Abstract
Background
The coronavirus disease 2019 (COVID-19) pandemic has presented as a therapeutic challenge for clinicians worldwide due to its rapid spread along with evolving evidence and understanding of the disease. Internationally, recommendations to guide the management of COVID-19 have been created and updated continuously by the WHO and CDC, which have been locally adapted by different countries. Similarly, Pakistan's National Command Operation Center (NCOC), in its national COVID-19 management strategy, generated guidelines for national implementation. Keeping the guidelines updated has proved challenging globally and locally. Here, we present a summary of the process to assess the evidence, including a time-restricted systematic review based on NCOC Clinical Management Guidelines for COVID-19 Infections v4 published on 11th December 2020 version, correlating it with current recommendations and with input one of the guidelines authors, particularly noting the methodological challenges.
Methods
We conducted a systematic review synthesizing global research on treatment options for COVID-19 hospitalized patients, limiting it to pharmacological interventions for hospitalized COVID-19 patients included in Pakistan's NCOC's national guidelines v4 published on 11th December 2020. Each treatment recommendation's strength and quality of evidence was assessed based on the grading of recommendations assessment, development, and evaluation (GRADE) methodology. These were then compared to the most current living WHO COVID-19 pharmacological treatment guidelines v7.1. One of the authors of the NCOC guidelines reviewed and commented on the findings as well.
Results
We note that the data from our systematic review strongly supports corticosteroids use in treating severe and critically ill COVID-19 hospitalized patients correlating with WHO v7.1 guidelines 24 September 2021. However, evidence from our review and WHO v7.1 for the use of tocilizumab had some conflicting evidence, with data from our review until December 2020 supporting only a weak recommendation for its use, compared to the strong recommendation by the WHO for the use of tocilizumab in patients with severe or critical COVID-19 infection. Regarding the use of antibiotics and ivermectin use in treating COVID-19 hospitalized patients, data from our review and WHO v 7.1 recommend against their use.
Conclusion
Research data about the efficacy and safety of pharmacological interventions to treat hospitalized patients with COVID-19 are rapidly evolving, and based on it, the evidence for or against recommendations changes accordingly. Our study illustrates the challenges of keeping up with the evidence; the recommendations were based on studies up till December 2021, and we have compared our recommendations with the WHO v7.1, which showed some significant changes in the use of pharmacological treatment options.
1. Introduction
Pakistan, like other countries worldwide, has seen many cases of coronavirus disease 2019 (COVID-19) since the pandemic began [1]. The national government-led response included the creation of a central National Command Operation Center (NCOC), setting up designated hospitals, isolation testing facilities, and following dedicated treatment guidelines based on WHO recommendations. National guidelines were created, 2nd April 2020 (v1), with most recent version (v4) currently in use, “Clinical Management Guidelines for COVID-19 Infections” published by the Government of Pakistan on 11th December 2020 [2]. These have been formulated by national experts incorporating international guidelines and adapting them to local contexts.
2. Methods
Here, we present a summary of the process to assess the evidence, including a time-restricted systematic review based on NCOC version, correlating it with current recommendations specifically looking at it from a local perspective; along with input from NCOC guidelines.
We describe the methodological challenges that exist in the developing evidence-based guidelines for an evolving pandemic. We performed a systematic review to evaluate the interventions noted in the NCOC guidelines v4 and to GRADE recommendations for pharmacological interventions for hospitalized patients. Then, we compared our recommendations to WHO v7.1 COVID-19 therapeutics guidelines and subsequently invited an expert narrative review by NCOC experts specifically looking at it from a local perspective.
This study was conducted at the Center for Clinical Best Practices (CCBP), Clinical and Translational Research Incubator (CITRIC), Aga Khan University, Karachi, Pakistan, after approval from the institutional ethical review committee.
The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [3]. We aimed to review the effectiveness of pharmacological interventions included in the NCOC guidelines on mortality and length of stay in hospitalized patients with COVID-19 including evidence available until 11th December 2020. The WHO clinical progression scale for clinical improvement (ordinal scale) was used to categorize the disease severity for each study. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria were used to evaluate and formulate recommendations for or against and strength by considering the quality of evidence and balance between benefits and harms [4] (Table 1 and Supplementary Figure 1).
Table 1.
Selection criteria and search strategy.
| Characteristics | Inclusion criteria | Exclusion criteria | Search string |
|---|---|---|---|
| Study participants | Studies including adult human participants/patients (age ≥18 years) of either sex with a confirmed diagnosis of COVID-19 in a hospital setting. | Studies including pregnant women. | (COVID-19 [MeSH] OR corona∗ OR SARS-CoV-2 OR “coronavirus disease” OR “coronavirus infection”[MeSH] OR “Severe acute respiratory syndrome coronavirus 2” OR “coronavirus-2019” OR “novel coronavirus” OR “COVID-19 pandemic” OR 2019nCoV) AND (adult∗[MeSH] OR young adult∗[MeSH] OR “adulthood”) AND (“admission” OR “admitted inpatient” OR “in-patient” [MeSH] OR “Hospitalization” [MeSH] OR “Hospitalized” [MeSH] OR “stay”) AND |
| Interventions | Observational and interventional studies describing the use of the following pharmacologic interventions for the treatment of COVID-19: (i) Steroids (dexamethasone, hydrocortisone, and prednisone methylprednisolone) (ii) Anticoagulation (iii) Remdesivir (iv) Antibiotics (v) Colchicine (vi) Tocilizumab (vii) Other investigational therapies (convalescent plasma, intravenous immunoglobulin, plasmapheresis, ivermectin, and famotidine). |
Pharmacologic or nonpharmacologic treatment interventions other than those specified in inclusion criteria. | (intervention∗ OR drug∗ OR pharma∗ OR medic∗ OR treatment∗) AND (“Hydroxychloroquine”[Mesh] OR “Azithromycin”[Mesh] OR “Doxycycline”[Mesh] OR “Amoxicillin”[Mesh] OR anticoagul∗ OR “ Low-Molecular-Weight Heparin” OR “Unfractionated Heparin” OR “remdesivir”[MeSH] OR “antibiotics”[MeSH] OR “antiviral” OR “investigational therapies”[MeSH] OR “convalescent plasma” OR “intravenous immunoglobulin”[MeSH] OR “plasmapheresis”[MeSH] OR “ivermectin”[MeSH] OR “famotidine”[MeSH] OR “tocilizumab” OR steroid∗ OR “dexamethasone”[MeSH] OR “hydrocortisone”[MeSH] OR “Methylprednisolone” OR “prednisone”[MeSH]) OR “colchicine”[MeSH]) AND |
| Outcomes | Studies describing at least one of the following primary or secondary outcome measures: (a) Primary outcomes: (i) In-hospital mortality (ii) Length of hospital stay. (b) Secondary outcomes: (i) Progression of disease (ii) Treatment of adverse effects |
— | (“survival” [MeSH] OR recover∗ OR discharge∗ OR “death” [MeSH] OR “mortality” [MeSH] OR “fatality”) |
Studies in English published from 1st November 2019 to 31st December 2020 were included in the review. Data extraction and synthesis data extraction were performed by two independent investigators using a structured data extraction form to ensure consistency. Any disagreements were noted and resolved by further discussion with a third investigator. The extracted data are given in Tables 2–5). The quality of the final included studies was assessed according to each study design. Observational studies were assessed by the National Institute of Health Study Quality Assessment Tool [5]. Randomized control trials were evaluated by Cochrane Risk of Bias (RoB) [6]. Quasiexperimental studies were assessed by the Cochrane Effective Practice and Organization of Care (EPOC) risk of bias tool [7] (Supplementary Figures 2–9).
Table 2.
Description of study characteristics: cross-sectional and cohort studies.
| S. no. | Author, country | Title | Study duration in days | Intervention group | Comparator group | Concomitant group | Outcome measures | Outcome measures applicable to this review |
|---|---|---|---|---|---|---|---|---|
| 1 | Stessel et al., Belgium | Impact of implementation of an individualized thromboprophylaxis protocol in critically ill ICU patients with COVID-19: A longitudinal controlled before-after study. | 52 | Nadroparin calcium 2850 IU (preimplementation of protocol) | Nadroparin calcium 2850 IU (postimplementation of protocol) | — | (i) One-month mortality (ii) Two-week and three-week mortality (iii) Hospital length of stay |
(i) One-month mortality (ii) Two-week and three-week mortality (iii) Hospital length of stay |
| 2 | Jonmarker et al., Sweden | Dosing of thromboprophylaxis and mortality in critically ill COVID-19 patients | 56 | (i) Tinzaparin or dalteparin low (2500–4500 IU tinzaparin or 2500–5000 IU dalteparin) (ii) Tinzaparin or dalteparin medium (> 4500 IU but < 175 IU/kilogram, kg, of bodyweight tinzaparin or > 5000 IU but < 200 IU/kg of bodyweight dalteparin) (iii) High dose (≥ 175 IU/kg of bodyweight tinzaparin or ≥ 200 IU/kg of bodyweight dalteparin) |
— | — | (i) 28 days mortality (ii) ICU stay (iii) Thromboembolic events |
(i) 28 days mortality (ii) ICU stay (iii) Thromboembolic events |
| 3 | Salton et al., Italy | Prolonged low-dose methylprednisolone in patients with severe COVID-19 pneumonia | 58 | Methylprednisolone loading dose of 80 mg intravenously, followed by an infusion of 80 mg/d in 240 ml of normal saline at 10 ml/h for at least 8 days | — | Standard of care (antibiotics, antivirals, vasopressors, and renal replacement therapy) | (i) Mortality (ii) Transfer to intensive care unit (iii) Invasive mechanical ventilation |
(i) Mortality (ii) Transfer to intensive care unit (iii) Invasive mechanical ventilation |
| 4 | Mutair et al., Saudi Arabia | Clinical, epidemiological, and laboratory characteristics of mild-to-moderate COVID-19 patients in Saudi Arabia: An observational cohort study | 31 | Hydroxychloroquine in mild cases | Hydroxychloroquine in moderate cases | (i) Hydroxychloroquine (ii) Azithromycin (i) Oseltamivir (iii) Vitamin C (iv) Vitamin E (v) Ceftriaxone (vi) Enoxaparin |
(i) Days of hospitalization (ii) SARS-CoV-2 PCR negative (iii) Treatment outcomes |
(i) Days of hospitalization (ii) SARS-CoV-2 PCR negative (iii) Treatment outcomes |
| 5 | Annie et al., the United States | Hydroxychloroquine in hospitalized patients with COVID-19: real-world experience assessing mortality | 116 | (i) Hydroxychloroquine alone (ii) Hydroxychloroquine plus azithromycin |
— | — | Mortality | Mortality |
| 6 | Arshad et al., the United States | Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19 | — | (i) Hydroxychloroquine alone (ii) Azithromycin alone 500 mg once daily on day 1 followed by 250 mg once daily for the next 4 days. (iii) Hydroxychloroquine plus azithromycin |
Neither treatment | (i) Steroid (ii) Tocilizumab |
(i) Mortality (ii) Hospital length of stay in days. |
(i) Mortality (ii) Hospital length of stay in days |
