significant features at admission except: TCZ patients had a higher Charlson comorbidity index (5.3 [±2.4] vs 3.4 [±2.6]; p=0.014) and were more frequently > 70yo (75% vs 44%, p=0.036)

     • During hospitalization (before tocilizumab), toci group had high O2 requirements, higher CRP

     • Primary: Combined endpoint (death and/or ICU admission) higher in toci group (72% vs 25%, p=0.002)

     • Secondary: need for invasive ventilation for toci lower (32% vs 0%, p=0.006)

     • Secondary: mortality trended lower for toci (48% vs 25%, p=0.066).

   • Overall outcomes: kudos to authors for some attempt at patient matching. positive.

8. Quartuccio L, Sonaglia A, McGonagle D, et al. Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care [published online ahead of print, 2020 May 15]. J Clin Virol. DOI:10.1016/j.jcv.2020.104444

   • Study design: retrospective case series subdivided into those that did and did not receive tocilizumab, 111 patients total (42 of which received tocilizumab)

   • Inclusion: COVID+

   • Exclusion: none

   • SOC: most received Antiviral treatments

   • Treatment: 8 mg/kg intravenously tocilizumab as a single infusion. 2 patients received SQ 200 mg anakinra for 3 days once considered toci treatment failure.

   • Caveats: usual caveats of case series, should not be interpreted as retrospective case control as no attempt at matching was made. Data should not be reported as mean+/-SD (need to use median unless they have formally tested for normality).

   • Outcomes:

     • 18 (43%) of TOCI were on ID ward and 3 subsequently transferred to ICU before tocilizumab administration. Overall, 24 of 42 TOCI patients transferred to ICU within 24 hours of admission.

     • 3 died in ICU group, 1 died from ID ward, 0 died in SOC group

   • Overall outcomes: equivocal to worst?

Case Series (n ≤ 10)

1. Di Giambenedetto S, Ciccullo A, Borghetti A, et al. Off-label Use of Tocilizumab in Patients with SARS-CoV-2 Infection [published online ahead of print, 2020 Apr 16]. J Med Virol. DOI: 2020;10.1002/jmv.25897. (severe patients, up to 3 doses of 8 mg/kg tocilizumab, decreased dyspnea)

2. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure [published online ahead of print, 2020 Apr 17]. Cell Host Microbe. 2020;S1931-3128(20)30236-5. doi:10.1016/j.chom.2020.04.009

3. Hassoun A, Thottacherry ED, Muklewicz J, Aziz QU, Edwards J. Utilizing tocilizumab for the treatment of cytokine release syndrome in COVID-19 [published online ahead of print, 2020 May 16]. J Clin Virol. 2020;128:104443. doi:10.1016/j.jcv.2020.104443 (nicely defined Cytokine storm, varied dose from 162 mg SQ to 800 mg IV, moderate to severe COVID patients)

4. Morillas JA, Marco Canosa F, Srinivas P, et al. Tocilizumab therapy in five solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2 [published online ahead of print, 2020 May 31]. Am J Transplant. DOI:10.1111/ajt.16080 (5 solid tx pt; combinations of MMF, tacro, prednisone, cyclsoporine; ⅗ with IL-6 measurements between 7 - 438 pg/mL, 400 mg IV toci 1x dose; 1 died, multiple with infections)

Case Reports

1. Ferrey et al. 2020. Am J Nephrol. DOI: 10.1159/000507417

2. De Luna et al. 2020. Am J Hematol. DOI: 10.1002/ajh.25833 (patient with sickle cell)

3. Cellina et al. 2020. Diagn Interv Imaging. DOI:10.1016/j.diii.2020.03.010

4. Bjornsson et al. 2020. Laeknabladid. DOI:10.17992/lbl.2020.05.581

5. Xu et al. 2020. QJM. DOI:10.1093/qjmed/hcaa153

6. Radbel. 2020. Chest. DOI:10.1016/j.chest.2020.04.024

7. Jacobs et al. 2020. ASAIO J. DOI:10.1097/MAT.0000000000001185 (ECMO patient case series, 2 treated with tocilizumab)

8. Muhović et al. 2020 May 17]. Liver Int. DOI: 10.1111/liv.14516. doi:10.1111/liv.14516 (drug induced liver injury from tocilizumab)

