|Year : 2020 | Volume
| Issue : 2 | Page : 233-243
Management of COVID-19: A brief overview of the various treatment strategies
Burhanuddin Qayyumi, Florida Sharin, Arjun Singh, Vidisha Tuljapurkar, Pankaj Chaturvedi
Department of Head and Neck Oncology, Tata Memorial Centre and HBNI, Mumbai, Maharashtra, India
|Date of Submission||09-May-2020|
|Date of Decision||14-May-2020|
|Date of Acceptance||23-May-2020|
|Date of Web Publication||19-Jun-2020|
1227, HBB, Tata Memorial Hospital, Dr Ernest Borges Rd., Parel East, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Coronavirus disease 2019 (COVID-19) has posed a new challenge to the entire world. Many speculations revolve around its treatment. Numerous theories have been put forth and several medications have been tried, but not many promising results have been achieved.
Objective: We aim to provide an overview of the various treatment modalities for patients with COVID-19.
Methodology: A systematic search was performed to identify all the relevant studies on PubMed, Embase, and Google Scholar published until May 23, 2020, as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles that reported the various treatment modalities for COVID-19 were included in the analysis.
Results: Currently, only remdesivir has been approved by the Food and Drug Administration (FDA) for the treatment of severe COVID-19. Corticosteroids and anticoagulant therapy have been recommended in patients with severe acute respiratory distress syndrome (ARDS). Some drugs such as lopinavir–ritonavir and Chinese herbal medicine have been shown to be beneficial in a few trials, while others such as chloroquine/hydroxychloroquine, tocilizumab, sarilumab, oseltamivir, and plasma therapy are being tested in ongoing trials.
Conclusion: No treatment has been definitively proven to be effective against COVID-19 to date. The only FDA-approved drug is remdesivir, and several others are under investigation. Anticoagulant therapy and corticosteroids (weak recommendation) have been recommended in patients with severe ARDS.
Keywords: Chloroquine, coronavirus, coronavirus disease 2019, drug therapy, plasma therapy, remdesivir, severe acute respiratory syndrome-coronavirus-2, tocilizumab
|How to cite this article:|
Qayyumi B, Sharin F, Singh A, Tuljapurkar V, Chaturvedi P. Management of COVID-19: A brief overview of the various treatment strategies. Cancer Res Stat Treat 2020;3:233-43
|How to cite this URL:|
Qayyumi B, Sharin F, Singh A, Tuljapurkar V, Chaturvedi P. Management of COVID-19: A brief overview of the various treatment strategies. Cancer Res Stat Treat [serial online] 2020 [cited 2021 Jun 21];3:233-43. Available from: https://www.crstonline.com/text.asp?2020/3/2/233/287233
| Introduction|| |
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is the etiological agent of coronavirus disease 2019 (COVID-19) that emerged in China in December 2019, causing a pandemic. The literature and experience with the virus so far suggest that patients with COVID-19 manifest huge variations in their symptoms and outcomes, ranging from a lack of symptoms to the acute respiratory distress syndrome (ARDS). The role of host genetic susceptibility in the manifestation of COVID-19 symptoms is unclear, and many speculations revolve around the treatment of COVID-19. Numerous theories have been put forth and several medications have been tried, but not many promising results have been achieved. There are no specific guidelines for managing patients with COVID-19, other than providing supportive care to symptomatic patients. The first and most essential step is to isolate the infected individual to prevent further spread of the virus. Adequate hydration and nutrition are important, and antibiotics are to be administered if a bacterial co-infection is suspected. In case of hypoxia, delivery of oxygen using nasal prongs, cannula, or face mask, or non-invasive ventilation, is indicated. Mechanical ventilation and oxygen support may be provided when symptoms worsen. The various medications suggested for the management of COVID-19 have been discussed in this review.
| Methodology|| |
A systematic search was performed to identify all the relevant studies in PubMed, Embase, and Google Scholar published until May 23, 2020, as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following search terms were used: “beta coronavirus” OR “severe acute respiratory syndrome coronavirus 2” OR “COVID-19” OR “coronavirus infections” OR “coronavirus AND treatment” OR “drug therapy” OR “drug treatment.” To avoid missing out on any published studies, an additional search was performed from the reference lists of the included articles, and a manual search was done in Google for each of the medications identified. All relevant articles reporting the various treatment modalities for COVID-19 were included in the analysis. The search resulted in 73 articles that were screened further. Out of these, 53 articles fulfilled the inclusion criteria [Figure 1]. The most important studies are summarized in [Table 1].