| 7 | Ashinyo et al., Ghana | Clinical characteristics, treatment regimen, and duration of hospitalization among COVID-19 patients in Ghana: A retrospective cohort study | 93 | (i) Chloroquine + hydroxychloroquine (ii) Hydroxychloroquine + azithromycin (iii) Hydroxychloroquine only (iv) Azithromycin only (v) Supportive treatment |
— | — | Duration of hospitalization | Duration of hospitalization |
| 8 | Ayerbe et al., Spain | The association between treatment with heparin and survival in patients with COVID-19 | 55 | (i) Heparin | — | (i) Hydroxychloroquine (ii) Azithromycin (iii) Steroids (iv) Tocilizumab (v) Lopinavir with ritonavir (vi) Oseltamivir |
Mortality | Mortality |
| 9 | Ayerbe et al., Spain | The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients | 55 | Hydroxychloroquine was dosed as 400 mg twice daily the first day, followed by 200 mg twice daily for 4–6 days. | — | (i) Azithromycin (ii) Steroids (iii) Heparin (iv) Tocilizumab (v) Lopinavir with ritonavir (vi) Oseltamivir |
Mortality | Mortality |
| 10 | Bartoletti et al., Italy | Efficacy of corticosteroid treatment for hospitalized patients with severe COVID-19: A multicentre study | 130 | Corticosteroid ≥0.5 mg/kg of prednisone | — | (i) Hydroxychloroquine (ii) Lopinavir/ritonavir (iii) Darunavir/ritonavir (iv) Darunavir/cobicistat (v) Remdesivir (vi) Low-molecular-weight heparin (vii) Other standard of care |
Mortality | Mortality |
| 11 | Camprubí et al., Spain | Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients | 21 | Ivermectin 200 μg/kg for 8–18 days | No ivermectin | (i) Tocilizumab (ii) Steroids (iii) Anakinra (iv) Remdesivir (v) Lopinavir/ritonavir (vi) Hydroxychloroquine (vii) Azithromycin (viii) Beta-interferon (ix) Hydroxychloroquine (x) Azithromycin |
Severe adverse events | Severe adverse events |
| 12 | Canoglu et al., Turkey | Therapeutic dosing of low-molecular-weight heparin may decrease mortality in patients with severe COVID-19 infection | 51 | Heparin prophylactic dose LMWH (0.5 mg/kg twice daily) | Heparin therapeutic dose LMWH (1 mg/kg twice daily) | (i) Favipiravir (ii) Lopinavir-ritonavir (iii) Supportive treatment |
(i) Mortality (ii) ICU admission (iii) Hospital stay |
(i) Mortality (ii) ICU admission (iii) Hospital stay |
| 13 | Catteau et al., Belgium | Low-dose hydroxychloroquine therapy and mortality in hospitalized patients with COVID-19: A nationwide observational study of 8075 participants | 72 | Hydroxychloroquine 2400 mg over 5 days | No hydroxychloroquine | (i) Lopinavir/ritonavir (ii) Hydroxychloroquine (iii) Tocilizumab (iv) Remdesivir (v) Macrolides (vi) Anakinra |
(i) Mortality (ii) Hospital stay (iii) Invasive mechanical ventilation (iv) Admission to ICU |
(i) Mortality (ii) Hospital stay (iii) Invasive mechanical ventilation (iv) Admission to ICU |
| 14 | Ana Fernández-Cruz, Spain | A retrospective controlled cohort study of the impact of glucocorticoid treatment in SARS-CoV-2 infection mortality | 35 | Steroid | No steroid | (i) Hydroxychloroquine (ii) Lopinavir-ritonavir (iii) Azithromycin (iv) Interferon (v) Tocilizumab (vi) Anakinra |
Mortality | Mortality |
| 15 | Freedberg et al., the United States | Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients: A propensity score matched retrospective cohort study | 56 | Famotidine | No famotidine | — | Mortality or intubation | Mortality or intubation |
| 16 | Geleris et al., United States | Observational study of hydroxychloroquine in hospitalized patients with COVID-19 | 50 | Hydroxychloroquine 600 mg twice on day 1 and then 400 mg daily for a median of 5 days | No hydroxychloroquine | (i) Systemic glucocorticoid (ii) Anticoagulant or warfarin (iii) Azithromycin (iv) Antibiotic agent (v) Tocilizumab (vi) Remdesivir |
Intubation or death | Intubation or death |
| 17 | Berry et al., United States | Hydroxychloroquine and tocilizumab therapy in COVID-19 patients: An observational study | 66 | (i) Hydroxychloroquine 800 mg on day 1 and 400 mg on days 2–5, followed by 200 mg TID (ii) Hydroxychloroquine in combination with azithromycin (iii) Tocilizumab first dose 400 mg, followed by 800 mg |
(i) Neither hydroxychloroquine/azithromycin (ii) Azithromycin alone (iii) No tocilizumab |
For patients in tocilizumab/no tocilizumab group: (i) Steroid (ii) Hydroxychloroquine alone (iii) Azithromycin alone (iv) Azithromycin plus hydroxychloroquine |
(i) Mortality (ii) Adverse drug events |
(i) Mortality (ii) Adverse drug events |
| 18 | Karolyi et al., Austria | Hydroxychloroquine versus lopinavir/ritonavir in severe COVID-19 patients | 57 | Hydroxychloroquine loading dose of 400 mg twice on the first day, followed by 200 mg twice daily | Lopinavir/ritonavir 400 mg/100 mg administered twice daily | Concomitant antibiotic | (i) In-hospital mortality (ii) Intensive care unit (ICU) admission (iii) Length of stay (iv) PCR (polymerase chain reaction) negativity (v) Side effects of treatment |
(i) In-hospital mortality (ii) Intensive care unit (ICU) admission (iii) Length of stay (iv) PCR (polymerase chain reaction) negativity (v) Side effects of treatment |
| 19 | Kirenga et al., Uganda | Characteristics and outcomes of admitted patients infected with SARS-CoV-2 in Uganda | — | Hydroxychloroquine | No hydroxychloroquine | (i) Antibiotics (azithromycin, ampicillin/cloxacillin combination, and augmentin) (ii) Vitamin C |
(i) Admission to ICU (ii) Mechanical ventilation (iii) Death (iv) Negative reverse transcriptase PCR (RT-PCR) tests (v) Length of hospitalization |
(i) Admission to ICU (ii) Mechanical ventilation (iii) Death (iv) Negative reverse transcriptase PCR (RT-PCR) tests (v) Length of hospitalization |
| 20 | Lagier et al., France | Outcomes of 3737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis | 56 | (i) Azithromycin + hydroxychloroquine >3 days (hydroxychloroquine 200 mg of oral hydroxychloroquine, 3 times daily for 10 days and 500 mg of oral azithromycin on day 1 followed by 250 mg daily for the next 4 days) (ii) Other treatment (azithromycin-hydroxychloroquine for at least 3 days) (iii) Azithromycin + hydroxychloroquine <3 days (iv) Hydroxychloroquine alone (v) Azithromycin alone (vi) No azithromycin and hydroxychloroquine |
— | — | (i) Death (ii) Transfer to the intensive care unit (ICU) (iii) ≥10 days of hospitalization (iv) Viral shedding |
(i) Death (ii) Transfer to the intensive care unit (ICU) (iii) ≥10 days of hospitalization (iv) Viral shedding |
| 21 | Albertini et al., France | Observational study on off-label use of tocilizumab in patients with severe COVID-19 | 16 | Tocilizumab 8 mg/kg | No tocilizumab | (i) Hydroxychloroquine (ii) Azithromycin |
(i) Mortality (ii) Mechanical ventilation (iii) Length of stay (iv) Adverse events |
(i) Mortality (ii) Mechanical ventilation (iii) Length of stay (iv) Adverse events |
| 22 | Almazrou et al., Saudi Arabia | Comparing the impact of hydroxychloroquine-based regimens and standard treatment on COVID-19 patient outcomes: A retrospective cohort study | 20 | Hydroxychloroquine | Standard care (i) Oseltamivir (ii) Azithromycin (iii) Levofloxacin (iv) Hydroxychloroquine (v) Ceftriaxone (vi) Piperacillin/tazobactam (vii) Vancomycin (viii) Cefuroxime (ix) Doxycycline (x) Tazocin (xi) Moxifloxacin |
— | (i) Hospital length of stay (ii) Time in ICU, days (iii) ICU admission (iv) Mechanical ventilation |
(i) Hospital length of stay (ii) Time in ICU, days (iii) ICU admission (iv) Mechanical ventilation |
| 23 | Billet et al., the United States | Anticoagulation in COVID-19: effect of enoxaparin, heparin, and apixaban on mortality | 30 | (i) Apixaban prophylaxis (ii) Apixaban full therapy (iii) Enoxaparin prophylaxis (iv) Enoxaparin full therapy (v) Unfractionated Heparin standard prophylaxis (vi) Unfractionated heparin high prophylaxis (vii) Unfractionated heparin full therapy |
— | — | (i) Mortality (ii) Respiratory support |
(i) Mortality (ii) Respiratory support |
| 24 | Capra et al., Italy | Impact of low-dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia | — | Tocilizumab | No tocilizumab | Standard care (i) Hydroxychloroquine 400 mg (ii) Lopinavir 800 mg (iii) Ritonavir 200 mg |
Mortality | Mortality |
| 25 | Mario Fernández‐Ruiz et al., Spain | Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: A single-center cohort study | — | Tocilizumab | — | (i) Hydroxychloroquine (ii) Lopinavir (iii) Ritonavir (iv) Azithromycin (v) Interferon (vi) Corticosteroids |
(i) Clinical improvement at day 7 (ii) Clinical improvement at day 14 |
(i) Clinical improvement at day 7 (ii) Clinical improvement at day 14 |
| 26 | Gupta et al., the United States | Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19 | 122 | Tocilizumab patients received tocilizumab within 2 days of ICU admission | Tocilizumab patients did not receive tocilizumab within 2 days of ICU admission | (i) Hydroxychloroquine (ii) Azithromycin (iii) Corticosteroid (iv) Anticoagulation |
(i) Mortality (ii) Adverse event |
(i) Mortality (ii) Adverse event |
| 27 | Kaminski et al., the United States | Tocilizumab therapy for COVID-19: A comparison of subcutaneous and intravenous therapies | 54 | Tocilizumab, 400 mg IV | Tocilizumab, subcutaneous dose of 324 mg (given as two simultaneous doses of 162 mg) | (i) Hydroxychloroquine 400 mg twice for one day, followed by 200 mg twice a day for additional 4 days plus azithromycin 500 mg once, followed by 250 mg oral once daily for additional 4 days. (ii) Tocilizumab therapy (iii) Corticosteroids for 3–5 days |
(i) Survival rate (ii) Ventilatory status |
(i) Survival rate (ii) Ventilatory status |
| 28 | Kim et al., Korea | Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild-to-moderate coronavirus disease 2019 | 44 | Lopinavir-ritonavir 400 and 100 mg twice daily | Hydroxychloroquine 400 mg once daily | (i) Antibiotic agent (ii) Glucocorticoid (iii) IV immunoglobulin |
(i) Time to negative conversion of viral RNA (ii) Time to clinical improvement (iii) Adverse events |
(i) Time to negative conversion of viral RNA (ii) Time to clinical improvement (iii) Adverse events |
| 29 | Lammers et al., Netherlands | Early hydroxychloroquine but not chloroquine use reduces ICU admission in COVID-19 patients | — | Hydroxychloroquine on day 1, 400 mg, and 400 mg after 12 hours, 200 mg BID on days 2–5 | Chloroquine on 1st day 600 mg and 300 mg after 12 h, 300 mg BID on days 2–5 | Azithromycin | (i) Death (ii) Transfer to the intensive care unit (ICU) |
(i) Death (ii) Transfer to the intensive care unit (ICU) |
| 30 | Lauriola et al., Italy | Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in patients with COVID-19 | — | (i) Azithromycin and hydroxychloroquine (hydroxychloroquine dose of 200 mg TID (alone or in combination) and azithromycin 500 mg QD for 10 days) (ii) Hydroxychloroquine 200 mg TID |
No treatment (standard care not specified) | — | Mortality | Mortality |
| 31 | Lee et al., the United States | Remdesivir for the treatment of severe COVID-19: A community hospital's experience | 111 | Remdesivir 200 mg loading dose on day 1, followed by a 100 mg daily on days 2–5 | — | (i) Antibiotics (ii) Convalescent plasma (iii) Dexamethasone |
(i) Mortality (ii) Length of stay (iii) ICU admission |
(i) Mortality (ii) Length of stay (iii) ICU admission |
| 32 | Yiming Li et al., China | Corticosteroid therapy in critically ill patients with COVID-19: A multicenter, retrospective study | 62 | Corticosteroids | No corticosteroids | — | (i) 90 days mortality (ii) Viral clearance |
(i) 90 days mortality (ii) Viral clearance |
| 33 | Liu et al., China | Clinical characteristics and corticosteroids application of different clinical types in patients with coronavirus disease 2019 | 121 | (i) Corticosteroid (ii) Methylprednisolone (1-2) mg/kg day general type, 1–5 mg/kg day severe type, and 1–4 mg/kg day critical type |
No corticosteroids | (i) Interferon-α (IFN-α) (ii) Lopinavir/ritonavir |
(i) Discharges (ii) Mechanical ventilation (iii) Intensive care unit (ICU) admission (iv) Mortality |
