Current Research on Medications for COVID-19
July 21, 2020
After a new study from the United Kingdom (UK) was published in June, the World Health Organization (WHO) stated that “dexamethasone, a corticosteroid, can be lifesaving for patients who are critically ill with COVID-19."
This article will review the following medications in the treatment of COVID-19:
The role of ACE inhibitors and ARBs
After a new study from the United Kingdom (UK) was published in June, the World Health Organization (WHO) stated that “dexamethasone, a corticosteroid, can be lifesaving for patients who are critically ill with COVID-19” (1).
In severe cases of COVID-19 disease, the body's immune system overreacts to the virus and mounts an attack on the cells that contain it. This is known as a cytokine storm, where chemicals called cytokines are released by cells of the immune system, causing excessive inflammation (5).
Dexamethasone is a steroid-based anti-inflammatory drug that acts on the immune system to dampen the response and reduce the cytokine storm (5). Dexamethasone prevents the massive inflammation seen in the lungs and the heart, which are responsible for severe respiratory problems in acutely ill patients in ICU or who have been intubated (5).
The results of the trial, which have not yet been published in a peer-reviewed journal, show the largest benefit in those patients on ventilators, where dexamethasone reduced the risk of death from 40 to 28 percent. For those requiring oxygen, there was a reduction from 25 to 20 percent (5).
Convalescent plasma (CP)
Convalescent plasma (CP) for the treatment of infectious diseases has been used since the early 20th century for diseases like SARS and H1N13 flu (3). The procedure in each study was either a meta-analysis of data or a case study (3). In the early stages of these studies, the use of convalescent plasma in patients with coronavirus disease (2019) COVID-19 has suggested a possible benefit (3).
A study looking for improvement of clinical symptoms like fever, cough, shortness of breath, and chest pain, showed that “All symptoms in the ten patients, especially fever, cough, shortness of breath, and chest pain, disappeared or largely improved within 1-3 days upon CP transfusion. There was a reduction of pulmonary lesions on chest CT examinations. According to chest CTs, all patients showed different degrees of absorption of pulmonary lesions after CP transfusion” (4).
In the study, 61 patients were diagnosed with severe COVID-19 and treated with at least one dose of CP. A total of 25 of the 61 patients were discharged, and seven patients died. This puts the mortality rate at 18% among the patients who were on external ventilators and critically ill (4). For patients who were not on mechanical ventilators, 1 out of 19 died, which is a 5% mortality rate (4). Randomized clinical trials, including a control group and ten patients, was formed by a random selection of 10 patients from the cohort treated in the same hospitals and matched by age, gender, and severity of the disease (4). Baseline characteristics of patients between the CP treatment group and control group matched, while the clinical outcome of the two groups was different. In the CP group, 3 cases were discharged, and seven cases were in much-improved status and ready for discharge. Comparatively, the control group reported three deaths, 6 cases in stabilized status, and 1 case in improvement (4). Data from these studies show positive results in the use of convalescent plasma for the treatment of COVID-19 (4).
In a study with compensated use of Remdesivir, 36 of 53 patients either clinically improved or decreased the duration of the disease (5). Remdesivir is a nucleotide analog that inhibits RNA polymerase, which decreases the activity of the virus in vitro (5). The design of the study included following up on patients at a median of 18 days (13-23 day range). The results showed improvement in all the patients who were on ambient air or receiving low-flow supplemental oxygen (5).
Management of Patients with COVID-19 and Other Comorbidities
A retrospective study of 112 COVID-19 patients with diabetes, cardiovascular disease, or chronic kidney disease, was analyzed in regards to ACE receptors (6). This study suggests that patients with pneumonia due to COVID-19, who continued to take ACE inhibitors, had reduced rates of death and intubation (6). This study was conducted because of the concern that increased expression of ACE-2 receptors could increase the risk of infection with SARS-CoV-2 (6). The researchers also found that there was no significant difference in the proportion of ACEI/ARB medication between non-survivors and survivors of COVID-19 (6).
The ACE-2 receptor, the binding site for SARS-CoV-2, is expressed in several locations outside of the lungs, mainly in the gastrointestinal tissue, renal tubules and Leydig cells in the testis. This might be associated with the extrapulmonary manifestations and possible complications seen in COVID-19 (6). A significant number of patients with COVID-19 reported diarrhea, vomiting, and abdominal pain. This is due to the fact that ACE-2 is highly expressed in the small intestinal epithelium (6).