|Figure 1: The search strategy to identify studies related to drug therapy for COVID-19 (Acronyms: COVID-19, coronavirus disease 2019; SARS, severe acute respiratory syndrome; MERS, Middle East respiratory syndrome)|
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|Table 1: Summary of the various drug therapies for coronavirus disease 2019|
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| Corticosteroids|| |
The role of corticosteroids has not yet been established, as there are no randomized controlled trials in patients with COVID-19. According to the World Health Organization (WHO), routine systemic corticosteroids are not recommended outside the trial setting. The Centers for Disease Control and Prevention suggests that the indication for the use of glucocorticoids should be based on evidence, as in the case of conditions such as adrenal insufficiency, acute exacerbation of chronic obstructive pulmonary disease, and non-responsive septic shock. The Chinese guidelines recommend a short course of corticosteroids in low-to-moderate doses for COVID-19 ARDS., Wu et al. in their retrospective study on 201 patients with COVID-19 pneumonia admitted to the Wuhan Jinyintan hospital observed that 84 (41.8%) patients developed ARDS, 53 (26.4%) required intensive care unit (ICU) admission, 67 (33.3%) required mechanical ventilation, and 44 (21.9%) died. A total of 196 (97.5%) patients received empirical antiviral (including oseltamivir, ganciclovir, lopinavir–ritonavir, and interferon) and antibiotic treatment. In addition, 106 (52.7%) patients received antioxidant therapy, 70 (34.8%) received immunomodulators, and 62 (30.8%) patients received methylprednisolone. The investigators observed that patients who developed ARDS were more likely to receive methylprednisolone, and the majority of patients who received steroids were categorized as high grade according to the Pneumonia Severity Index. The use of methylprednisolone decreased the risk of death (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.72) among the patients with ARDS, but there were several confounding factors. Fadel et al. evaluated the role of early steroid therapy (0.5–1 mg/kg/day divided into two intravenous doses for 3 days) in moderate-to-severely affected patients with COVID-19. It was observed that the need for ICU admission and mechanical ventilation and mortality for the post-corticosteroid group was less than that for the pre-corticosteroid group (34.9% vs. 54.3%, P = 0.005). It should be noted that these data are from a pre-print manuscript and are therefore not peer-reviewed yet and should not be used to guide clinical management.
A Cochrane Systematic Review and Meta-analysis by Lansbury et al. on patients with influenza revealed that high-dose steroids were associated with greater mortality (odds ratio [OR], 2.76; 95% CI, 2.06–3.69). Lewis et al. stated that steroids reduced the mortality and the need for mechanical ventilation, but these were not limited to viral ARDS. Siemieniuk et al. in their systemic review and meta-analysis on community-acquired pneumonia stated that steroids reduced the mortality by approximately 3% (risk ratio [RR], 0.67; 95% CI, 0.45–1.01) and the need for mechanical ventilation by 5% (RR, 0.45; 95% CI, 0.26–0.79).
The Surviving Sepsis Campaign in its guidelines on the management of patients with COVID-19 gave a weak recommendation for the use of corticosteroids in patients with respiratory failure requiring mechanical ventilation, but not in those without ARDS. Given the benefit of glucocorticoids in all types of ARDS, the Society of Critical Care Medicine has made a weak conditional recommendation for glucocorticoid use in severe and moderate-to-severe ARDS.
| Antivirals|| |
Learning from the experiences with SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV), the use of antivirals such as lopinavir–ritonavir and ribavirin has been suggested. Other drugs such as remdesivir, arbidol, chloroquine, interferons, immunoglobulins, and the plasma of patients who have recovered from COVID-19 infection have also been tried with varying degrees of success., The WHO has launched the “Solidarity” international trial to evaluate the four most promising therapies for the management of COVID-19 compared to the standard of care. The various drugs included in this trial are remdesivir, chloroquine or hydroxychloroquine, lopinavir–ritonavir, and interferon-β-1a. As of April 21, 2020, over 100 countries were participating in the trial.
Although there are many ongoing trials, there are very limited data supporting their use in patients with COVID-19. Initially, ritonavir and lopinavir were introduced as antiretroviral drugs under the brand names Kaletra and Aluvia, respectively. Doctors from the Rajvithi Hospital in Bangkok in February, 2020, reported that a cocktail of drugs against flu and human immunodeficiency virus (HIV) had improved the outcomes in several patients with COVID-19, including a 70-year-old Chinese woman who recovered completely.
Chu et al. in their virological and clinical assessment of patients with SARS stated that lopinavir–ritonavir reduced the viral load and the chances of adverse clinical outcomes. A retrospective study by Chan et al. assessed the use of lopinavir–ritonavir as an initial treatment in patients with severe acute respiratory symptoms; initial treatment with lopinavir–ritonavir led to better clinical outcomes compared to when it was given as rescue therapy. A randomized controlled trial by Cao et al. included 199 patients hospitalized due to COVID-19 pneumonia (oxygen saturation [SpO2] ≤94% and ratio of partial pressure of oxygen [PaO2] to fractional inspired oxygen [FiO2] <300 mmHg). One hundred patients were randomized to the standard care group and 99 to the lopinavir–ritonavir (400 mg and 100 mg, respectively, orally twice a day) group. The primary endpoint, the median time to clinical improvement, was 16 days in both the arms; HR for clinical improvement, 1.31; 95% CI, 0.95–1.8, P = 0.09. No difference was observed between the mortality at 28 days in patients receiving lopinavir–ritonavir and standard care (19.2% vs. 25.0%, respectively; difference, −5.8% points; 95% CI, −17.3 to 5.7). The duration of ICU stay was reduced (median 6 days vs. 11 days; difference, −5 days; 95% CI, −9-0), and the gastrointestinal side effects were more in the lopinavir–ritonavir group (all grades of vomiting in 6% vs. 0 in standard group, and diarrhea in 4% vs. 0). A Phase II randomized trial by Hung et al. compared the 14-day course of lopinavir (400 mg)–ritonavir (100 mg) twice a day to a 14-day course of triple therapy (lopinavir [400 mg]–ritonavir [100 mg] twice a day, ribavirin [400 mg] twice a day, and interferon-β [three doses of 8 million IU subcutaneously on alternate days]). The triple-therapy group had a shorter time to a negative nasopharyngeal swab than the lopinavir–ritonavir group (7 days vs. 12 days, respectively; HR 4.37; 95% CI, 1.86–10.24, P = 0.001). There was no difference in adverse events, which were mild in both the groups.