(i) Discharges (ii) Mechanical ventilation (iii) Intensive care unit (ICU) admission (iv) Mortality |
| 34 | Gautret et al., France | Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a 6-day follow-up: A pilot observational study | — | Hydroxychloroquine (200 mg of oral TID for 10 days) and azithromycin (500 mg on day 1 followed by 250 mg per day for 4 days) | — | — | (i) Requiring oxygen therapy or transfer to the ICU after at least three days of treatment (ii) Length of stay in the infectious diseases ward (iii) Contagiousness as assessed by PCR and culture |
(i) Requiring oxygen therapy or transfer to the ICU after at least three days of treatment (ii) Length of stay in the infectious diseases ward (iii) Contagiousness as assessed by PCR and culture |
| 35 | Yu et al., China | Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19 | — | Hydroxychloroquine oral 200 mg BID for 7–10 days | Nonhydroxychloroquine | (i) Lopinavir and ritonavir (ii) Ribavirin (iii) Intravenous immunoglobulin |
(i) Mortality (ii) Length of stay |
(i) Mortality (ii) Length of stay |
| 36 | Guaraldi et al., Italy | Tocilizumab in patients with severe COVID-19: A retrospective cohort study | — | (i) Tocilizumab 8 mg/kg IV (up to a maximum of 800 mg) in two infusions, 12 h apart, or subcutaneously at 162 mg administered in two simultaneous doses, one in each thigh (i.e., 324 mg in total) (ii) Hydroxychloroquine (iii) Azithromycin (iv) Antiretrovirals (v) Low-molecular-weight heparin |
(i) Hydroxychloroquine (ii) Azithromycin (iii) Antiretrovirals (iv) Low-molecular-weight heparin (v) Lopinavir-ritonavir |
(i) Hydroxychloroquine (ii) Azithromycin (iii) Antiretrovirals (iv) Low-molecular-weight heparin (v) Lopinavir-ritonavir |
(i) Death (ii) Invasive mechanical ventilation |
(i) Death (ii) Invasive mechanical ventilation |
| 37 | Grein et al., multicenter | Compassionate use of remdesivir for patients with severe COVID-19 | — | Remdesivir loading dose of 200 mg intravenously on day 1 plus 100 mg daily for the following 9 days | — | Supportive care | (i) Clinical improvement (ii) Changes in oxygen support requirements (iii) Adverse events (iv) Death |
(i) Clinical improvement (ii) Changes in oxygen support requirements (iii) Adverse events (iv) Death |
| 38 | Alexis K. Okoh et al., the United States | Tocilizumab use in COVID-19 associated pneumonia | 61 | Tocilizumab 8 mg/kg IV (maximum: 800 mg/dose) | No tocilizumab | Standard of care | (i) Deescalation in oxygen therapy (ii) In-hospital death (iii) Septic shock (iv) Acute kidney injury (AKI) requiring hemodialysis |
(i) Deescalation in oxygen therapy (ii) In-hospital death (iii) Acute kidney injury (AKI) requiring hemodialysis |
| 39 | Shao et al., China | Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19: A multicenter retrospective cohort study | 122 | IVIG 0.1–0.5 g/kg per day | Non-IVIG | — | (i) 28 days mortality (ii) 60 days mortality (iii) In‐hospital days (iv) Total course of disease |
(i) 28 days mortality (ii) 60 days mortality (iii) In‐hospital days |
| 40 | Kewan et al., the United States | Tocilizumab for treatment of patients with severe COVID-19: A retrospective cohort study | 61 | Tocilizumab 8 mg/kg and received 400 mg tocilizumab as a 60 min single intravenous infusion | No tocilizumab | (i) Hydroxychloroquine with a loading dose of 400 mg twice daily followed by 200 mg BID for 5 days (ii) Azithromycin 500 mg per day for 5 days (iii) Steroid |
(i) Intubated patients' improvement in oxygen support (ii) Noninvasive oxygen support improvement in oxygen support (iii) Clinical improvement among patients required mechanical ventilation (iv) Length of stay in hospital (v) Mortality |
(i) Intubated patients' improvement in oxygen support (ii) Noninvasive oxygen support improvement in oxygen support (iii) Clinical improvement among patients required mechanical ventilation (iv) Length of stay in hospital (v) Mortality |
| 41 | Ramiro et al., Netherlands | Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19 associated cytokine storm syndrome: results of the CHIC study | 92 | (i) Methylprednisolone 250 mg intravenously on day 1, followed by MP 80 mg intravenously on days 2–5 (ii) Tocilizumab single dose 8mg/kg bodyweight intravenous, maximum 800 mg between day 2 and day 5 |
— | (i) Ceftriaxone 2 g every 24 hours for 7 days (ii) Chloroquine 300 mg every 12 hours following a loading dose of 600 mg |
(i) Clinical improvement (ii) WHO ordinal scale (iii) Hospital mortality (iv) Mechanical ventilation (v) Duration of hospitalization |
(i) Clinical improvement (ii) WHO ordinal scale (iii) Hospital mortality (iv) Mechanical ventilation (v) Duration of hospitalization |
| 42 | Colaneri et al., Italy | Tocilizumab for treatment of severe COVID-19 patients: preliminary results from SMAtteo COVID-19 Registry (SMACORE) | 14 | Tocilizumab 8 mg/kg (up to a maximum 800 mg per dose) IV repeated 12 hours plus standard of care | Standard of care (i) Hydroxychloroquine 200 mg BID (ii) Azithromycin 500 mg once (iii) Prophylactic dose of low weight heparin (iv) Methylprednisolone (a tapered dose of 1 mg/kg up to a maximum of 80 mg) for 10 days |
— | (i) ICU admission (ii) 7 days mortality rate (iii) Clinical and laboratory data (iv) Days of hospitalization |
(i) ICU admission (ii) 7 days mortality rate (iii) Days of hospitalization |
| 43 | Mather et al., the United States | Impact of famotidine use on clinical outcomes of hospitalized patients with COVID-19 | 80 | (i) Famotidine 80 mg (range 40–160 mg) was received over a median of 4 days (ii) Hydroxychloroquine 600 mg/day |
(i) No famotidine | (i) Hydroxychloroquine, 600 mg/day (ii) Azithromycin (iii) Remdesivir (iv) Corticosteroids |
(i) Death (ii) Disease severity (iii) Mechanical ventilation |
(i) Death (ii) Mechanical ventilation |
| 44 | Million et al., France | Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France | 29 | Hydroxychloroquine + azithromycin: a combination of 200 mg of oral HCQ, 3 times daily for 10 days combined with 5 of AZ (500 mg on day 1 followed by 250 mg daily for the next 4 days) | Hydroxychloroquine + azithromycin early treatment, as standard care. | — | (i) Length of hospitalization (ii) Death (iii) Contagiousness as assessed by PCR and culture. |
(i) Length of hospitalization (i) Death (iii) Contagiousness as assessed by PCR and culture. |
| 45 | Morrisona et al., the United States | Clinical characteristics and predictors of survival in adults with coronavirus disease 2019 receiving tocilizumab | 34 | (i) Tocilizumab was administered as an 8 mg/kg IV dose using actual bodyweight with a maximum dose of 800 mg. Doses were rounded to 400 mg, 600 mg, or 800 mg. (ii) Corticosteroids (iii) Hydroxychloroquine (iv) Lopinavir/ritonavir with ribavirin (v) Remdesivir |
(i) Lopinavir/ritonavir with ribavirin, received as supportive care (ii) Hydroxychloroquine, received as supportive care |
— | (i) WHO ordinal scale (ii) 28 day in-hospital survival (iii) Duration of hospitalization |
(i) WHO ordinal scale (ii) 28 day in-hospital survival (iii) Duration of hospitalization |
| 46 | Pasquini et al., Italy | Effectiveness of remdesivir in patients with COVID-19 under mechanical ventilation in an Italian ICU | 21 | Remdesivir, first dose of 200 mg IV on day 1 plus 100 mg daily from day 2 on. | No remdesivir | (i) Tocilizumab (ii) Hydroxychloroquine (iii) Lopinavir/ritonavir with ribavirin |
Mortality | Mortality |
| 47 | Patel et al., India | Safety and efficacy of tocilizumab in the treatment of severe acute respiratory syndrome coronavirus 2 pneumonia: A retrospective cohort study | 31 | Tocilizumab dosed at 8 mg/kg, up to a maximum dose of 800 mg | — | (i) Hydroxychloroquine. 400 mg/day for 5 days after a loading dose of 400 mg twice a day on 1st day. (ii) Azithromycin 500 mg/day for 5 days. (iii) IV ceftriaxone 1 g per day for 5 days. (iv) Anticoagulation: low-molecular-weight heparin or unfractionated heparin infusion was used if the patient's D-dimer was >1000 ng/ml. (v) Methylprednisolone: some patients also received a single dose of 80 mg IV methylprednisolone before receiving tocilizumab. |
(i) Mortality (ii) Admission to the intensive care unit (ICU) with invasive mechanical ventilation or death (iii) Hospital stay |
(i) Mortality (ii) Admission to the intensive care unit (ICU) with invasive mechanical ventilation or death (iii) Hospital stay |
| 48 | Rahmani et al., Iran | Comparing outcomes of hospitalized patients with moderate and severe COVID-19 following treatment with hydroxychloroquine plus atazanavir/ritonavir | 58 | Hydroxychloroquine + atazanavir/ritonavir has 400 mg BD on the first day and then 200 mg. 300/100 mg daily was started within 24 h of the hospital admission for all patients | (i) ARB (ii) Metformin (iii) Aspirin (iv) Beta-blockers (v) Insulin (vi) Corticosteroids (vii) Hydroxychloroquine (viii) Immunosuppressants (ix) NSAIDs (x) Methotrexate (xi) ACEI (xii) Azathioprine (xiii) Sulfasalazine |
(i) Interferon (ii) Ribavirin (iii) Corticosteroid (iv) IVIG (v) Vitamin C (vi) Antibiotics |
(i) 28 days mortality (ii) Hospital stay (iii) ICU stays (iv) Rate of ICU admissions and intubation |
(i) 28 days mortality (ii) 56 days mortality (iii) Hospital stay (iv) Rate of ICU admissions and intubation |
| 49 | Rodrı'guez-MolineroI et al., Spain | Observational study of azithromycin in hospitalized patients with COVID-19 | 52 | Azithromycin prescribed at a dose of 500 mg on the first day (oral or intravenous), followed by 250 mg daily, until completing 5 days of treatment. | Standard of care | (i) Azithromycin (ii) Tocilizumab (iii) Methylprednisolone (iv) Dexamethasone |
(i) Hospital stays (ii) Mortality (iii) Oxygen requirement |
(i) Hospital stays (ii) Mortality (iii) Oxygen requirement |
| 50 | Rosenberg et al., the United States | Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State | 19 | (i) Hydroxychloroquine with or without azithromycin (ii) Azithromycin |
— | — | (i) In-hospital mortality (ii) Cardiac arrest and abnormal electrocardiographic (ECG) findings (defined as arrhythmia or prolonged QT fraction) (iii) Length of stay |
(i) In-hospital mortality (ii) Length of stay |
| 51 | Rubio-Rivasa et al., Spain | Beneficial effect of corticosteroids in preventing mortality in patients receiving tocilizumab to treat severe COVID-19 illness | 22 | Tocilizumab as a single IV infusion at a dose of 400 mg (weight <80 kg) or 600 mg (weight >80 kg) or using methylprednisolone at doses ranging from 0.5 mg/kg/d to 250 mg IV in 3 pulses | — | (i) Hydroxychloroquine (ii) Azithromycin (iii) Lopinavir/ritonavir (iv) Remdesivir (v) Prophylactic anticoagulation therapy (vi) Subcutaneous interferon beta-1b 0.25 mg/48 h. |
(i) In-hospital mortality | (i) In-hospital mortality |
| 52 | Shi et al., China | Evaluation of antiviral therapies for coronavirus disease 2019 pneumonia in Shanghai, China | 19 | (i) Arbidol group 200 mg, three times/day (ii) Lopinavir/ritonavir group two tablets, two times/day (iii) Arbidol + lopinavir/ritonavir group (iv) Interferon group 100 000 U/kg, two times/day (v) Interferon + lopinavir/ritonavir group (vi) Interferon + darunavir group one tablet, one time/day. |
— | — | (i) Improvements in pulmonary involvement (ii) Length of hospital stay |
(i) Pneumonia resolution after treatment (ii) Length of hospital stay |
| 53 | Tang et al., China | Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy | 34 | Unfractionated heparin or low-molecular-weight heparin (LMWH) for 7 days or longer. | No heparin or less than 7 days | — | 28 days mortality | 28 days mortality |
| 54 | Tong et al., China | Ribavirin therapy for severe COVID-19: a retrospective cohort study | 60 | Intravenous ribavirin 500 mg every 12 h | — | Corticosteroids | (i) Mortality (ii) Negative conversion time for the SARS-CoV-2 RT-PCR test |
(i) Mortality (ii) Negative conversion time for the SARS-CoV-2 RT-PCR test |
