Table 2.
Characteristics of included cohort studies
| Study/Publication type | Country | No. of pts | Study type | Cohort selection | Treatment criteria | Exclusion criteria | Primary outcome | Analytical method | Variables adjusted for | Immortal time bias adjustment |
|---|---|---|---|---|---|---|---|---|---|---|
| Biran et al.a (same cohort as Ip et al.) | United States | 630 | Multicentre retrospective cohort | Patients admitted to ICU without prior exposure to tocilizumab | ARDS on MV, or worsening oxygenation with high oxygen requirements (80–100%) on high-flow nasal cannula or 15 L non-rebreather mask Symptoms had to be present for 7 days |
Pregnant, enrolled in an RCT, death within 24 h | 30-day mortality | Multivariate Cox regression with propensity score | Comorbidities, gender, age, race Steroids: no (equal in both groups) |
No |
| Colaneri et al.a | Italy | 42 | Single-center retrospective cohort | Hospitalized adult patients with a confirmed COVID-19 pneumonia | TCZ was administered if: CRP > 5 mg/dl, PCTI < 0.5 ng/mL, PF ratio <300 | ALT >500 U/L | ICU admission and 7-day in-hospital mortality rate. | Propensity matched logistic regression | Age, sex, LDH, neutrophils Steroids: (100%) received |
No |
| Eimerb et al. | Sweden | 44 | Single-center retrospective cohort | Patients admitted to ICU for severe ARDS | Rising O2 at least 5L/min, ≥ 7 days from symptom onset, CRP >100 mg/L or ferritin >500 ug/L and no contraindication to tocilizumab | Patients with COVID-19 admitted to ICU for primary diagnosis other than ARDS | 30-day all-cause mortality after ICU admission | Cox proportion-hazard model | Age, diabetes, hypertension, obesity, d-dimer, interlukin-6, troponin T and PaO2/FiO2 ratio | No |
| Garciaa et al. | Spain | 171 | Single-center Retrospective Cohort | COVID-19 patients with pneumonia who did not require ICU transfer during the first 24h of admission | Patients with pneumonia, progressive respiratory failure CRP ≥8 mg/dL or ferritin ≥800 ng/mL or lymphocyte count <800 | NR | In-hospital mortality or ICU admission | Multivariate logistic regression analysis with propensity scoring | Age, HTN, DM, heart disease, respiratory disease, lymphoma Steroids: No |
Inadequate: patients not requiring ICU admission within 24 hours |
| Gokhaleb et al. | India | 269 | Single-center Retrospective Cohort | Severe COVID-19 pneumonia with persistent hypoxia | Persistent hypoxia, bilateral pulmonary infiltrates and raised CRP, LDH and ferritin | Altered sensorium, terminal malignancy, EF < 20% | Survival | Multivariate Cox regression analysis | Age, oxygen saturation, creatinine, tocilizumab and invasive ventilation | No |
| Guaraldia et al. | Italy | 544 | Multi-center Retrospective Cohort | Patients with severe∗ COVID-19 infection | SaO2< 93% and a PaO2/FiO2 ratio <300 mm Hg in room air or a >30% decrease in their PaO2/FiO2 ratio in the past 24 h during hospitalization. | Coexisting infection, PaO2/FiO2 > 300, steroid use, neutrophils <500 platelet< 50,000 High risk for bowel perforation | Composite of mortality or invasive mechanical ventilation | Multivariate Cox regression analysis | Sex, age, recruiting center, duration of symptoms, and baseline SOFA score Steroids: yes |
Yes |
| Hillb el al. | United States | 88 | Multi-center retrospective cohort | Patients admitted to hospital and requiring supplemental oxygen | Persistent fever with impending or current respiratory failure, hemodynamic instability, IL-6 > 5 times normal. | Sepsis, transaminases >5 times normal, ANC <500 cells/mm3 or platelets <50 cells/mm3 | Clinical improvement i.e. two-point reduction in severity, discharge and 28 day mortality | Cox proportion-hazard model | Age, sex, ethnicity, BMI, diabetes, cardiovascular disease, hospital, code status, oxygen support category | No |
| Holtb et al. | United States | 62 | Single-center case-control study | Patients admitted to hospital meeting inclusion criteria | oxygen ≥ 4L and; IL-6 > 40 pg/mL, CRP >10 mg/dL, D- dimer >1 mcg/mL FEU, ferritin >1000 ng/mL, or LDH >350 units | NR | Effect of tocilizumab on mortality | Cox proportion-hazard model | Age, chronic hypoxia, nursing home, IL6 > 580, ferritin >1631, ICU admission, tocilizumab, hypoxia on admission, solid tumor, diabetes, Caucasian and altered mental status | No |
| Martinez-Sanzb et al. | Spain | 1229 | Multi-center Retrospective Cohort | COVID-19 patients. | Treatment criteria not reported | Death or transfer within 24 hours | In-hospital? Mortality | Multivariate Cox regression with Propensity score | Age, gender, comorbidities, lab values Steroids: NA |