9. Holzhauser et al. 2020 Am J Transplant. DOI: 10.1111/ajt.15982. doi:10.1111/ajt.15982 (2 heart transplant patients)

10. Sernicola et al. 2020 J Eur Acad Dermatol Venereol. DOI:10.1111/jdv.16620 (toxic erythema and eosinophilia associated with tocilizumab)

11. Luo et al 2020. Zhejiang Da Xue Xue Bao Yi Xue Ban. 49(2):227‐231. (PLEX v. tocilizumab)

12. Anand et al. 2020. 10.1002/mus.26918. DOI:10.1002/mus.26918 (1 patients with MS)

13. Allam et al. 2020. Transpl Infect Dis. DOI; e13326. doi:10.1111/tid.13326

14. Valencia-Sanchez et al. 2020. Mult Scler Relat Disord. DOI: 42:102182. doi:10.1016/j.msard.2020.102182 (1 patient with MS)

15. Faguer et al. 2020. Ann Intern Med. DOI: 10.7326/L20-0419. (kidney transplant)

16. Mazzitelli et al. 2020. May 15]. J Med Virol. DOI:10.1002/jmv.26016 (SQ only)

List of major peer-reviewed studies providing context for therapy:

1. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.

2. Qin 2020 IDSA Dysregulation of immune response in patients with COVID-19 in Wuhan, China

3. Wu 2020 JAMA IM Risk factors associated with acute respiratory distress syndrome and death in Patients with coronavirus disease 2019 Pneumonia in Wuhan, China

4. Goyal 2020 NEJM Clinical Characteristics of Covid-19 in New York City http://doi.org/10.1056/NEJMc2010419

5. Mihai C, Dobrota R, Schröder M, et alCOVID-19 in a patient with systemic sclerosis treated with tocilizumab for SSc-ILDAnnals of the Rheumatic Diseases 2020;79:668-669. http://dx.doi.org/10.1136/annrheumdis-2020-217442

6. Aziz M, Fatima R, Assaly R. Elevated Interleukin-6 and Severe COVID-19: A Meta-Analysis [published online ahead of print, 2020 Apr 28]. J Med Virol. 2020;10.1002/jmv.25948. http://dx.doi.org/10.1002/jmv.25948

7. Chen Tao, Wu Di, Chen Huilong, Yan Weiming, YangDanlei, Chen Guang et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study BMJ 2020; 368 :m1091 https://doi.org/10.1136/bmj.m1091

8. Antinori S, Bonazzetti C, Gubertini G, et al. Tocilizumab for cytokine storm syndrome in COVID-19 pneumonia: an increased risk for candidemia? [published online ahead of print, 2020 May 3]. Autoimmun Rev. 2020;102564. http://dx.doi.org/10.1016/j.autrev.2020.102564

   • 43 consecutive patients treated with tocilizumab

   • 3 patients (16,3%) developed candidaemia ~13 days after tocilizumab, one with endophthalmitis and endocarditis

   • All three had received 8 mg/kg (800 mg max) given twice, 12 hours apart

   • Only one had central line at time of diagnosis

   • CRP remained within normal range and patients did not have fever but they did mount a leukocytosis

List of pre-peer reviewed/pre-publication studies:

1. Gritti 2020 Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1

   • Study design: retrospective cohort with control of IL-6 inhibitor in addition to standard of care

   • Location: Papa Giovanni XXIII Hospital in Bergamo, Italy, with7 day f/u

   • N = 21

   • Patient inclusion criteria: COVID+, ARDS

   • Exclusion criteria: none specified

   • Dosing: 11 mg/kg/day siltuximab over 1 hour. Some received second dose at physician’s discretion (5 patients received second dose after 2-3 days)

   • Clinical Outcomes:

     • Presenting symptoms: fever (90%), dry cough (62%), dyspnea (71%), all with bilateral infiltrates

     • Comorbidites mainly HTN, CVD, DM, but one patient had malignancy.