Li et al. in their randomized trial on 86 patients with mild/moderate COVID compared lopinavir (200 mg)–ritonavir (50 mg) twice daily to arbidol (200 mg three times daily) and standard treatment. After 2 weeks of treatment, there was no difference in the rate of conversion from positive to negative COVID-19 testing in the three groups of patients; 85.3% in the lopinavir–ritonavir group, 91.4% in the arbidol group, and 76.5% in the standard therapy group, P = 0.352. There was also no difference in the rate of clinical deterioration, symptoms, or radiological improvement between the three groups of patients.
It is an antiviral, neuraminidase inhibitor widely used against influenza and sold under the brand name Tamiflu. It was initially recommended by the WHO as a preventive measure during the influenza pandemic. Guan et al. reported the use of oseltamivir in 35.8% of their 1099 patients with COVID-19, and Huang et al. reported the use of oseltamivir in 93% of their cohort of 41 patients. However, no conclusive data were available regarding the effectiveness of the drug.
Arbidol hydrochloride (umifenovir)
It is a broad-spectrum antiviral used in the treatment of influenza, parainfluenza, hepatitis C, etc. Xu et al. performed a retrospective analysis of 111 patients with COVID-19 pneumonia who received an empirical antiviral drug with or without arbidol. They found that patients who received arbidol along with empirical treatment had higher virological conversion (59.2% vs. 40.3%) and less need for oxygen therapy, than those who did not. They concluded that patients with mild symptoms benefitted the most from the use of arbidol. A study by Zhu et al. retrospectively compared arbidol (0.2 g three times a day) monotherapy to lopinavir–ritonavir (400 mg/100 mg twice a day) in fifty Chinese patients with laboratory-confirmed COVID-19. They reported that after 2 weeks of admission, the viral load was undetectable in all the arbidol-treated patients versus in 44% of the lopinavir/ritonavir-treated group; arbidol shortened the duration of the positive RNA test compared to lopinavir–ritonavir (P < 0.01). In the trial by Li et al. that was discussed earlier under the lopinavir/ritonavir section, there was no significant benefit noted from arbidol. Thus, the efficacy of arbidol hydrochloride has not yet been established in COVID-19.
Remdesivir was formally known as GS-5734 and was discovered during the screening of antimicrobial agents against RNA viruses; it was first used for the treatment of Ebola. Its promising antiviral properties against SARS and MERS-CoV have been recognized lately. Grein et al. reported on the results of the use of remdesivir on a compassionate basis in 53 patients with severe COVID-19. Remdesivir was administered as a loading dose of 200 mg intravenously on day 1 and 100 mg daily thereafter for 9 days. However, only 75% of the patients received the complete treatment, 19% received the treatment for 5–9 days, and 6% received it for <5 days. Clinical improvement (lowering of oxygen requirement) was observed in 36 of 53 patients (68%); 57% of the patients on the ventilator were extubated. The mortality was 18% in the patients who required ventilatory support and 5% in those who did not.
The National Institutes of Health funded a randomized, adaptive, double-blind, and multicentric trial called the Adaptive COVID-19 Treatment Trial (ACTT) to evaluate the efficacy and safety profile of remdesivir in patients hospitalized with COVID-19. There were 1063 patients who were hospitalized for COVID-19 infection with radiographic infiltrates on imaging (chest X-ray, computed tomography [CT] scan, etc.), SpO2 ≤94%, or requiring oxygen supplementation or mechanical ventilation who were included. Patients in the experimental arm received 200 mg of remdesivir intravenously on day 1, followed by a 100 mg daily maintenance dose for 10 days, with time to recovery as the primary outcome. Recently, this trial, which started on February 21, 2020, has shown 31% faster recovery rates in the remdesivir arm as compared to the placebo arm (11 days in remdesivir-treated patients and 15 days in patients who received placebo; [rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P < 0.001]), as observed by the Independent Data Safety Monitoring board. The mortality at 14 days in the remdesivir arm was 7.1% vs 11.9% in the placebo arm (HR for death, 0.7; 95% CI, 0.47 to 1.04). Grade 3 and higher toxicities occurred in 28.8% of patients in the remdesivir arm and 33% of patients in the placebo arm. Thus, remdesivir shortened the time to recovery in adult patients who were hospitalized with COVID-19 pneumonia.
In the Phase III SIMPLE trial (GS-US-540-5773), remdesivir had similar efficacy when administered for 5 days as compared to 10 days in patients with severe manifestation of COVID-19 who did not require mechanical ventilation P = 0.14 on day 14. According to a multicentric randomized trial reported by Wang et al. in 237 patients with COVID-19-associated pneumonia, remdesivir (200 mg on day 1 followed by 100 mg daily for 9 days) failed to result in any significant clinical improvement (HR, 1.23; 95% CI, 0.87–1.75). The side effects reported in patients who received remdesivir included constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, and elevated bilirubin.