Yes: Marginal structure model |
| Mikulskab et al. | Italy | 196 | Single-center Retrospective Cohort | Patients with severe∗ or critical∗∗ COVID-19 infection | Treatment criteria was not reported | Death intubation or discharge before day 3 of admission | Intubation mechanical ventilation or mortality | Overlap-weighted Cox proportional hazard regression model | Age, gender, presence of comorbidities, week treatment began, NIV, and labs Steroids: NA, Tcz compared with steroids |
Yes: landmark analysis |
| Naraina et al. | United States | 3098 | Multi-center Retrospective Cohort | Patients with cytokine storm defined as ferritin >700ng/mL or CRP >30mg/dL or LDH >300U/L | Treatment criteria not reported | Immunomodulatory drugs used prior to the diagnosis of cytokine storm | In-Hospital mortality | Multivariate Cox proportional hazard regression model | Age, gender, race, comorbidities, lab data, insurance status Steroids: NA, patients receiving steroids were in their own group |
No |
| Ramaswamyb et al. | United States | 86 | Multi-center Case-Control | Patients who died during hospitalization were cases, while patients discharged alive were controls. The exposure was treatment with tocilizumab | Treatment criteria was not reported | NR | In-hospital Mortality | IPSW Cox regression adjusted for competing risk of mortality | Age, race, gender, Elixhauser comorbidity score, MEWS score Steroids: included in IPW analysis |
No |
| Roomib et al. | United States | 176 | Single-center Retrospective Cohort | Hospitalized adult patients with a confirmed COVID-19 infection | Treatment criteria was not reported | NR | In-hospital mortality, ICU admission, mechanical ventilation | Multivariate logistic regression | Baseline comorbidities and medication use | No |
| Rossib et al. | France | 246 | Single-center Case Control | Patients with severe∗ COVID-19 pneumonia | Treatment criteria was not reported | Patients on IMV or admitted to the ICU | Composite of mortality and mechanical ventilation | IPSW Cox regression | Age, engagement status, systolic blood pressure SpO2/FiO2 ratio Steroids: Equal between groups after matching |
Inadequate: time between admission and inclusion was adjusted for in propensity-score matching |
| Rossottia et al. | Italy | 222 | Single-center Retrospective Cohort | Patients with severe cCOVID-19 infection | CT scan showing severe bilateral pneumonia; CRP >1 mg/dL, IL-6 >40 pg/mL, D-dimer >1.5 mcg/mL, or ferritin >500 ng/mL | ALT value > 5 x ULN; neutrophil cell count <500 cell/mmc; platelet count <50,000 cell/mmc | In-hospital Mortality | Cox regression models | NR Steroids: NA |
No |
| Roumierb et al. | France | 59 | Single-center Retrospective Cohort | NR | COVID-19 patients with requiring >6L O2, elevated CRP levels | NR | Mortality, Mechanical ventilation, and ICU admission | IPTW matched logistic regression | Age, gender and disease severity Steroids: No |
No |
| Somersa et al. | United States | 154 | Single-center retrospective Cohort | Critical dCOVID-19 patients requiring invasive mechanical ventilation | Abnormal chest imaging consistent with COVID-19, rapidly worsening respiratory status, suspicion of cytokine release storm, MV for <48 hours | Death within 48 hours of intubation, intubation for conditions unrelated to COVID-19 or enrolled into an RCT for sarilumab | In-hospital mortality | IPTW Cox regression model | Age, gender, race, ferritin, LDH, AST Steroids: No (equal between usage groups) |
Inadequate: patients who died within 48 hours of intubation were excluded |
| Tsaib et al. | United States | 132 | Single-center consecutive Cohort | Hospitalized patients who meet treatment criteria | Ferritin >300 ug/mL and SpO2 < 94% requiring supplemental oxygen or mechanical ventilation | NR | In-hospital mortality | Propensity matched logistic regression | Age, sex, body mass index, lactic acid, ferritin, LDH, procalcitonin, creatinine, hypertension and comorbidity score | No |
ALT: Alanine aminotransferase; ARDS: acute respiratory distress syndrome; CRP: C-reactive protein; DM: Diabetes mellitus; HTN: Hypertension; NR: Not reported; NA: Not applicable; IMV: Invasive mechanical ventilation; IPTW: Inverse probability treatment weighted; IPW: Inverse probability weighted; MV: Mechanical ventilation; UNL: upper normal limit; TCZ: Tocilizumab.
a
Peer-reviewed.
b
Pre-print.
c
Severe COVID-19 defined by one of the following 1) respiratory rate ≥30 breaths/min, 2) peripheral capillary oxygen saturation (SpO2) ≤ 93% while breathing room air, 3) PaO2/FiO2 ≤ 300 mmHg.
d
Critical patients requiring mechanical ventilation.