     • 33% improved (removed from CPAP/NIV)

     • 43% stabilized

     • 24% worsened & were intubated

     • 1 patient with CVA

   • Overall outcome: equivocal

List of pre-peer reviewed/pre-publication studies providing context for therapy:

1. Herold 2020 “IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients.” Preprint. https://doi.org/10.1101/2020.04.01.20047381

2. Liu et al 2020 “The potential role of IL-6 in monitoring severe case of coronavirus disease 2019” Preprint. https://doi.org/10.1101/2020.03.01.20029769

Discussion

Please note: At this time there are no high quality studies for immunomodulatory therapies for COVID19. The following background, descriptions, and recommendations attempt to summarize and utilize limited, low quality data from epicenters of COVID19 infection. What randomized control trials have been published suffer from poor study design. We will also utilize case reports, laboratory research, and basic immune-pathophysiology to fill in gaps when possible. However, historically and repeatedly, pathophysiology does not always translate to meaningful clinical information or improvement.

• Are high IL-6 levels predictive/prognostic for hyper-inflammation (a cytokine release like picture) in patients with severe COVID19? Is IL-6 level associated with/predictive/prognostic of worse clinical outcomes?

Though high IL-6 levels have been reported in severe/critical patients with COVID who have developed ARDS, there is scant data for IL-6 as prognostic or predictive in regard to disease severity. This may in part be associated with timing of IL-6 measurements: depending on hospital admission policies, admission IL-6 levels may be draw “too soon” and once decompensated it may be “too late.” Alternatively, as with many inflammasome pathways, IL-6 as an end product of the inflammatory cascade may be a late sign once decompensation has already occurred.

1. Herold et al (PRE-PEER REVIEW) https://doi.org/10.1101/2020.04.01.20047381

   • 40 patients, IL-6 > 80 pg/mL and serum creatinine in particular are assocaited with clinical decompensation within ~1.5 days. Less strongly assocaited, but still associated, were CRP, procalcitonin, heart rate, and LDH.

2. Aziz et al. J Med Virol. http://dx.doi.org/10.1002/jmv.25948

   • Meta-analysis of poor quality data and article is currently missing its figures. Nonetheless, includes 7 studies total in analysis of severity and 5 studies looking at overall mortality. All studies from China. Severe covid disease defined as RR>30 or SpO2<93% on room air or PaO2/FiO2 < 300 or ICU admission or death. There is no information on time-to-decompensation or timing of IL-6 check in this dataset. Severe patients had a mean IL-6 of 56.8 pg/mL whereas non-severe had a 17.3 pg/mL. It is unclear why, or why this should be considered useful clinically, but authors selected to analyze for relationship between mean difference of IL-6 level and risk of severity and found a statistical correlationation (mean difference was 38.6 pg/mL, 95% CI 24.3 - 52.9, p<0.001, i2 = 98%). They found a weaker correlation of mean difference of IL-6 levels with overall mortality (p<0.05)

• To what extent do COVID19 patients demonstrate IL-6 elevation?

1. Xu et al chinaXiv:202003.00026v1. Now published, see summary under peer-reviewed papers

PRE-PEER-REVIEW/PUBLICATION. Nonetheless, one of the first available reports.

21 total patients treated in Anhui Province, just east of Wuhan province, at First Affiliate Hospital of University of Science and Technology and Second People’s Hospital. All patients had a chronic medical illness— predominant comorbidities were hypertension and diabetes. Seventeen patients (81%) were considered severe as defined as meeting any of the following conditions: (1) SpO2<93% on room air, (2) RR> 30, and/or (3) PaO2/FiO2 < 300. Three patients (19%) were considered critical (requiring intubation or in shock). These patients presented with predominant fever, dry cough, fatigue/myalgia, and dyspnea and were found to have bilateral airspace opacities. Dyspnea onset was ~6 days post from onset of fever. Only 2 patients were ultimately intubated (10%).

It is important to note that these are the same criteria used in Wuhan papers to distinguish severe cases and certainly patients with ARDS would meet these criteria. Yet the data from both Wuhan papers DID NOT show such elevated IL-6 levels and in fact did not go above the normal range unless looking at the ICU/critical subset and even then not to this extent. One possibility is that the method of IL-6 detection differed between the previous case series and this current paper. This paper used electrochemical luminescence method (Roche Diagnostics GmbH; dynamic range 2.6-5000 pg/mL) whereas the Qin et al Wuhan review (IDSA) does not specify method, nor does the Wu et al review (JAMA IM), and the Huang et al (LANCET) utilized a Bio-Rad 200 system assay panel with dynamic range 2.3-18,880 pg/mL. Another possibility, and one I feel is more likely, is that the Xu et al paper selected for patients with elevated IL-6 levels.