Remdesivir has received an emergency use authorization by the Food and Drug Administration (FDA) based on the reports from two randomized trials (ACTT and GS-US-540-5773) and the available data from the Ebola outbreak. The recommended intravenous dosage to be administered over 30–120 min is as follows.
- Patients (≥40 kg) requiring invasive mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO): a loading dose of 200 mg on day 1 followed by a maintenance dose of 100 mg daily for 9 days
- Patients (≥40 kg) not requiring invasive mechanical ventilation and/or ECMO: a single dose of 200 mg on day 1 followed by 100 mg daily for 4 days. If there is no clinical improvement, then treatment may be extended for up to 5 additional days
- Pediatric patients (3.5–39 kg) requiring invasive mechanical ventilation and/or ECMO: A single loading dose of 5 mg/kg on day 1 followed by 2.5 mg/kg daily for 9 days
- Pediatric patients (3.5–39 kg) not requiring invasive mechanical ventilation and/or ECMO: A single loading dose of 5 mg/kg on day 1 followed by 2.5 mg/kg for 4 days). If there is no clinical improvement, treatment may be extended for up to 5 additional days
Patients should have the estimated glomerular filtration rate determined (serum creatinine in neonates) prior to receiving the drug. Liver function tests should be performed in all patients prior to receiving the drug and daily during the course of treatment. Remdesivir is contraindicated in patients with hypersensitivity.
It is a prodrug of purine nucleotide, previously known as T-705, that acts by inhibiting RNA polymerase. The preclinical data are currently available in Japan and are from its activity against the influenza, Ebola, and other RNA viruses. Chen et al. in a randomized study compared the role of oral favipiravir (1600 mg twice a day on day 1 followed by 600 mg twice a day for the next 9 days) with arbidol (200 mg three times a day for 10 days) in 240 patients with COVID-19. However, there was no significant improvement in the clinical recovery after 1 week (favipiravir [61%] vs. arbidol [52%]; difference in recovery rate, 0.0954; 95% CI, −0.0305 to 0.2213; P = 0.1396) in both groups; favipiravir was associated with an increase in uric acid in 13.8%. Recently, a Phase III, multicentric trial (CTRI/2020/05/025114) has been initiated in India and has proposed to enroll about 100 patients with mild-to-moderate SARS-CoV-2 infection, to evaluate the efficacy of favipiravir with supportive care.
It is a guanine analog that acts by inhibiting viral RNA-dependent RNA polymerase. It was used extensively during the SARS outbreak, but there were concerns regarding the safety profile as it caused hemolytic anemia and is a teratogen. Owing to its activity against other coronaviruses, it can be tried in the treatment of COVID-19. Ribavirin was a part of the triple-therapy regimen in a Phase II randomized trial, which showed that the combination of ribavirin and lopinavir–ritonavir with interferon-β-1b led to a significant shortening in the duration of viral shedding. However, no clinical data are available to support its role as a single-agent antiviral against SARS-CoV-2.
It is an antiretroviral drug that acts by inhibiting the HIV protease; it has also been shown to inhibit the replication and cytopathic effect induced by SARS-CoV-2 in vitro and, therefore, can be considered a treatment option for COVID-19.,
| Chloroquine or Hydroxychloroquine|| |
These are widely used antimalarial drugs that have been reported to have antiviral properties. They act by glycosylation of receptors, acidification of endosomes, and proteolysis. A news briefing from around ten hospitals in China stated that chloroquine was successful in treating and reducing the progression of COVID-19 in more than 100 patients; additional details are awaited. Serious adverse effects are associated with chloroquine and hydroxychloroquine, including QT interval prolongation, neuropsychiatric side effects, and retinopathy in <10% of the patients. An observational study was performed by Geleris et al. in hospitalized patients with COVID-19, excluding patients who were intubated or discharged within 24 h and those who died. Hydroxychloroquine (600 mg twice a day) was given on day 1, then daily (400 mg) for 5 days. There was no significant association between the administration of hydroxychloroquine and the rate of intubation or death (HR, 1.04; 95% CI, 0.82–1.32).
Rosenberg et al. in their retrospective study on 1438 patients admitted with COVID-19 observed that there was no significant difference between the in-hospital mortality in patients receiving hydroxychloroquine alone (HR, 1.08; 95% CI, 0.63–1.85), azithromycin alone (HR, 0.56; 95% CI, 0.26–1.21), or the combination of hydroxychloroquine with azithromycin (HR, 1.35; 95% CI, 0.76–2.40).
Gao et al. stated that based on Chinese trials, chloroquine phosphate appears to be safe and effective in the treatment of COVID-19 pneumonia.