| 55 | Toniati et al., Italy | 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 | 12 | (i) Tocilizumab. at a dosage of 8 mg/kg (max 800 mg) by two consecutive intravenous infusions 12 h apart. (ii) Lopinavir + ritonavir 400 mg and 100 mg twice a day. (iii) Remdesivir (iv) Azithromycin (v) Ceftriaxone (vi) Piperacillin/tazobactam (vii) Hydroxychloroquine 400 mg/day (viii) Dexamethasone 20 mg/day |
— | — | Improvement in acute respiratory failure | Improvement in acute respiratory failure |
| 56 | Tsai et al., China | Successful treatment of 28 patients with coronavirus disease 2019 at a medical center in Taiwan | 154 | (i) Hydroxychloroquine + azithromycin + ceftriaxone + teicoplanin (ii) Hydroxychloroquine + azithromycin + ceftriaxone (iii) Hydroxychloroquine + azithromycin (iv) Hydroxychloroquine + ceftriaxone (v) Hydroxychloroquine, azithromycin |
— | — | None | None |
| 57 | Vu et al., Florida | Effects of tocilizumab in COVID-19 patients: A cohort study | 19 | Tocilizumab 400 mg (30–100 kg) and 600 mg (> 100 kg) | — | (i) Hydroxychloroquine (ii) Methylprednisolone (iii) Intravenous immunoglobulin (iv) Convalescent plasma |
(i) WHO ordinal scale (ii) Length of stay (iii) Mortality |
(i) WHO ordinal scale (ii) Mortality (iii) Length of stay |
| 58 | Wu et al., China | Systemic corticosteroids and mortality in severe and critical COVID-19 patients in Wuhan, China | 81 | (i) Corticosteroid (ii) Hydrocortisone 5 mg (iii) Methylprednisolone 1 mg (iv) Dexamethasone 0.1875 mg |
No corticosteroid | — | (i) Mortality (ii) Hospital stays |
(i) Mortality (ii) Hospital stays |
| 59 | Yan et al., China | Factors associated with prolonged viral shedding and impact of lopinavir/ritonavir treatment in hospitalized noncritically ill patients with SARS-CoV-2 infection | 39 | (i) Lopinavir/ritonavir 400 mg and 100 mg, orally twice daily (ii) Corticosteroid therapy (iii) Antibiotics (iv) High-flow nasal cannula oxygen therapy (v) Noninvasive mechanical ventilation (vi) Invasive mechanical ventilation |
— | — | (i) Length of stay (ii) Viral shedding days |
(i) Length of stay (ii) Viral shedding days |
| 60 | Yang et al., China | The role of methylprednisolone on preventing disease progression for hospitalized patients with severe COVID‐19 | 67 | Methylprednisolone 50–80 mg/d | (i) Nonmethylprednisolone (ii) Oseltamivir (iii) Arbidol hydrochloride (iv) Lopinavir/ritonavir (v) Darunavir and/cobicistat |
— | (i) Progression to critical illness (ii) Deaths |
(i) Progression to critical illness (ii) Deaths |
| 61 | You et al., China | The use of methylprednisolone in COVID-19 patients: A propensity score matched retrospective cohort study | 60 | Methylprednisolone 40 mg once or twice per day within 48 hours of admission for one week. | Nonmethylprednisolone | — | (i) Hospital mortality (ii) Positive nucleic acid test to turn negative (iii) Length of hospital stay (iv) Oxygen requirement |
(i) Hospital mortality (ii) Positive nucleic acid test to turn negative (iii) Length of hospital stay (iv) Oxygen requirement |
| 62 | Yuan et al., China | Effects of corticosteroid treatment for nonsevere COVID-19 pneumonia: A propensity score-based analysis | 37 | (i) Corticosteroid (ii) Methylprednisolone |
Noncorticosteroid group | (i) Ribavirin (ii) Oseltamivir (iii) Arbidol (iv) Lopinavir/ritonavir (v) Interferon |
(i) Progressed to severe cases (ii) Secondary infection (iii) Hospital stays (iv) Duration of viral shedding (v) Fever time |
(i) Progressed to severe cases (ii) Hospital stay (iii) Duration of viral shedding |
| 63 | Mushtaq et al., Pakistan | Outcome of COVID-19 patients with use of tocilizumab: A single-center experience | 62 | Tocilizumab 4–8 mg/kg. | — | (i) Azithromycin (ii) Ceftriaxone or piperacillin/tazobactam (iii) Methylprednisolone (iv) Hydroxychloroquine |
(i) Mortality (ii) Length of hospital stay (iii) Weaning from a mechanical ventilator, weaning from oxygen support, improvement in laboratory parameters |
(i) Mortality (ii) Length of hospital stay (iii) Weaning from a mechanical ventilator, weaning from oxygen support, improvement in laboratory parameters |
| 64 | Yan Zuo et al., China | Lopinavir/ritonavir and interferon combination therapy may help shorten the duration of viral shedding in patients with COVID‐19: A retrospective study in two designated hospitals in Anhui, China | 56 | (i) Corticosteroid (ii) Lopinavir/ritonavir (iii) Chloroquine (iv) Ribavirin (v) IFN‐α (vi) Arbidol (vii) Intravenous immunoglobulin (viii) Traditional Chinese medicine |
— | — | Length of stay | Length of stay |
| 65 | Yu et al., China | COVID‐19 patients benefit from early antiviral treatment: A comparative, retrospective study | 27 | (i) Arbidol (ii) Interferon (iii) Oseltamivir (iv) Ribavirin (v) Ganciclovir (vi) Antibiotic treatment (vii) Antifungal treatment (viii) Oxygen therapy (ix) Glucocorticoids (x) Immunotherapy |
— | — | (i) Time from illness onset to be confirmed by SARS‐Cov‐2 RNA detection (ii) Time from illness onset to initiation of antiviral treatment (iii) Duration of total antiviral medication during the illness (iv) Time from illness onset to SARS‐CoV‐2 negative |
(i) Time from illness onset to be confirmed by SARS‐Cov‐2 RNA detection (ii) Time from illness onset to SARS‐CoV‐2 negative |
| 66 | Llitjos et al., France | High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients | 9 | Prophylactic anticoagulation | Therapeutic anticoagulation 0.3–0.7 U/ml | — | (i) Acute respiratory distress syndrome (ii) Acute kidney injury (iii) Liver dysfunction (iv) Death |
(i) Acute respiratory distress syndrome (ii) Death |
| 67 | Borie et al., France | Glucocorticoids with low-dose anti-IL1 anakinra rescue in severe non-ICU COVID-19 infection: A cohort study | 42 | (i) Corticosteroid ± anakinra (ii) Methylprednisolone 120 mg (daily dose) on three consecutive days (iii) Glucocorticoid |
Thrombosis prophylaxis with LMWH. From February 15 to March 27, 2020 | (i) Lopinavir-ritonavir (ii) Hydroxychloroquine (iii) Ivermectin, 12–15 mg (iv) Remdesivir (v) Thrombosis prophylaxis with LMWH (vi) Tocilizumab (vii) Corticosteroids, 120 mg (viii) Anakinra, 100 mg anakinra daily was added subcutaneously for ≤5days |
(i) Death (ii) Invasive mechanical ventilation requirement within 15 days |
(i) Death (ii) Invasive mechanical ventilation requirement within 15 days |
| 68 | Majmundar et al., the United States | Efficacy of corticosteroids in nonintensive care unit patients with COVID-19 pneumonia from the New York metropolitan region | 57 | (i) Corticosteroids (ii) Methylprednisolone (iii) Prednisone (iv) Dexamethasone |
Noncorticosteroids | (i) Hydrocortisone (ii) Tocilizumab (iii) Enoxaparin therapeutic dose |
(i) Intensive care unit (ICU) transfer (ii) ICU transfer (iii) Intubation (iv) Death (v) Discharge (vi) Length of stay |
(i) Intensive care unit (ICU) transfer (ii) Intubation (iii) Death (iv) Length of stay |
| 69 | Martínez-Sanz et al., Spain | Effects of tocilizumab on mortality in hospitalized patients with COVID-19: A multicenter cohort study | 24 | Tocilizumab | Standard of care | (i) Corticosteroids (ii) Hydroxychloroquine (iii) Azithromycin (iv) Lopinavir/ritonavir |
(i) Non-ICU length of stay (days) (ii) ICU admission (iii) ICU length of stay (days) (iv) Overall mortality (v) ICU mortality (vi) Non-ICU mortality (vii) ICU or mortality |
(i) Non-ICU length of stay (days) (ii) ICU length of stay (days) (iii) Overall mortality (iv) ICU mortality (v) Non-ICU mortality (vi) ICU or mortality |
| 70 | Menzella et al., Italy | Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation | 70 | (i) Tocilizumab + standard therapy (ii) Hydroxychloroquine (iii) Antivirals (lopinavir/ritonavir or darunavir/cobicistat) (iv) Anticoagulants (full dosage) (v) Steroids (methylprednisolone 0.5–1 mg/kg/die) |
(i) Standard therapy | (i) Hydroxychloroquine (ii) Antivirals (lopinavir/ritonavir or darunavir/cobicistat) (iii) Anticoagulants (full dosage) (iv) Steroids (methylprednisolone 0.5–1 mg/kg/die) |
(i) Intubation/death (ii) Death |
(i) Intubation/death (ii) Death |
| 71 | Mikulska et al, Italy | Tocilizumab and steroid treatment in patients with COVID-19 pneumonia | — | (i) Tocilizumab. 8 mg/kg (maximum 800 mg) (ii) Methylprednisolone. 1 mg/kg for 5 days intravenously, then 0.5 mg/kg for 5 days (iii)Standard of care |
Standard of care | (i) Hydroxychloroquine. 400 mg bid (ii) Darunavir/ritonavir. 800/100 qd (iii) Low-molecular-weight heparin prophylaxis |
(i) Time to failure, defined as intubation and mechanical ventilation or death (ii) Overall survival (iii) Time of hospitalization for the comparison between tocilizumab/methylprednisolone/SOC |
(i) Time to failure, defined as intubation and mechanical ventilation or death (ii) Overall survival (iii) Time of hospitalization for the comparison between tocilizumab/methylprednisolone/SOC |
| 72 | Monreal et al., Spain | High versus standard doses of corticosteroids in severe COVID-19: A retrospective cohort study | 61 | High doses of corticosteroids: short-term pulse therapy of methylprednisolone-equivalent dosages from 250 to 1000 mg/day during one or more consecutive days. | Standard doses of corticosteroids. Methylprednisolone-equivalent dosages ranging from 0.5 to 1.5 mg/kg/day. | — | (i) Mortality (ii) A combined variable of need for mechanical or noninvasive MV and death. (iii) The development of severe ARDS, according to the Berlin definition |
(i) Mortality (ii) A combined variable of need for mechanical or noninvasive MV and death |
| 73 | Pérez et al., Spain | Experience with tocilizumab in severe COVID-19 pneumonia after 80 days of follow-up: A retrospective cohort study | 52 | Tocilizumab: initial 600 mg, with a second or third dose (400 mg) in case of persistent or progressive disease | Not received tocilizumab | (i) Hydroxychloroquine (ii) Lopinavir/ritonavir (iii) Azithromycin. |
(i) All-cause mortality (either in-hospital or after discharge) and associated factors. (ii) The impact of an early clinical response to tocilizumab in hospital and ICU stay. (iii) Evaluate safety of tocilizumab therapy. |
(i) All-cause mortality (either in-hospital or after discharge) and associated factors. (ii) The impact of an early clinical response to tocilizumab in hospital and ICU stay. (iii) Evaluate safety of tocilizumab therapy. |
| 74 | Nadkarni et al., the United States | Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19 | 61 | (i) Therapeutic anticoagulation (ii) Prophylactic anticoagulation |
No anticoagulation | — | (i) Mortality (ii) Intubation and major bleeding |
(i) Mortality (ii) Intubation and major bleeding |
| 75 | Nasir et al., Pakistan | Tocilizumab for COVID-19 acute respiratory distress syndrome: outcomes assessment using the WHO ordinal scale | 121 | Before tocilizumab | After tocilizumab | Concomitant steroids | (i) WHO ordinal scale (ii) Mortality (iii) Length of stay (iv) Development of nosocomial infection during hospitalization. |
(i) WHO ordinal scale (ii) Mortality (iii) Length of stay |
| 76 | Omrani et al., Qatar | Convalescent plasma for the treatment of patients with severe coronavirus disease 2019: A preliminary report | 62 | Convalescent plasma | Standard of care | (i) Hydroxychloroquine (ii) Azithromycin (iii) lopinavir-ritonavir (iv) Tocilizumab (v) Methylprednisolone |
(i) WHO ordinal scale (ii) Improvement in the respiratory status (iii) Discharged alive from ICU by study day 28 (iv) Viral clearance |
(i) WHO ordinal scale (ii) Improvement in the respiratory status (iii) Discharged alive from ICU by study day 28 (iv)Viral clearance |
| 77 | Paccoud et al., France | Compassionate use of hydroxychloroquine in clinical practice for patients with mild to severe COVID-19 in a French university hospital | 79 | Hydroxychloroquine, 200 mg 3 times daily for 10 days | (i) Oxygen therapy to maintain an oxygen saturation >96% (ii) Intravenous or oral acetaminophen (iii) Antibiotics |