Patient inclusion criteria: it is likely that these patients were selected for elevated IL-6 levels though this is not specified in the paper. All patients received standard care which included lopinavir, methylprednisolone, symptom relievers, O2 therapy in addition to tocilizumab.

Exclusion criteria: none specified

Dosing: 400 mg 1x, with repeat dosing within 12 hours if persistent or recurrent fever.

Clinical Outcomes:

• All patients were afebrile after treatment and remained so through day 5

• Clinical symptoms and SpO2 improved within the several days after infusion

• 75% (15 patients) lowered their O2 intake

• One patient was extubated the day after infusion, one remained intubated

• 19 patients were ultimately discharged (90%), Mean hospital time post tocilizumab was 13 days +/- 3 days (unclear if this includes those that were still hospitalized at time of study write up)

Lab value changes:

• Note that tocilizumab will decrease CRP and ferritin, and can eliminate fevers, without actually treating the underlying process. This may be what we are looking for but certainly CRP & ferritin should be considered unreliable until proven otherwise.

• Mean +/- SD; from pre-tocilizumab to d5 post tocilizumab

• CRP dropped from mean of 75 +/- 67 mg/L to 2.7 +/- 3.6 mg/L (normal range 0-5)

• Lymphocyte percentage rose from 15.5 +/- 8.9 to 22.6 +/- 13.5 (normal range 20-50)

• Procalcitonin was never elevated above normal range of 0-0.5

• White blood cell count remained within normal range throughout with notable transient rise of ~2 x 10^9 cells/L on day

2. Liu et al https://doi.org/10.1101/2020.03.01.20029769

PRE-PEER REVIEW/PUBLICATION

This series evaluates cytokines in 69 severe patients from Tongji Medical College in Hubei province in Wuhan treated between January and February 2020. They also selected and included 11 additional, non-severe patients for which I will not review the data as it is impossible to interpret without a description of how these 11 additional patients were selected. Patients were designated as severe if meeting any of the following criteria: (1) RR>30, (2) SpO2 < 93% on room air, and/or (3) PaO2/FiO2 < 300. Cytokine measurements done by ELISA with human Th1/2 cytokine kit II (BD).

While presentation of severe patients was as previously reported though this cohort had slightly higher chance of being a smoker (12%) and having symptoms of diarrhea (16%) and vomiting (7%). Patients developed pneumonia 4 days +/- 4 days after initial symptom onset. 36% of patients had at least one comorbidity and for this paper hepatitis B viral infection was included as a comorbidity. Also, 4 patients (6%) had underlying tumor—a higher proportion of patients than previously reported. Notably only 10% developed ARDS and only 4% required ICU admission. Nearly all patients antibiotics and some antiviral. 15% received antifungals, 42% received methylprednisone, 50% received IVIG, and 87% received nebulized interferon-alpha.

In regards to lab abnormalities, 13% of severe patients had neutrophilia, 13% with neutropenia, and the remainder within normal limits. 24% had thrombocytopenia. As previously reported, 80% of severe patients had leukopenia. 25% had thrombocytopenia. Overall, lab findings are more severe in this severe cohort than in previous, equally severe, cohorts from China.

Serum/plasma lab abnormalities among severe patients:

• 85% with CRP>10 mg/L

• 65% with LDH>250 U/L

• 38% with AST>40 U/L or ALT>40 U/L

• 15% with CK>200 U/L

• 65% with d-dimer>0.5 mg/L

• ESR mean 45 mm/h +/-26

• Ferritin mean 827 ug/L +/- 917

• CD4+ and CD8+ cell counts appear to have a mean and median within normal limits (graphs only, not quantified)

• IL-6 levels ranged from 5-200 pg/mL, mean is shown at 35 pg/mL, median is not reported (mean is inappropriate as reporting mechanism for non-normally distributed data)

• IL-10 ranged from wnl to 15 pg/mL, mean is shown as ~5 pg/mL, median not reported.

• Il-2, IL-4, IFNgamma, and TNFalpha were wnl

• Graphs showing a nadir of CRP and IL-6 10 days after symptom onset (for one patient? It’s not clear)