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 [Reference Moher, Liberati, Tetzlaff and Altman3]. 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 [Reference Guyatt, Oxman and Vist4] (Table 1 and Supplementary Figure 1).
Table 1 Selection criteria and search strategy.
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) [Reference Sterne, Savović and Page6]. 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.
Table 3 Description of study characteristics: case-control studies.
Table 4 Description of study characteristics: interventional studies.
Table 5 Description of study characteristics: quasiexperimental studies.
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.
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
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(i) For the use of corticosteroids in severe and critical patients, hospitalized COVID-19 patients. Strong recommendation, moderate-quality evidence.
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(ii) 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 [Reference Ramiro, Mostard and Magro-Checa8–Reference Morrison, Johnson and Griebe28]. 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 [Reference Nasir, Mahmood, Habib, Khanum and Jamil29]. 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
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(i) 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
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(i) 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 [Reference Gautret, Lagier and Parola30]. 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
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(i) 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 [Reference Stessel, Vanvuchelen and Bruckers31–Reference Hanif, Khan and Mantri34]. 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 [Reference Llitjos, Leclerc and Chochois35–Reference Billett, Reyes-Gil and Szymanski38]. 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 [Reference Stessel, Vanvuchelen and Bruckers31, Reference Jonmarker, Hollenberg and Dahlberg33, Reference Llitjos, Leclerc and Chochois35, Reference Nadkarni, Lala and Bagiella39]. 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
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(i) For the use of anticoagulant therapeutic doses. Therapeutic: strong recommendation, moderate-quality evidence.
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(ii) 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 [Reference Pasquini, Montalti and Temperoni40, Reference Olender, Perez and Go41]. 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 [Reference Antinori, Cossu and Ridolfo42]. 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 [Reference Tong, Su and Yu43, Reference Huang, Tang and Xu44]. 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
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(i) For the use of remdesivir in hospitalized COVID-19 patients. Weak recommendation, high-quality evidence.
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(ii) 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 [Reference Abolghasemi, Eshghi and Cheraghali45–Reference Liu, Lin and Baine47]. 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
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(i) 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 [Reference Bourinbaiar and Fruhstorfer48]. Freedberg et al., in a single-centered retrospective cohort study, reported reduced mortality with famotidine use [Reference Freedberg, Conigliaro and Wang49]. 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) [Reference Mather, Seip and McKay50]. 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
-
(i) 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) [Reference Shao, Feng and Zhong51]. Similarly, a randomized trial by Gharebaghi et al. also proved that IVIGs reduced mortality [Reference Gharebaghi, Nejadrahim, Mousavi, Sadat-Ebrahimi and Hajizadeh52]. 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
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(i) 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 [Reference Schlesinger, Firestein and Brunetti53]. 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 [Reference Scarsi, Piantoni and Colombo54]. 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
-
(i) 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 [Reference Siemieniuk, Bartoszko and Ge56, Reference Juul, Nielsen and Feinberg57]. 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 [Reference Wu, Huang and Zhu58, Reference You, Wu and Fu59]. 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 [Reference Stessel, Vanvuchelen and Bruckers31, Reference Jonmarker, Hollenberg and Dahlberg33, Reference Billett, Reyes-Gil and Szymanski38]. Trials assessing tocilizumab supported its use to limit mortality and length of stay [Reference Vu, DeRonde and Vega13, Reference Morrison, Johnson and Griebe28, Reference Nasir, Mahmood, Habib, Khanum and Jamil29, Reference Sarfraz, Sarfraz, Sarfraz, Aftab and Pervaiz60]. One study found that the addition of corticosteroids to tocilizumab was a significant protective factor against mortality [Reference Fernández‐Ruiz, López‐Medrano and Pérez‐Jacoiste Asín61].
Studies assessing remdesivir failed to show any conclusive difference in mortality and length of stays of patients with COVID-19 [Reference Antinori, Cossu and Ridolfo42]. 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 [Reference Yan, Liu and Zhu62]. Data from RCTs led to recommendation against the use of convalescent plasma [Reference Agarwal, Mukherjee, Kumar, Chatterjee, Bhatnagar and Malhotra63–Reference Simonovich, Burgos Pratx and Scibona66], 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 [Reference Gautret, Lagier and Parola30].
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 [Reference Marshall, Murthy and Diaz68]. 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. (Supplementary Materials)
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