— | (i) Death (ii) Admission to an ICU (iii) Time to death (iv) Time to hospital discharge for a return home or in an aftercare and rehabilitation (v) Adverse events recorded in patients receiving hydroxychloroquine treatment |
(i) Death (ii) Admission to an ICU (iii) Adverse events recorded in the patients receiving hydroxychloroquine treatment |
| 78 | Price et al., the United States | Tocilizumab treatment for cytokine release syndrome in hospitalized patients with coronavirus disease 2019: survival and clinical outcomes | 22 | (i) Hydroxychloroquine (ii) Glucocorticoids (iii) Tocilizumab, 8 mg/kg intravenously, not to exceed 800mg; |
— | — | (i) Survival (ii) 14 days survival (iii) Mechanical ventilation (iv) Days mechanically ventilated (v) Days of symptoms prior to hospitalization (vi) Days hospitalized (vii) Hospitalized at day 14 |
(i) Survival (ii) 14 days survival (iii) Mechanical ventilation (iv) Days mechanically ventilated (v) Days hospitalized (vi) Hospitalized at day 14 |
| 79 | Rodríguez-Baño et al., Spain | Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: A multicenter cohort study (SAM-COVID-19) | 59 | (i) Tocilizumab (ii) Corticosteroid pulse dose (iii) Corticosteroids intermediate-high dose (iv) Combination therapy |
No treatment | - | (i) WHO ordinal scale (ii) Death or intubation | (i) WHO ordinal scale (ii) Death or intubation |
| 80 | Roomi et al., United States | Efficacy of hydroxychloroquine and tocilizumab in patients with COVID-19: single-center retrospective chart review | 91 | (i) Hydroxychloroquine (ii) Tocilizumab |
(i) No hydroxychloroquine (ii) No tocilizumab |
(i) Steroids (ii) Anticoagulation |
(i) Invasive mechanical ventilation (ii) Mortality (iii) Discharge |
(i) Invasive mechanical ventilation (ii) Mortality (iii) Dialysis |
| 81 | Antorán et al., Spain | Combination of tocilizumab and steroids to improve mortality in patients with severe COVID-19 infection: A Spanish, multicenter, cohort study | 49 | Tocilizumab | No tocilizumab | (i) Hydroxychloroquine (ii) Lopinavir/ritonavir (iii) Azithromycin (iv) Remdesivir (v) Interferon (vi) Steroids |
Mortality | Mortality |
| 82 | Tortajada et al., Spain | Corticosteroids for COVID‐19 patients requiring oxygen support? Yes, but not for everyone: effect of corticosteroids on mortality and intensive care unit admission in patients with COVID‐19 according to patients' oxygen requirements | 59 | (i) Corticosteroids (ii) Methylprednisolone 250 mg iv once and 40 mg BIQ for 4 days (iii) Dexamethasone 20 mg iv QD for 5 days, followed by 10 mg QD for 5 more days |
No corticosteroids | (i) Hydroxychloroquine (ii) Azithromycin (iii) Lopinavir/ ritonavir (iv) Tocilizumab (v) Interferon beta |
(i) WHO ordinal scale. (ii) Admission to ICU or in‐hospital death (iii) Clinical improvement |
(i) WHO ordinal scale. (ii) Admission to ICU or in‐hospital death (iii) Clinical improvement |
| 83 | Magagnoli et al., the United States | Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19 | 21 | (i) Hydroxychloroquine (ii) Hydroxychloroquine + azithromycin (iii) No hydroxychloroquine |
— | — | (i) Mortality (ii) Use of mechanical ventilation |
(i) Mortality (ii) Use of mechanical ventilation |
| 84 | Joyner et al., United States | Early safety indicators of COVID-19 convalescent plasma in 5000 patients | 39 | Convalescent plasma | — | — | The safety of transfusion of COVID-19 convalescent plasma assessed as the incidence and relatedness of severe adverse events including death. | The safety of transfusion of COVID-19 convalescent plasma assessed as the incidence and relatedness of severe adverse events including death. |
| 85 | Rajter et al., South Florida, the United States | Use of ivermectin is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The ivermectin in COVID-19 study | 58 | Ivermectin 200 μg/kg | No ivermectin | (i) Corticosteroid (ii) Hydroxychloroquine (iii) Azithromycin |
(i) Mortality (ii) Successful extubation (iii) Length of hospital stay |
(i) Mortality (ii) Successful extubation (iii) Length of hospital stay. |
| 86 | Hanif et al., the United States | Thrombotic complications and anticoagulation in COVID-19 pneumonia: A New York City hospital experience | 31 | (i) Therapeutic anticoagulation prior to admission (ii) Therapeutic anticoagulation during the admission (iii) Prophylactic anticoagulation only during the hospital stay (iv) No anticoagulation |
— | — | (i) Mortality (ii) Length of stay (iii) Intubation (iv) Successful extubation |
(i) Mortality (ii) Length of stay (iii) Intubation (iv) Successful extubation |
| 87 | Duan et al., China | Effectiveness of convalescent plasma therapy in severe COVID-19 patients | 30 | Convalescent plasma: one dose of 200 ml of inactivated CP with neutralization activity of >1:640 was transfused into the patients within 4 h following the WHO blood transfusion protocol. | — | (i) Antiviral therapy (ii) Other supportive care (iii) Antibiotic treatment (iv) Antifungal treatment (v) Glucocorticoid (vi) Oxygen support at the appropriate situation |
(i) The safety of convalescent plasma transfusion. (ii) The improvement of clinical symptoms and laboratory and radiological parameters within 3 days after (iii) Convalescent plasma transfusion. |
(i) The safety of convalescent plasma transfusion. (ii) The improvement of clinical symptoms and laboratory and radiological parameters within 3 days after (iii) Convalescent plasma transfusion. |
Table 3.
Description of study characteristics: case-control studies.
| S. no. | Author, country | Title | Study duration in days | Intervention group | Control group | Concomitant intervention | Outcome measures | Outcome measures applicable to this review |
|---|---|---|---|---|---|---|---|---|
| 1 | Klopfenstein et al., France | Impact of tocilizumab on mortality and/or invasive mechanical ventilation requirement in a cohort of 206 COVID-19 patients | 72 | Tocilizumab 8 mg/kg per dose, 1 or 2 doses | (i) Standard treatment (ii) Hydroxychloroquine (iii) Lopinavir-ritonavir therapy (iv) Antibiotics (v) Corticosteroids |
(i) Hydroxychloroquine (ii) Lopinavir-ritonavir therapy (iii) Antibiotics (iv) Corticosteroids |
(i) Mortality (ii) Intensive mechanical ventilation (iii) Duration to hospitalization |
(i) Mortality (ii) Intensive mechanical ventilation (iii) Duration to hospitalization |
| 2 | Klopfenstein et al., France | Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients | 24 | Tocilizumab 8 mg/kg per dose, 1 or 2 doses | (i) Standard treatment (ii) Hydroxychloroquine (iii) Lopinavir-ritonavir therapy (iv) Antibiotics (v) Corticosteroids |
(i) Hydroxychloroquine (ii) Lopinavir-ritonavir therapy (iii) Antibiotics (iv) Corticosteroids |
(i) Death (ii) ICU admission (iii) Invasive mechanical ventilation (iv) Duration of hospitalization |
(i) Death (ii) ICU admission (iii) Invasive mechanical ventilation (iv) Duration of hospitalization |
| 3 | Sean et al., the United States | Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study | 16 | Convalescent plasma therapy | — | (i) Azithromycin (ii) Hydroxychloroquine (iii) Broad-spectrum antibiotics (iv) Therapeutic dose anticoagulation (v) Corticosteroids (vi) Remdesivir (vii) Mesenchymal stem cells and interleukin (IL)-1 and IL-6 inhibitors |
(i) Survival (ii) Oxygen requirement |
(i) Survival (ii) Oxygen requirement |
| 4 | Abolghasemi et al., Iran | Clinical efficacy of convalescent plasma for treatment of COVID-19 infections: results of a multicenter clinical study | 61 | Convalescent plasma 500 cc (one unit) | No convalescent plasma | (i) Lopinavir/ritonavir (ii) Hydroxychloroquine |
(i) Mortality (ii) Intubation (iii) Length of stay (iv) Improvements in clinical symptoms (v) Adverse events from treatment |
(i) Mortality (ii) Intubation (iii) Length of stay (iv) Improvements in clinical symptoms (iv) Adverse events from treatment |
| 5 | Rossotti et al., Italy | Safety and efficacy of anti-IL-6 receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis | — | Tocilizumab | (i) Hydroxychloroquine plus lopinavir/ritonavir (ii) Remdesivir |
— | (i) Survival (ii) Length of stay |
(i) Survival (ii) Length of stay |
| 6 | Matthieu et al., France | Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen: observational comparative study using routine care data | 43 | Hydroxychloroquine | No hydroxychloroquine | (i) Azithromycin (ii) Amoxicillin (iii) Tocilizumab (iv) Lopinavir-ritonavir (v) Remdesivir |
(i) Survival (ii) Weaning from oxygen |
(i) Survival (ii) Weaning from oxygen |
| 7 | Perrone et al., Italy | Tocilizumab for patients with COVID-19 pneumonia: The single-arm TOCIVID-19 prospective trial | 34 | Tocilizumab 8 mg/kg up to a maximum of 800 mg per dose | — | (i) Antiretroviral (ii) Hydroxy chloroquine (iii) Antibiotics (iv) Steroids (v) Low-molecular-weight heparin |
Lethality rate | Lethality rate |
| 8 | G. Rojas-Marte et al., the United States | Outcomes in patients with severe COVID-19 disease treated with tocilizumab: a case-controlled study | 49 | Tocilizumab | (i) Hydroxychloroquine (ii) Azithromycin (iii) Corticosteroids (iv) Anticoagulation (v) Remdesivir (vi) Antibiotics (vii) Vasopressors |
(i) Hydroxychloroquine (ii) Azithromycin (iii) Corticosteroids (iv) Anticoagulation (v) Remdesivir (vi) Antibiotics (vii) Vasopressors |
(i) Overall mortality rate (ii) Mortality in nonintubated patients only (iii) Mortality in intubated patients (iv) Length of stay |
(i) Overall mortality rate. (ii) Mortality in nonintubated patients only (iii) Mortality in intubated patients (iv) Length of stay |
| 9 | Scarsi et al., Italy | Association between treatment with colchicine and improved survival in a single-center cohort of adult hospitalized patients with COVID-19 pneumonia and acute respiratory distress syndrome | 32 | (i) Colchicine 1 mg/day (ii) Standard of care (hydroxychloroquine, lopinavir/ritonavir, and intravenous dexamethasone) |
Standard of care (hydroxychloroquine, lopinavir/ritonavir, and intravenous dexamethasone) | — | Survival rate | Survival rate |
| 10 | Keller et al., The Bronx | Effect of systemic glucocorticoids on mortality or mechanical ventilation in patients with COVID-19 | 34 | Early glucocorticoid first 48 hours | No glucocorticoid | — | (i) In-hospital mortality (ii) In-hospital mechanical ventilation. (iii) Mortality in mechanical ventilation |
(i) In-hospital mortality (ii) In-hospital mechanical ventilation. (iii) Mortality in mechanical ventilation |
| 11 | Yu et al., China | Lopinavir/ritonavir is associated with pneumonia resolution in COVID-19 patients with influenza coinfection: A retrospective matched-pair cohort study | 30 | Lopinavir/ritonavir treatment | No lopinavir/ritonavir treatment | (i) Glucocorticoid treatment (ii) Ribavirin treatment (iii) Lopinavir/ritonavir treatment (iv) Oseltamivir (v) Arbidol |
(i) Dead or deteriorated (ii) Cured |
(i) Dead or deteriorated (i) Cured |
| 12 | Qu et al., not mentioned | Comparative effectiveness of lopinavir/ritonavir-based regimens in COVID-19 | — | (i) Lopinavir/ritonavir (LPV/r) alone (ii) Lopinavir/ritonavir (LPV/r) + Novaferon (iii) Lopinavir/ritonavir (LPV/r) + interferon (iv) Lopinavir/ritonavir (LPV/r) + interferon + Novaferon (v) Lopinavir/ritonavir (LPV/r) + interferon + Arbidol (LPV/r: PO 500 mg (400 mg lopinavir + 100 mg ritonavir) BID; Novaferon: aerosol 20 microgram BID; Arbidol: PO 0.2 g TID; interferon: aerosol 500 × 104 IU·BID) |
— | — | (i) Time of negative nucleic acid conversion. (ii) Length of hospitalization (iii) The rate of adverse reaction (iv) Transferring to ICU and clinical mechanical therapy |
(i) Time of negative nucleic acid conversion. (ii) Length of hospitalization. (iii) The rate of adverse reaction (iii) Transferring to ICU and clinical mechanical therapy |
Table 4.
