More details about outcomes and disease severity
We predefined the following critical and important outcome measures:
The following outcomes with related time points reported as days (D) of follow-up were considered:
- Clinical improvement (D28 / ≥ D60) defined as a hospital discharge or improvement on the scale used by trialists to evaluate clinical progression and recovery. We recorded the scale and the threshold used by authors to define improvement as appropriate.
- WHO Clinical Progression Score of level 7 or above (i.e. mechanical ventilation +/- additional organ support [ECMO, vasopressors or dialysis] OR death (D28 / ≥ D60)
- All-cause mortality (D28 / ≥ D60)
All assessments performed at D60 and later are reported under ≥ D60. When outcomes are assessed at time points other than those selected by the review, we chose the closest (e.g. D15 for D28).
- Incidence of any adverse events (AEs)
- Incidence of serious AEs (SAEs)
- Time to clinical improvement
- Time to WHO Clinical Progression Score of level 7 or above
- Time to death
Disease severity was classified as described below according to the clinical status or clinical management of patients. This classification relies on existing classification and clinical expertise (WHO 2020a, WHO 2020b). We considered the description of eligibility criteria as well as the baseline characteristics of participants and classified the severity as follow:
- Mild disease ambulatory — "outpatients" whose clinical symptoms are mild with no sign of pneumonia on imaging.
- Mild disease — clinical symptoms requiring hospitalization but no need for supplemental oxygen
- Moderate disease — fever and respiratory symptoms with radiological findings of pneumonia and requiring standard oxygen therapy O2 (3–5 L/min).
- Severe disease — meeting any of the following criteria:
- respiratory distress (≧ 30 breaths/min)
- oxygen saturation ≤ 93% at rest in ambient air or oxygen saturation ≤97% with O2 > 5 L/min
- PaO2/FiO2 ≦ 300 mmHg (l mmHg=0.133 kPa). PaO2/FiO2 in high-altitude areas (> 1000 m above sea level) is corrected by the following formula: PaO2/FiO2 x [atmospheric pressure (mmHg)/760]
- patients hospitalized on Non-invasive ventilation (NIV)/High flow Nasal oxygen (HFNO).
- Critical disease — cases meeting any of the following criteria
- respiratory failure requiring invasive mechanical ventilation
- other organ failure requiring Intensive Care Unit care
Worth mentioning that since the classification of severity class was heterogenous among studies, we reclassified the participant disease severity based on the above severity criteria. Consequently, the severity reported by investigators might differ from the severity reported in this review.