Tang et al. studied the efficacy of hydroxychloroquine (1200 mg/day for 3 days, followed by 800 mg daily for 2 weeks in patients with mild-to-moderate disease, and for 3 weeks in patients with severe COVID) compared to standard of care in 150 patients. By day 28, the hydroxychloroquine-treated patients had a negative conversion rate of 85.4% (95% CI, 73.8% to 93.8%) versus 81.3% (95% CI, 71.2% to 89.6%); difference, −4.1% (95% CI, −10.3% to 18.5%). Adverse events were significantly higher in the hydroxychloroquine-treated patients at 30% compared to those who received standard of care (9%). A study by Gautret et al., demonstrated that chloroquine significantly reduced the viral load on day 6 and decreased the oxygen requirement and need for ICU admission. In the most recent data from Mehra et al. in 96,032 patients from 671 hospitals in six continents (a multinational registry study), therapy with quinolones with or without a macrolide was associated with a higher in-hospital mortality (hydroxychloroquine, 18%; HR, 1.34; 95% CI, 1.22–1.46; hydroxychloroquine with a macrolide, 23.8%; HR, 1.45, 95% CI, 1.37–1.53; chloroquine, 16.4%; HR, 1.37, 95% CI, 1.22–1.53; and chloroquine with a macrolide, 22.2%; HR, 1.37, 95% CI, 1.27–1.47) than patients on standard therapy, who had a mortality of 9.3%. There was an increased risk of ventricular arrhythmia in patients who received the quinolones ± macrolide (standard therapy: 0.3%, hydroxychloroquine: 6.1%, hydroxychloroquine + macrolide: 8.1%, chloroquine: 4.3%, and chloroquine + macrolide: 6.5%). Due to the inability to perform an independent third-party peer review of the complete data, client contracts and the full International Organization for Standardization (ISO) audit report, the study was withdrawn by the authors and retracted by the Lancet.
Boulware et al. recently reported the results of the postexposure hydroxychloroquine trial. They randomized 821 asymptomatic patients who had either a high-risk exposure (in 87.6% patients, who had exposure at less than 6 feet for longer than 10 minutes with no face mask or an eye shield) or a moderate-risk exposure (same as above, but with a face mask) to a confirmed COVID-19 positive case and were randomized within 4 days of exposure to receive hydroxychloroquine (800mg once, then 600 mg 6 to 8 hours later, followed by 600mg orally daily for 4 days). Symptomatic COVID-19 developed in 11.8% of the hydroxychloroquine-treated persons versus 14.3% in the placebo arm, absolute difference, −2.4% (95% CI, −7 to 2.2; P = 0.35). Side-effects occurred in 40.1% of the hydroxychloroquine-treated persons (nausea, diarrhea, abdominal discomfort) versus 16.8% of the placebo-treated persons (P < 0.001), but there were no serious adverse reactions or cardiac arrhythmias.
Ongoing studies with chloroquine include NCT04303507 on prophylaxis among health-care workers, NCT04328285, and NCT04334148 (HERO-HCQ).
| Ivermectin|| |
In an observational, propensity-matched, case–controlled study on 1408 patients admitted with COVID-19, ivermectin administered as a one-time dose of 150 μg/kg reduced the in-hospital mortality (1.4% vs. 8.5%; HR, 0.2; 95% CI, 0.11–0.37; P < 0.0001), the mortality in patients who were on mechanical ventilation (7.3% vs. 21.3%), and length of hospital stay. The authors concluded that invermectin led to a decreased mortality and shorter length of hospitalization in patients hospitalized for COVID-19. Of note, this study has not yet been published in a peer reviewed journal, and must not be used to guide clinical practice.
| Antibiotics|| |
Azithromycin is a macrolide antibiotic used to treat a variety of bacterial infections that acts by interfering with protein synthesis. Gautret et al. reported that azithromycin helps to reinforce the action of hydroxychloroquine in reducing the viral load in patients infected with SARS-CoV-2. However, the study had the limitations of a small sample size and the concerns of cardiotoxicity.
| Miscellaneous Agents|| |
Interferon-α prevents the replication of human and animal coronaviruses, while interferon-β acts against MERS.,, Most of the studies in the literature report the results of the combination of interferon with ribavirin, lopinavir, or ritonavir. There are no human or animal studies demonstrating its efficacy against COVID-19.
Based on the demonstration of pulmonary microthrombi in critically ill patients who succumbed to COVID-19, it was proposed to consider anticoagulants in the management of the disease. Coagulopathy, a feature observed in COVID-19, is associated with high mortality. Mortality in patients with severe COVID-19 reduced with the use of heparin. It is recommended that all patients should receive thromboprophylaxis, unless contraindicated, preferably with low-molecular-weight heparin.,
Nitazoxanide is an anthelminthic with antiviral properties; it has demonstrated activity against SARS and MERS in vitro.
Camostat mesylate acts by inhibiting the host transmembrane protease, serine 2, (TMPRSS2), and thus prevents the entry of coronavirus into the host cell in vitro. However, its safety profile and its antiviral activity against SARS-CoV-2 warrant further studies.
Tocilizumab, a monoclonal antibody against the interleukin (IL)-6 receptor, is used as an immunosuppressive agent. According to a case series from China, significant lung damage is caused by the triggered immune response and cytokine release, and IL-6 appears to play a major role in the cytokine storm. In a small series published by Xu et al., it was observed that by day 5, 75% of the patients had reduction in the oxygen intake and C-reactive protein levels and improved lung opacities on the CT thorax. No significantly elevated levels of transaminase, neutropenia, or infection were noted. Tocilizumab improved the clinical outcomes in critically ill patients and, thus, helped to reduce the mortality. It was also effective against the cytokine storm and, therefore, benefitted patients with COVID-19.
Toclizumab has also been successful in treating patients with severe COVID-19 in civic hospitals in Mumbai. Several randomized trials are underway for this drug (tocilizumab dosed at 4–8 mg/kg intravenously or 400 mg with a single dose not exceeding 800 mg) in China (NCT04310228, ChiCTR200002976).