Description of study characteristics: interventional studies.
| S. no. | Trial registration number | Author, country | Title | Study duration in days | Study arm | Intervention group | Control group | Concomitant drugs | Outcome measures | Outcome measures applicable to this review |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | NCT04353336 | Abd-Elsalam et al., Egypt | Hydroxychloroquine in the treatment of COVID-19: A multicenter randomized controlled study | 122 | 2 | Hydroxychloroquine | (i) Paracetamol (ii) Oxygen (iii) Fluids (iv) Empiric antibiotic (cephalosporins) (v) Oseltamivir (vi) Invasive mechanical ventilation with hydrocortisone |
— | (i) Death (ii) Duration of hospital stay |
(i) Death (ii) Duration of hospital stay |
| 2 | Trial registration not specified. | Antinori et al., Italy | Compassionate remdesivir treatment of severe COVID-19 pneumonia in intensive care unit (ICU) and non-ICU patients: clinical outcome and differences in posttreatment hospitalization status | 27 | 1 | Remdesivir (ICU and ward setting) | None | — | (i) WHO ordinal scale (ii) Hospitalization status (iii) Adverse events |
(i) WHO ordinal scale (ii) Hospitalization status (iii) Adverse events |
| 3 | NCT04323527 | Borba et al., Brazil | Effect of high vs. low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection | — | 2 | High-dose chloroquine (600 mg CQ; 4 × 150 mg tablets twice daily for 10 days; total dose 12 g) | Low-dose chloroquine (450 mg CQ twice daily on the first day and 450 mg once daily for 4 days) | (i) Intravenous ceftriaxone (1 g twice daily for 7 days) (ii) Azithromycin (500 mg once daily for 5 days) (iii) Oseltamivir (75 mg twice daily for 5 days) |
(i) Safety (ii) Lethality (iii) Clinical status (iv) Laboratory examinations (v) Electrocardiogram results |
(i) Safety (ii) Lethality (iii) Clinical status |
| 4 | ChiCTR2000029308 | Cao et al., China | A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19 | 17 | 2 | Lopinavir-ritonavir (400 mg and 100 mg twice daily) | (i) Supplemental oxygen (ii) Noninvasive ventilation (iii) Invasive ventilation (iv) Antibiotic agents (v) Vasopressor support (vi) Renal replacement therapy (vii) Extracorporeal membrane oxygenation (ECMO) |
— | (i) WHO ordinal scale (ii) Time to clinical improvement (iii) Day 28 mortality (iv) ICU length of stay |
(i) WHO ordinal scale (ii) Time to clinical improvement (iii) Day 28 mortality (iv) ICU length of stay |
| 5 | IRCT20200501047259N1 | Gharebaghi et al., Iran | The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: A randomized placebo-controlled double-blind clinical trial | — | 2 | Intravenous immunoglobulin (IVIG). Four vials of 5 g IVIG daily | Placebo and standard of care | — | Mortality | Mortality |
| 6 | NCT04383535 | Simonovich et al., Italy | A randomized trial of convalescent plasma in COVID-19 severe pneumonia | — | 2 | Convalescent plasma | Placebo and standard of care | (i) Antiviral agents (ii) Glucocorticoids |
(i) WHO ordinal scale (ii) Clinical status at 30 days (iii) 30 days mortality |
(i) WHO ordinal scale (ii) Clinical status at 30 days (iii) 30 days mortality |
| 7 | NCT04375098 | Balcells et al., Chile | Early anti-SARS-CoV-2 convalescent Plasma in patients admitted for COVID-19: A randomized phase II clinical trial | 70 | 2 | Early plasma, 400 ml of ABO compatible convalescent plasma | Deferred plasma, 400 ml plasma | (i) Steroids (ii) Tocilizumab (iii) Hydroxychloroquine (iv) Lopinavir/ritonavir (v) Thromboprophylaxis (vi) Anticoagulation |
(i) Mechanical ventilation (ii) Hospitalization >14 days (iii) Death (iv) Oxygen requirement |
(i) Mechanical ventilation (ii) Hospitalization >14 days (iii) Death (iv) Oxygen requirement |
| 8 | IRCT20150303021315N17 | Malekzadeh et al., Iran |
Subcutaneous tocilizumab in adults with severe and critical COVID-19: A prospective open-label uncontrolled multicenter trial | 100 | 1 | Tocilizumab at a dose of 324 mg | (i) Antiviral agents (ii) Hydroxychloroquine (iii) Interferon beta-1a (iv) Antibiotic agents |
— | (i) Hospital Stay (ii) Death (iii) Oxygen requirement (iv) Adverse events |
(i) Hospital stay (ii) Death (iii) Oxygen requirement (iv) Adverse events |
| 9 | NCT04346355 | Salvarani et al., Italy | Effect of tocilizumab vs. standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: A randomized clinical trial | 73 | 2 | Tocilizumab at a dose of 8 mg/kg up to a maximum of 800 mg | (i) Tocilizumab IV + steroids (ii) Steroids (iii) Canakinumab |
(i) Hydroxychloroquine (ii) Heparin (iii) LMWH (iv) Antiretroviral (v) azithromycin |
(i) Clinical worsening (ii) At 14 days: admissions to ICU (iii) At 14 days: deaths (iv) At 14 days: discharges (v) At 30 days: admissions to ICU (vi) At 30 days: deaths (vii) At 30 days: discharges |
(i) Clinical worsening (ii) At 14 days: admissions to ICU (iii) At 14 days: deaths (iv) At 14 days: discharges (v) At 30 days: Admissions to ICU (vi) At 30 days: deaths (vii) At 30 days: discharges |
| 10 | NCT04356937 | Stone et al., the United States | Efficacy of tocilizumab in patients hospitalized with COVID-19 | 57 | 2 | Tocilizumab, 8 mg per kilogram of bodyweight administered intravenously, not to exceed 800 mg | Placebo and standard of care | (i) Remdesivir (ii) Dexamethasone (iii) Hydroxychloroquine (iv) Glucocorticoids |
(i) Death (ii) Intubation (iii) Oxygen requirement |
(i) Death (ii) Intubation (iii) Oxygen requirement |
| 11 | NCT04257656 | Wang et al., China | Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicenter trial | 36 | 2 | Remdesivir, 200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions | Placebo and standard of care | (i) Lopinavir-ritonavir (ii) Interferons (iii) Corticosteroids |
(i) Time to clinical improvement within 28 days (ii) Mortality at day 28 (iii) Safety outcomes included treatment-emergent adverse events, serious adverse events, and premature discontinuation of study drugs. |
(i) Time to clinical improvement within 28 days (ii) Mortality at day 28 (iii) Safety outcomes included treatment-emergent adverse events, serious adverse events, and premature discontinuation of study drugs. |
| 12 | NCT04405843 | Medina et al., Colombia | Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: A randomized clinical Trial | 17 | 2 | Ivermectin and standard of care: received 300 μg/kg | Placebo and standard of care | (i) NSAIDS (ii) Macrolides (iii) Antipyretics (iv) Antibiotics (v) Glucocorticoids (vi) Immunomodulating (vii) Anticoagulants |
(i) Deaths (ii) Clinical deterioration (iii) Adverse events |
(i) WHO ordinal scale (ii) Deaths (iii) Clinical deterioration (iv) Adverse events |
| 13 | NCT04276688 | Hung et al., Hong Kong | Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: An open-label, randomized, phase 2 trial | 40 | 2 arms | (i) Interferon beta-1b (ii) Lopinavir-ritonavir (iii) Ribavirin |
Lopinavir-ritonavir | — | (i) Mortality (ii) Length of hospital stay (iii) Negative RT-PCR result |
(i) Mortality (ii) Length of hospital stay (iii) Negative RT-PCR result |
| 14 | ChiCTR2000029387 | Huang et al., China | No statistically apparent difference in antiviral effectiveness observed among ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild-to-moderate coronavirus disease 2019: results of a randomized, open-labelled prospective study | 28 | 3 | (i) Ribavirin (ii) Lopinavir/ritonavir (iii) Interferon-alpha |
— | — | (i) Death (ii) Length of hospitalization (iii) Negative SARS-CoV-2 results (iv) Adverse events |
(i) Death (ii) Length of hospitalization (iii) Negative SARS-CoV-2 results (iv) adverse events |
| 15 | NCT04292899 | Olender et al., multicenter | Remdesivir for severe coronavirus disease 2019 (COVID-19) versus a cohort receiving standard of care | 33 | 2 | Remdesivir | No remdesivir | (i) Azithromycin (ii) Hydroxychloroquine (iii) HIV protease inhibitor (iv) Biologics (v) Ribavirin |
(i) WHO ordinal score (ii) Recovery on day 14 (iii) Death at day 14 (iv) Clinical improvement on day 14 |
(i) WHO ordinal score (ii) Recovery on day 14 (iii) Death at day 14 (iv) Clinical improvement on day 14 |
| 16 | ChiCTR2000029757 | Li et al., China | Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial | 48 | 2 | Convalescent plasma | Standard of care | (i) Antiviral (ii) Antibacterial (iii) Steroids (iv) Human immunoglobulin |
(i) WHO ordinal scale (ii) Time to clinical improvement (iii) Discharge rate at 28 days (iv) Mortality at 28 days (v) Negative PCR |
(i) WHO ordinal scale (ii) Time to clinical improvement (iii) Discharge rate at 28 days (iv) Mortality at 28 days (v) Negative PCR |
| 17 | NCT 04321421 | Perotti et al., Italy | Mortality reduction in 46 severe COVID-19 patients treated with hyperimmune plasma: A proof-of-concept single arm multicenter interventional trial | 32 | 1 | Plasma infusion | None | (i) Antiviral (ii) Antibiotics (iii) Hydroxychloroquine (iv) Anticoagulant |
(i) Mortality (ii) Changes in PaO2/FiO2, LDH |
(i) Mortality (ii) Oxygen requirement |
| 18 | NCT04292730 | Spinner et al., multicenter | Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial | 35 | 3 | 10 days remdesivir | (i) 5 days remdesivir (ii) Standard of care |
(i) Steroids (ii) Hydroxychloroquine/chloroquine (iii) Lopinavir-ritonavir (iv) Tocilizumab (v) Azithromycin |
(i) Death (ii) Discharge (iii) Adverse events |
(i) Death (ii) Discharge (iii) Adverse events |
| 19 | CTRI/2020/04/024775 | Agarwal et al., India | Convalescent plasma in the management of moderate COVID-19 in adults in India: open-label phase II multicenter randomized controlled trial (PLACID trial) | 84 | 2 | Convalescent plasma (two doses of 200 ml) + best standard of care. | Standard of care | (i) Hydroxychloroquine (ii) Remdesivir (iii) Lopinavir (iv) Ritonavir (v) Oseltamivir (vi) Antibiotics (vii) Steroids (viii) Tocilizumab |
(i) Mortality (ii) Clinical improvement on the World Health Organization ordinal scale |
(i) Mortality (ii) Clinical improvement on the World Health Organization ordinal scale |
Table 5.