Sarilumab is another IL-6 receptor antagonist recommended for rheumatoid arthritis. Currently, the NCT04315298 trial is evaluating its safety and efficacy in patients with severe effects of COVID-19. The Phase II results of the trial (reported so far only in a press release) revealed that a higher dose (400 mg) of sarilumab was associated with lower mortality (23% vs. 27%), less inability to wean off the ventilator (9% vs. 27%), more hospital discharges (53% vs. 41%), and better clinical improvement (59% vs. 41%) compared to the placebo. The Phase III portion of this trial will test only the higher dose of the drug.
Other ongoing drug trials in patients with COVID-19 include NCT04280588 for fingolimod, an immunomodulator approved for multiple sclerosis; NCT04275414 for bevacizumab, an inhibitor of the vascular endothelial growth factor; and NCT04288713 for eculizumab, an antibody against the terminal complement. Based on the receptor-binding motif and sequence analysis, it was observed that SARS-CoV-2 uses the angiotensin-converting enzyme (ACE2) as a cellular entry receptor. Emodin, an anthraquinone, and promazine, an antipsychotic, compete with the binding site of ACE2 and, therefore, can abolish the action of SARS-CoV-2. Hence, these can be tried as potential therapeutic agents for COVID-19.
Valproate, when introduced early, may prevent inflammation and lung injury secondary to COVID-19 due to its antiviral and anti-inflammatory properties.
Intravenous gamma globulins (IVIGs) are perhaps the safest immunomodulators for prolonged use across all age groups. Thomas et al. used IVIG extensively during the 2003 SARS outbreak in Singapore; they found that despite using low-molecular-weight heparin, around one-third of the patients developed thromboembolic complications. Some case series have demonstrated the benefit of high-dose IVIG during the early phase of clinical deterioration; they also help to prevent further progression and improve the outcomes. IVIG, when administered as an adjuvant treatment in severely ill patients with COVID-19, can reduce the need for mechanical ventilation, improve recovery, reduce mortality, and shorten the hospital stay.
Convalescent plasma or passive immunotherapy has been tried when no specific drugs or vaccines are available for infectious diseases. Its use has also been suggested by the WHO under the Blood Regulators Network for any emerging epidemic where treatment is not yet developed. It has been found to benefit critically ill patients during the MERS and SARS outbreaks., Duan et al. reported the safety of a single dose of 200 mL of convalescent plasma obtained from persons who had recently recovered from COVID and had neutralizing antibody titers over 1:640, in ten patients with severe COVID-19. The clinical outcomes of the patients improved, and 70% of the patients had clearance of the viremia. A case series by Shen et al. demonstrated that convalescent plasma improved the clinical status of five critically ill patients with COVID-19. Ye et al. also reported that the transfusion of convalescent plasma led to resolution of the ground-glass opacities (GGOs) and consolidation in five out of six patients and virus clearing in two out of six patients. A Phase II, open-label, randomized controlled trial (NCT04374487) has been approved by the Indian Council of Medical Research to assess the efficacy and safety of convalescent plasma in patients with COVID-19. As the safety profile of convalescent plasma of patients recovered from COVID-19 is not much of a concern, the Phase I portion of the trial has been skipped. In addition, it is not necessary for a donor to test negative for COVID-19; however, resolution of symptoms for at least 2 weeks before the donation is essential. Many countries are currently conducting clinical trials for patients with COVID-19, however, concrete results regarding their actual benefit are still awaited.
Bromhexine hydrochloride is a commonly used mucolytic agent and is also used as a cough suppressant. It is known that bromhexine hydrochloride is a strong suppressor of the TMPRSS2 which plays a significant role in the cellular entry of SARS-CoV-2 via S protein activation in cell lines. Thus, bromhexine hydrochloride may be further investigated and warrants clinical trials.
Bacillus Calmette–Guérin vaccine
Based on its property to induce metabolic and epigenetic changes to confer innate immunity and its effective role in SARS, Bacillus Calmette–Guérin (BCG) has been recommended for the treatment of COVID-19.
The Drug Control General of India has given permission to start BCG trials in patients with COVID-19 in India.
Janus kinase and numb-associated kinase inhibitors
Baritinicib because of its action against various cytokines may decrease the cytokine response in COVID-19; additionally, because of its antiviral properties, it may also reduce the endocytosis of SARS-CoV-2.
Vitamins and supplements
In addition, vitamin supplements; minerals; trace elements such as iron, selenium, and zinc; and flavonoids have been recommended for the management of COVID-19.
Shuang-Huang-Lian (SHL), a Chinese herbal formula containing three herbs, namely Scutellaria baicalensis, honeysuckle, and forsythia, is a traditional patented medicine used to treat a variety of ailments. A clinical trial (ChiCTR2000029605) was started to explore the effects of SHL against COVID-19; the preliminary findings suggest that SHL may be effective, but additional studies are warranted. Glycyrrhizin, an active constituent of liquorice roots, has been reported to prevent the replication of SARS-CoV in vitro. Baicalin, a flavonoid from Radix Scutellaria, showed in vitro antiviral activity against SARS-CoV. Diarylheptanoids extracted from the bark of Alnus japonica have been found to inhibit the papain-like protease in SARS-CoV. Herbal medicines can therefore be tried to enhance the immunity against COVID-19.