Description of study characteristics: quasiexperimental studies.
| S. no. | Trial registration number | Author, country | Title | Study duration in days | Study arm | Intervention group | Control group | Concomitant interventions | Outcome measures | Outcome measures applicable to this review |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | NCT04374071 | Fadel et al., United States | Early short-course corticosteroids in hospitalized | 8 | 2 | Corticosteroid methylprednisolone 0.5–1 mg/kg/day divided in 2 intravenous doses for 3 days | (i) Standard care (ii) Lopinavir-ritonavir (iii) Ribavirin (iv) Hydroxychloroquine (v) Steroid |
(i) Lopinavir-ribavirin (ii) Hydroxychloroquine (iii) Tocilizumab (iv) Methylprednisolone (v) Oral prednisone |
(i) Death (ii) Respiratory failure requiring mechanical ventilation. (iii) Overall mechanical ventilation (iv) Length of stay |
(i) Death (ii) Respiratory failure requiring mechanical ventilation. (iii) Overall mechanical ventilation (iv) Length of stay |
| 2 | NCT04374071 | Fatima et al., Pakistan | Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe COVID-19 disease. | 30 | 2 | Intravenous methylprednisolone 1 mg/kg/day in 2 divided | Intravenous dexamethasone 8 mg/day given for 5 days | (i) Plasma therapy (ii) Antibiotics (iii) Tocilizumab |
(i) Mortality (ii) ICU transfer (iii) Ventilator needed |
(i) Mortality (ii) ICU transfer (iii) Ventilator needed |
| 3 | NCT4357106 | Olivares-Gazca et al., Mexico | Infusion of convalescent plasma is associated with clinical improvement in critically ill patients with COVID-19: A pilot study | 22 | 1 | Convalescent plasma | — | — | Mortality | Mortality |
| 4 | 2020-000890-25 | Philippe Gautret et al., France | Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial | — | 2 | Hydroxychloroquine 200 mg, 3 times per day for 10 days | No hydroxychloroquine | (i) Azithromycin 500 mg on day 1 and 250 mg per day for the next four days (hydroxychloroquine-treated patients) (ii) Combination of hydroxychloroquine and azithromycin |
(i) Virological clearance at day 6 (ii) Virological clearance over the time (iii) Occurrence of side effects |
(i) Virological clearance at day 6 (ii) Virological clearance over the time (iii) Occurrence of side effects |
3. Results
In our systematic review, a total of 122 studies were included (Supplementary Figure 1). Data extracted from these final studies are given in Table 2 (cohort and cross-sectional studies), Table 3 (case-control studies), Table 4 (interventional studies), and Table 5 (quasiexperimental studies).
All drugs in the NCOC v4 guidelines were included, and their efficacy was assessed by evaluating length of hospitalization, mortality, and ordinal scores, and a recommendation was made based on GRADE methodology. As per the NCOC panel recommendation, we additionally included colchicine in the review and comparison of WHO, NCOC v4, and our review between drugs, as given in Table 6.
Table 6.
Comparison of recommendations.
| S. no. | Intervention | Recommendations | ||
|---|---|---|---|---|
| Drugs | National guidelines | Systematic review | WHO | |
| 1 | Corticosteroids | (i) To use in severe or critical patients (ii) Not to use in nonsevere or asymptomatic |
(i) For the use of corticosteroids in severe and critical patients, hospitalized COVID-19 patients. Strong recommendation, moderate-quality evidence (ii) Against the use of corticosteroids in nonsevere patients, hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence |
Recommended the use of systematic corticosteroid rather than no corticosteroids in severe and critical COVID-19 patients. |
| 2 | Tocilizumab | (i) To use in patients who have worsened despite the initial 24–48 hours of steroids (ii) To not use in patients who have not received a trial of steroids or with elevated markers only |
For the use of tocilizumab in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence | Recommended the use of tocilizumab in patients with severe or critical COVID-19 infection. |
| 3 | Ivermectin therapy | This is not recommended in the national guidelines | Against the use of ivermectin therapy in the use of COVID-19 hospitalized patients. Weak recommendation, low-quality evidence | Recommended against the use of ivermectin in patients with COVID-19 |
| 4 | Hydroxychloroquine/chloroquine | There is no role for prophylactic chloroquine and hydroxychloroquine to prevent COVID-19 infection after exposure | Against the use of hydroxychloroquine alone or in combination with other antibiotics in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence | Recommended against the use of hydroxychloroquine or chloroquine for treatment of COVID-19 |
| 5 | Antibiotics | (i) To use in proven or strong suspicion of secondary infection (ii) To not use for “prevention” of secondary infections or in patients with no clear evidence of bacterial infection |
No evidence available | No evidence available |
| 6 | Anticoagulation therapy | Prophylactic anticoagulation (i) To use in all hospitalized patients (ii) To not use in nonsevere or asymptomatic patients Therapeutic anticoagulation (i) To use in proven or high suspicion of VTE (ii) To not use in patients with isolated elevated D-dimers or no evidence of VTE |
(i) For the use of anticoagulant therapeutic doses. Therapeutic: strong recommendation, moderate-quality evidence (ii) For the use of prophylactic dose anticoagulants to treat COVID-19 hospitalized patients. Prophylactic: strong recommendation, moderate-quality evidence |
No evidence available |
| 7 | Remdesivir | (i) To use in severe patients with less than 10 days of symptoms (ii) To not use in nonsevere, asymptomatic, or critical patients or in whom symptoms are longer than 10 days |
For the use of remdesivir in hospitalized COVID-19 patients. Recommendation, high-quality evidence | Conditional recommendation against administering remdesivir in addition to usual care. |
| 8 | Lopinavir/ritonavir | (i) To use in severe patients with less than 10 days of symptoms (ii) To not use in nonsevere, asymptomatic, or critical patients or in whom symptoms are longer than 10 days |
Against the use of ritonavir/lopinavir in hospitalized COVID-19 patients. No recommendation, moderate-quality evidence | Recommended against administering lopinavir/ritonavir for treatment of COVID-19. |
| 9 | Convalescent plasma | No evidence available | Against the use of convalescent plasma in the management of hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence | No evidence available |
| 10 | Famotidine | Not recommended in the national guidelines | For the use of famotidine in hospitalized COVID-19 patients. Weak recommendation, low-quality evidence | No evidence available |
| 11 | Immunoglobulin therapy | No evidence available | For the use of immunoglobulin therapy in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence | No evidence available |
| 12 | Colchicine | No evidence available | Against the use of colchicine in hospitalized COVID-19 patients. No recommendation, low-quality evidence | No evidence available |
3.1. Corticosteroids
Multiple studies have evaluated the efficacy of corticosteroids in the management of COVID-19 (Tables 2 and 5). We gave strong recommendation for the use of corticosteroids because the studies were showing early recovery in severe and critical patients; however, we gave weak recommendation for its use in noncritical patients as it did not show any positive outcomes. Most of the studies in our systematic review were observational; hence, we gave a moderate quality of evidence.
As per our systematic review, we recommend
For the use of corticosteroids in severe and critical patients, hospitalized COVID-19 patients. Strong recommendation, moderate-quality evidence.
Against the use of corticosteroids in nonsevere patients, hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence.
WHO v7.1 dated 24/9/2021 recommended for the use of systematic corticosteroid rather than no corticosteroids in severe and critical COVID-19 patients.
3.2. Tocilizumab
In our systematic review, mortality rates with tocilizumab therapy ranged from 6.98% to 60% (depending on patient inclusion criteria), with many studies showing a protective effect of tocilizumab with regards to mortality, especially if given intravenously (as compared to subcutaneously) and within 12 days of admission [8–28]. Patients treated with tocilizumab alone were more likely to show improvement on the WHO ordinal scale (63.9% vs. 36.1%) and less likely to require ICU care (40.4% vs. 59.6%) as compared to those treated with corticosteroids in addition to tocilizumab [29]. We gave weak recommendation as the studies were showing controversial results on managing COVID-19 hospitalized adults with tocilizumab. Many of the studies were showing inconsistent results; therefore, we gave moderate certainty.
As per our systematic review, we recommend
For the use of tocilizumab in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence.
WHO v7.1 recommended for the use of tocilizumab in patients with severe or critical COVID-19 infection.
3.3. Ivermectin Therapy
Due to its effectiveness in various other viral infections, ivermectin was assessed as a therapeutic agent for COVID-19 infection (Tables 2 and 4). As studies showed no major difference in mortality, we gave weak recommendation for the use of ivermectin and low quality of evidence because of insufficient evidence.
As per our systematic review, we recommend
Against the use of ivermectin therapy in the use of COVID-19 hospitalized patients. Weak recommendation, low-quality evidence.
WHO v7.1 recommended against the use of ivermectin in patients with COVID-19.
3.4. Antibiotics
The macrolide azithromycin has demonstrated antiviral activity, especially in human bronchial epithelial cells where it reduces viral cell replication and causes an increase in viral-induced pattern recognition receptors. It has exhibited a synergistic effect with the drug hydroxychloroquine, and together, they decrease the production of inflammatory cytokines such as IL-1 and IL-6 [30]. We gave weak recommendation for the management of COVID-19 hospitalized adults with hydroxychloroquine alone or in combination with other antibiotics because the studies were not showing positive outcomes on mortality and length of stay. We gave moderate certainty of evidence as most of the studies in our systematic review were cohort and case-control studies.
As per our systematic review, we recommend
Against the use of antibiotics, including hydroxychloroquine alone or in combination with other antibiotics in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence.
WHO v7.1 recommended against the use of hydroxychloroquine or chloroquine for treatment of COVID-19.
3.5. Anticoagulation Therapy
As per our systematic review, the therapeutic doses of anticoagulation, i.e., nadroparin calcium (2850 IU) reduced mortality as compared to the prophylactic doses in the majority of studies [31–34]. While few studies found no difference, Billet et al. reported mortality reduction for prophylactic doses of both apixaban and enoxaparin and therapeutic doses of apixaban but not enoxaparin [35–38]. Therapeutic doses of apixaban did not provide an additional mortality reduction compared to prophylactic doses. Therapeutic doses of anticoagulation were shown to reduce the incidence of a venous thromboembolic event; however, both therapeutic and prophylactic doses of anticoagulation reduce in-hospital mortality compared to patients not receiving anticoagulation [31, 33, 35, 39]. We gave strong recommendation to both therapeutic and prophylactic doses of anticoagulants, as in several studies, it has shown to reduce mortality. Many studies in our systematic review were observational, so we rated the evidence as moderate.