In India, there is a healthy complementary co-existence of modern medicine with Ayurveda, Homeopathy, Unani, and Siddha. The Ayurvedic specialists, through the Government of India, have suggested ten measures which through a possible and potential psychoneuroimmune mechanism can help boost the immunity against COVID-19. Some of these include, practicing yoga daily; drinking warm water throughout the day; use of turmeric, coriander, and garlic; nasal application of sesame oil/ghee; oil pulling (oral rinsing with oil); steam inhalation; and the use of clove powder for relief from sore throat in patients with COVID-19. Homeopathic medicines such as arsenic album have also been recommended for the treatment of COVID-19.
The Unani traditional medicine generally suggests the use of some specific agents during epidemics to boost immunity. Drugs such as loban (Styrax benzoides W. G. Craib), sandroos (Hymenaea verrucosa Gaertn.), Za'fran (Crocus sativus L.), and vinegar have been suggested by centers such as the Jamia Hamdard, New Delhi.
| Conclusion|| |
No treatment has been definitively proven to be effective against COVID-19 to date. The only FDA-approved drug is remdesivir, and several others are under investigation. Corticosteroids and anticoagulant therapy have been recommended in patients with severe ARDS. With the limited proven efficacy of most of the drugs currently in use, it is of utmost necessity to investigate all the potential drug therapies in order to gather good-quality data amidst this pandemic.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmunity 2020;109:102433.
Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr 2020;87:281-6.
Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al
. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med Published online March 13, 2020. doi:10.1001/jamainternmed.2020.0994.
Lansbury LE, Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, Shen Lim W. Corticosteroids as adjunctive therapy in the treatment of influenza. Crit Care Med 2020;48:e98-106.
Chu CM, Cheng CC, Hung FN, Wong MM, Chan H, Chan S, et al
. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 2004;59:252-6.
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al
. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787-99.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al
. Clinical characteristics of coronavirus disease 2019 in China. N
Engl J Med 2020;382:1708-20.
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al
. Remdesivir for the Treatment of Covid-19 - Preliminary Report [published online ahead of print, 2020 May 22]. N
Engl J Med. 2020;NEJMoa2007764.
Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al
. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020. Published online April 10.DOI:10.1056/NEJMoa2007016.
Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, et al
. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 [published online ahead of print, 2020 May 27]. N
Engl J Med 2020;10.1056/NEJMoa2015301.
Chen C, Huang J, Cheng Z, Wu J, Chen S, Zhang Y, et al
. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. 2020.03.17.20037432; Apr 15, 2020.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al
. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020. doi:10.1016/j.ijantimicag.2020.105949.
Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al
. Efficacy of hydroxychloroquine in patients with COVID-19: Results of a randomized clinical trial. medRxiv. 7:2020.03.22.20040758; Apr 10, 2020.
Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al
. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci 2020;117:10970-10975. doi:10.1073/pnas.2005615117.
Zhao JP, Hu Y, Du RH, Chen ZS, Jin Y, Zhou M, et al
. Expert consensus on the use of corticosteroid in patients with 2019-nCoV pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:183-4.
Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:473-5.
Fadel R, Morrison A, Vahia A, Smith ZR, Chaudhry Z, Bhargava P, et al
. Early Short Course Corticosteroids in Hospitalized Patients with COVID-19. medRxiv; 2020.
Lewis SR, Pritchard MW, Thomas CM, Smith AF. Pharmacological agents for adults with acute respiratory distress syndrome. Cochrane Database Syst Rev 2019;7:CD004477.
Siemieniuk RA, Meade MO, Alonso-Coello P, Briel M, Evaniew N, Prasad M, et al
. Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: A systematic review and meta-analysis. Ann Internal Med 2015;163:519-28.
Alhazzani W, Hylander Møller M, Arabi YM, Loeb M, Ng Gong M, Fan E, et al
. Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Maurizio Cecconi 2020;46:854-87.
Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol 2020;92:479-90.
Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Chinese J Tuberc Respir Dis 2020;43:185-8.
Chan KS, Lai ST, Chu CM, Tsui E, Tam CY, Wong MM, et al
. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: A multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406.
Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al
. 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. Lancet 2020;395:1695-704.
Li Y, Xie Z. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: An exploratory randomized controlled trial. Med 2020. doi:10.1016/j.medj.2020.04.001.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Zhu Z, Lu Z, Xu T, Chen C, Yang G, Zha T, et al
. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect 2020;S0163-4453(20)30188-2.
Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis 2020;34:101615.
Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al
. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo controlled, multicenter trial. Lancet 2020;395:1569-78.
Administration D. Fact sheet for health care providers emergency use authorization (EUA) of remdesivir (GS-5734TM). Available from: http://www.clinicaltrials.gov
. [Last accessed on 2020 May 15].
Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Japan Acad Ser B 2017;93:449-63.
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020;323:1824-36. doi:10.1001/jama.2020.601.
Stockman LJ, Bellamy R, Garner P. SARS: Systematic review of treatment effects. Low D, editor. PLoS Med 2006;3:e343.
Yamamoto N, Yang R, Yoshinaka Y, Amari S, Nakano T, Cinatl J, et al
. HIV protease inhibitor nelfinavir inhibits replication of SARS-associated coronavirus. Biochem Biophys Res Commun 2004;318:719-25.
Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, et al
. Multidrug Treatment with Nelfinavir and Cepharanthine against COVID-19. bioRxiv; 2020.04.14.039925; Apr 15, 2020.
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14:72-3.
Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al
. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. [published online ahead of print, 2020 May 11]. JAMA 2020;e208630. doi:10.1001/jama.2020.8630.
Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al
. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. Published 2020 May 14.
Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Sevestre J,et al
. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: An observational study. Travel Med Infect Dis 2020;34:101663.
Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis [published online ahead of print, 2020 May 22] [Retracted in: Lancet. 2020 Jun 5;null]. Lancet. 2020;S0140-6736(20)31180-6.
Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al
. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 [published online ahead of print, 2020 Jun 3]. N
Engl J Med 2020;10.1056/NEJMoa2016638. doi:10.1056/NEJMoa2016638.
Pei J, Sekellick MJ, Marcus PI, Choi IS, Collisson EW. Chicken interferon type i inhibits infectious bronchitis virus replication and associated respiratory illness. J Interf Cytokine Res 2001;21:1071-7.
Turner RB, Felton A, Kosak K, Kelsey DK, Meschievitz CK. Prevention of experimental coronavirus colds with intranasal alpha-2b interferon. J Infect Dis 1986;154:443-7.
Morra ME, Van Thanh L, Kamel MG, Ghazy AA, Altibi AMA, Dat LM, et al
. Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis. Rev Med Virol 2018;28:e1977.
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020;18:1094-9.
Thachil J. The versatile heparin in COVID-19. J Thromb Haemost 2020;18:1020-2.
Spyropoulos AC, Ageno W, Barnathan ES. Hospital-based use of thromboprophylaxis in patients with COVID-19. Lancet 2020;395:e75.
Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health 2016;9:227-30.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al
. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is Blocked By A Clinically Proven Protease Inhibitor. Cell 2020;181:271-80.e8.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al
. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395:1054-62.
Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;10.1002/jmv.25801. doi:10.1002/jmv.25801.
Ho TY, Wu SL, Chen JC, Li CC, Hsiang CY. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res 2007;74:92-101.
Bhargava P, Panda P, Ostwal V, Ramaswamy A. Repurposing valproate to prevent acute respiratory distress syndrome/acute lung injury in COVID-19: A review of immunomodulatory action. Cancer Res Stat Treat 2020;3 Suppl S1:S65-70.
Lew TW, Kwek TK, Tai D, Earnest A, Loo S, Singh K, et al
. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003;290:374-80.
Cao W, Liu X, Bai T, Fan H, Hong K, Song H, et al
. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis 2020;7:ofaa102.
Xie Y, Cao S, Dong H, Li Q, Chen E, Zhang W, et al
. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect 2020;S0163-4453(20)30172-9. doi:10.1016/j.jinf.2020.03.044.
Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG, Al-Omari A, et al
. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: A study protocol. Springerplus 2015;4:1-8.
Cheng Y, Wong R, Soo YO, Hong Kong Red LC. Use of convalescent plasma therapy in SARS patients in Hong Kong Research correlation HDI with Poverty View project Simplified method for evaluating the effects of adjacent excavation on shield tunnel considering the shearing effect View project. Artic Eur J Clin Microbiol 2005;24:44-6.
Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al
. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-6.
Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J,et al
. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9.
Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al
. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020. https://doi.org/10.1002/jmv.25882
Habtemariam S, Nabavi SF, Ghavami S, Cismaru CA, Neagoe IB, Nabavi SM. Possible use of the mucolytic drug, bromhexine hydrochloride, as a prophylactic agent against SARS-CoV-2 infection based on its action on the Transmembrane Serine Protease 2. [published online ahead of print, 2020 Apr 30]. Pharmacol Res 2020;157:104853. doi:10.1016/j.phrs.2020.104853.
Netea MG, Domínguez-Andrés J, Barreiro LB, Chavakis T, Divangahi M, Fuchs E, et al
. Defining trained immunity and its role in health and disease. Nat Rev Immunol 2020;20:375-88.
Cantini F, Niccoli L, Matarrese D, Nicastri E, Stobbione P, Goletti D. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. [published online ahead of print, 2020 Apr 23]. J Infect 2020;S0163-4453(20)30228-0.
Zhang L, Liu Y. Potential interventions for novel coronavirus in China: A systematic review. J Med Virol 2020;92:479-90.
Ni L, Zhou L, Zhou M, Zhao J, Wen Wang D. Combination of western medicine and Chinese traditional patent medicine in treating a family case of COVID-19 in Wuhan. Front Med 2020;14:210-4
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003;361:2045-6.
Chen F, Chan KH, Jiang Y, Kao RY, Lu HT, Fan KW, et al
. In vitro
susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004;31:69-75.
Park JY, Jeong HJ, Kim JH, Kim YM, Park SJ, Kim D, et al
. Diarylheptanoids from Alnus japonica
inhibit papain-like protease of severe acute respiratory syndrome coronavirus. Biol Pharm Bull 2012;35:2036-42.
Rajkumar RP. Ayurveda and COVID-19: Where psychoneuroimmunology and the meaning response meet. Brain Behav Immun 2020. pii: S0889-1591(20)30637-1.
Parikh DP, Parikh N, Parikh D. Role of homoeopathy in covid-19 management-a clinical experience. Artic World J Pharm Res [Internet]. 2020;9:2459-66.
Nikhat S, Fazil M. Overview of COVID-19; its prevention and management in the light of Unani medicine. Sci Total Environ 2020;728:138859.