As per our systematic review, we recommend
For the use of anticoagulant therapeutic doses. Therapeutic: strong recommendation, moderate-quality evidence.
For the use of prophylactic dose anticoagulants to treat COVID-19 hospitalized patients. Prophylactic: strong recommendation, moderate-quality evidence.
No evidence available as per WHO v7.1.
3.6. Antivirals
Remdesivir, an antiviral agent, has been associated with lower mortality, with one study reporting 62% lower odds of mortality and greater clinical improvement [40, 41]. However, the results of other studies have not been as conclusive. Studies using the WHO ordinal scale have found weak associations between remdesivir use and improved patient outcomes [42]. With regards to other antivirals, there are conflicting data from studies. Varying WHO ordinal scale results were found for antivirals lopinavir-ritonavir. Multiple studies found no difference in mortality with the combination of ritonavir/lopinavir and remdesivir [43, 44]. We gave weak recommendation for the use of remdesivir because of the inconsistent results of the studies. However, we recommend against the use of ritonavir/lopinavir use due to conflicting research evidence. Most of the studies on remdesivir were randomized controlled trials; therefore, we rated it as high quality of evidence, while studies on ritonavir/lopinavir were mostly observational, so it has moderate certainty.
As per our systematic review, we recommend
For the use of remdesivir in hospitalized COVID-19 patients. Weak recommendation, high-quality evidence.
Against the use of ritonavir/lopinavir in hospitalized COVID-19 patients. No recommendation, moderate-quality evidence.
WHO v7.1: conditional recommendation against administering remdesivir in addition to usual care.
WHO v7.1 recommended against administering lopinavir/ritonavir for treatment of COVID-19.
3.7. Convalescent Plasma
Convalescent plasma initially was looked at as a possible therapy for COVID-19 infection due to its prior usefulness in other epidemic viruses. Some initial observational studies suggested the use of convalescent plasma in improving pulmonary function, decreasing adverse effects, increasing survival, and shortening hospital stay [45–47]. While most observational studies reported positive outcomes, RCTs have not supported convalescent plasma use. We gave weak recommendation for convalescent plasma use because RCTs have not shown significant improvement in patients' health status. As many of the studies were observational, therefore, we gave it a moderate quality of evidence.
As per our systematic review, we recommend
Against the use of convalescent plasma in the management of hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence.
There are no available evidence as per WHO v7.1.
3.8. Famotidine
While famotidine is conventionally used as an H2 receptor blocker, it also has antiviral properties [48]. Freedberg et al., in a single-centered retrospective cohort study, reported reduced mortality with famotidine use [49]. Similarly, when comparing a treatment regimen of HCQ, azathioprine, remdesivir, and corticosteroids with famotidine and those without famotidine, Mather et al. reported lower mortality in the famotidine arm (14% in the famotidine group vs. 26% in the nonfamotidine group) [50]. Despite these results, larger studies and RCTs have not yet established the role of famotidine, and therefore, we gave it low certainty. Given the minimal side effect profile of famotidine, our judgement based on data available at the time was for its use but with weak recommendation.
As per our systematic review, we recommend
For the use of famotidine in hospitalized COVID-19 patients. Weak recommendation, low-quality evidence.
There are no available evidence as per WHO v7.1.
3.9. Immunoglobulin Therapy
Based on the limited number of studies, a retrospective cohort study conducted by Shao et al. found IVIG therapy to reduce the 28-day mortality in critically ill patients (27% in the IVIG group vs. 53% in the non-IVIG group) [51]. Similarly, a randomized trial by Gharebaghi et al. also proved that IVIGs reduced mortality [52]. Studies have shown lower mortality; therefore, we supported its use with weak recommendation. As no significant interventional studies are supporting its use, we gave it moderate certainty.
As per our systematic review, we recommend
For the use of immunoglobulin therapy in hospitalized COVID-19 patients. Weak recommendation, moderate-quality evidence.
There are no available evidence as per WHO v7.1.
3.10. Colchicine
Colchicine works by inhibiting the assembly of microtubules during mitosis by binding to tubulin inside cells and forming tight tubulin-colchicine complexes. This is its major anti-inflammatory mechanism of action [53]. In our review, only 1 single-center cohort of adult hospitalized patients with COVID-19 pneumonia and acute respiratory distress syndrome was found using colchicine 1 mg/day, investigating the association between colchicine use and improved survival in adult hospitalized patients with COVID-19 pneumonia and acute respiratory distress syndrome and found a 20.8% decrease in mortality amongst patients treated with colchicine along with other standards of care drugs [54]. Because of the insufficient research evidence, we are not recommending colchicine use and gave it a low quality of evidence.
As per our systematic review, we recommend
Against the use of colchicine in hospitalized COVID-19 patients. No recommendation, low-quality evidence.
There are no available evidence as per the WHO v7.1.
4. Discussion
A great breadth of literature exists on the therapeutic management of hospitalized adults with COVID-19 based on disease severity, much of which have been analyzed and appraised systematically [55]. Currently, living systematic reviews provide information to guide clinical practice [56, 57]. However, this approach assumes that all treatment options are available or approved in each country or region, which is not the case. In Pakistan, the Government of Pakistan has released Clinical Management Guidelines for COVID-19 Infections, based on which clinicians are expected to prescribe and treat patients [2]. While such guidelines are beneficial in which they are region-specific and keep in mind various economic factors and drug availability, they are not regularly updated due to the resources required for systematic reviews and evidence synthesis. To consolidate the pool of information to assess the effectiveness of currently approved therapeutic options for COVID-19 infection in Pakistan, we have synthesized data relating to only those treatments that are recommended in our country's guidelines using global data from 1st November 2019 to December 31st, 2020 [2].
Of all the drug classes analyzed, corticosteroids were found to have the most consistent effect on mortality and length of stay. The WHO clinical progression (ordinal) scale showed a reduction in mortality among patients being treated with corticosteroids. All but a few studies support the use of corticosteroids in patients hospitalized with COVID-19 [58, 59]. Trials that assessed anticoagulation (especially therapeutic vs. prophylactic dosages) were also predominantly found to improve thromboembolic outcomes and mortality. However, variations in the type of anticoagulant used make it hard to recommend a single drug. Nadroparin, tinzaparin, dalteparin (LMWH), heparin, apixaban, and enoxaparin were all found to have reduced mortality [31, 33, 38]. Trials assessing tocilizumab supported its use to limit mortality and length of stay [13, 28, 29, 60]. One study found that the addition of corticosteroids to tocilizumab was a significant protective factor against mortality [61].
Studies assessing remdesivir failed to show any conclusive difference in mortality and length of stays of patients with COVID-19 [42]. Of the antivirals that are being used for COVID-19, lopinavir and ritonavir have predominantly been assessed by various observational studies as well as clinical trials, both of which have been uncertain. Ribavirin alone and in combination with other antivirals (lopinavir/ritonavir + interferon-alpha) was also shown to have minimal efficacy [62]. Data from RCTs led to recommendation against the use of convalescent plasma [63–66], which in the early days of COVID-19 was looked at as a major intervention.
Very few studies have been conducted on famotidine (an H2 receptor blocker) and IVIG. Studies have reported a significantly reduced mortality in patients being treated by famotidine or IVIG compared to control groups; however, further randomized trials and data are needed to make a concrete recommendation. Studies assessing ivermectin also report divided results and highlight the need for further studies. One of the studies assessing colchicine has reported better outcomes in adult hospitalized patients with COVID-19 pneumonia [30].
Our review is the first one to systematically review the drugs specified by the Government of Pakistan's Clinical Management Guidelines for COVID-19 Infections v4, and several other systematic reviews have been conducted to assess the efficacy of drugs used in the treatment of COVID-19, with the WHO living guidelines for pharmacological management including the most up to date data. It was thus imperative that our findings be compared and assessed against broader literature that has been published.
Our review found the lack of randomized trials to be a limitation for evidence regarding less extensively studied agents, while the more extensively investigated agents had been studied by randomized trials. Since then, newer studies, that have been conducted and included in our review, have shown tocilizumab, IVIGs, and colchicine to be effective as well. Larger trials, such as the solidarity trials, have since proven that remdesivir is not effective [67].
The urgency of information about COVID-19 infection treatment has resulted in poorly organized studies that use a variety of different outcome measures, which deters meaningful comparison between different therapeutic agents. Indeed, our review reported a wide range of outcome measures, resulting in difficulty synthesizing data.
To standardize outcome measures across studies, several international bodies worked in union and formulated a set of outcome measures, which included the WHO clinical progression scale. This is an ordinal scale, ranging from 0 (no infection) to 10 (mortality) that is especially useful in widespread diseases. The lower scores (for mild disease, which may or may not require assistance) are more subjective, and the higher scores (of severe disease requiring different levels of intervention) are likely to change based on regional practices. However, the scale is quick to use because the data required are readily available in medical records. Despite its usefulness in standardizing clinical research, the uptake of this scale has not been encouraging [68]. Our systematic review reports only 13 studies that have used this scale to report clinical progression. Gaps in reporting, with different studies grouping or failing to mention the number of patients for each score, undermines the use of a standardized scale to make sound accurate comparisons of clinical data. We recommend the use of the WHO clinical progression scale as a standard practice for studies on COVID-19 infection, with full reporting of all scores to enable comparison of study outcome measures and optimize the systematic analysis of clinical data.
There are several limitations to this systematic review, mostly stemming from considerable heterogeneity between articles. These include variations in participant inclusion criteria of studies, variations in outcome measures, variations in drugs used across the same class, variations in drug dosages, and variations in geographic locations and patient populations across studies. In addition, the retrospective nature of many studies, the limited sample sizes, and inadequate statistical adjustment for reported associations also adversely impact interpretability.
5. Conclusion
Data on pharmacological interventions to treat COVID-19 are rapidly evolving, and based on it, the recommendations have also been changed. In our systematic review, the recommendations were based on studies up till December 2021, and we have compared our recommendations with the WHO v7.1, which showed significant changes in recent treatment modalities of COVID-19 infection. Our understanding regarding the management of COVID-19 has evolved rapidly over the last two years and continues to do so. Given the urgent need to offer any therapeutic option, interim recommendations were often made based on the best available data at the time. These data were, however, often from studies that were exploratory or not as rigorously done. This is apparent in the disparate recommendation between the 2 guidelines and the systematic review (which is only looking at studies published during the early part of the pandemic). This also brings to light the need to continually assess the literature and be able to ready to change (previously established) therapeutic recommendations.
Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Supplementary Materials
Supplementary Figure 1. PRISMA flow diagram reporting various studies assessed for further evaluation and included in the review. Supplementary Figure 2. Risk of bias graph for quasiexperimental studies. Supplementary Figure 3. Risk of bias summary for quasiexperimental studies. Supplementary Figure 4. Risk of bias graph for randomized control trials. Supplementary Figure 5. Risk of bias summary for randomized control trials. Supplementary Figure 6. Risk of bias graph for case-control studies. Supplementary Figure 7. Risk of bias summary for case-control studies. Supplementary Figure 8. Risk of bias graph for observational cohort and cross-sectional Studies. Supplementary Figure 9. Risk of bias summary for observational cohort and cross-sectional studies.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Figure 1. PRISMA flow diagram reporting various studies assessed for further evaluation and included in the review. Supplementary Figure 2. Risk of bias graph for quasiexperimental studies. Supplementary Figure 3. Risk of bias summary for quasiexperimental studies. Supplementary Figure 4. Risk of bias graph for randomized control trials. Supplementary Figure 5. Risk of bias summary for randomized control trials. Supplementary Figure 6. Risk of bias graph for case-control studies. Supplementary Figure 7. Risk of bias summary for case-control studies. Supplementary Figure 8. Risk of bias graph for observational cohort and cross-sectional Studies. Supplementary Figure 9. Risk of bias summary for observational cohort and cross-sectional studies.
Data Availability Statement
The data used to support the findings of this study are available from the corresponding author upon request.