Patients with chronic kidney disease and those who have received renal transplants are at increased risk of COVID-19 infection and severity. Moreover, there are frequent renal function abnormalities and increased incidence of acute kidney injury in patients with COVID-19. It is not clear whether it is from the effects of sepsis or due to the nephrotoxicity of the virus itself (6).
Cardiac troponin I levels are significantly increased in patients with severe SARS-CoV-2 infection in comparison to those with milder forms of the disease. This may be similar to what is observed in many patients with acute respiratory illnesses, or it may indicate myocardial injury because of the virus as ACE-2 receptors are widely expressed in cardiomyocytes (6).
Toclizumab in Patients with COVID-19
Toclizumab (TCZ) is an IL-6 r-mab that was used for the treatment of COVID-19. In a retrospective study in treating severe or critical COVID-19 with TCZ and basic antiviral treatment, 20 patients were given 400 mg once intravenously (7). Within a few days, 75% showed improvement in oxygenation (7). Fifty-two percent of patients had lymphocytes return to the normal value (7). This data suggests that TCZ can be used for the treatment of severe COVID-19 patients (7). Until now, many clinical trials have registered the safety and efficacy of the TCZ treatment for novel coronary pneumonia (NCP) (7).
HCQ in hospitalized patients with COVID-19.
Overall, in the observational study performed in a large medical center in New York City, 346 patients (25.1%) had a primary end-point event, 180 patients were intubated, of whom 66 died, and 166 died without intubation (8). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32) (8). HCQ administration was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. Further studies are needed (8).
Hydroxychloroquine in COVID-19
There have been many observational studies and few randomized control trials on the efficacy of hydroxychloroquine (HCQ) in the treatment of COVID-19 (9). In one study, 2,354 patients received hydroxychloroquine alone or in combination with azithromycin, while 1,952 did not. The overall mortality rate was not significantly different from those who received HCQ compared to the control group (9). Clinical worsening or lack of symptom improvement and viral clearance assessed by RT-PCR did not vary significantly between both groups. “Evolution of changes on chest CT imaging was reported only in two studies; a more pronounced improvement was observed with the use of hydroxychloroquine compared to standard care” (9). The result of this meta-analysis was that there was not much improvement in clinical progression, mortality, or viral load clearance as reviewed by RT-PCR among patients with COVID-19 and treated with HCQ. There were more adverse reactions to HCQ reported (9).
Hydroxychloroquine and azithromycin as a treatment of COVID-19
The use of azithromycin and hydroxychloroquine (HCQ), in combination, was found to be efficient in the treatment against the SARS-CoV-2 virus in COVID-19 patients. In one study evaluating the role of HCQ on viral loads, six patients were asymptomatic, 22 had upper respiratory tract infection symptoms, and eight patients had lower respiratory tract infection symptoms (10). Twenty cases were treated and showed a significant decrease in the viral carriage on the sixth day compared to controls. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination (10). HCQ treatment is strongly associated with viral load disappearance in COVID-19 patients, and its effect is reinforced by azithromycin (10). With a 50% efficacy of HCQ in reducing the viral load on the seventh day, an 85% power, a type I error rate of 5%, and 10% loss to follow-up, the study calculated that a total of 48 COVID-19 patients would be necessary for the trial (10). The proportion of patients who had negative PCR significantly differed between treated patients and the control group on days 3-4-5 and six post-inclusion. At day 6 post-inclusion, 70% of HCQ-treated patients were virologically cured compared with 12.5% in the control group (p= 0.001) (10). On day 6, 100% of patients treated with the HCQ and azithromycin combination were virologically cured compared to 57.1% of patients treated with HCQ only and 12.5% in the control group (p<0.001) (10). The combination of HCQ and azithromycin shows promising results in the treatment of COVID-19.
1. Chaib, Fadela. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients [Internet]. World Health Organization. 2020. Available from: https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients
2. David C Gaze. Dexamethasone: What is the breakthrough treatment for COVID-19? [Internet]. 2020. Available from: https://medicalxpress.com/news/2020-06-dexamethasone-breakthrough-treatment-covid-.html
3. Casadevall A, Joyner MJ, Pirofski L-A. A Randomized Trial of Convalescent Plasma for COVID-19—Potentially Hopeful Signals. JAMA [Internet]. 2020 Jun 3 [cited 2020 Jun 17]; Available from https://jamanetwork.com/journals/jama/fullarticle/2766940
4. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. The feasibility of convalescent plasma therapy in severe COVID-19 patients: a pilot study [Internet]. Infectious Diseases (except HIV/AIDS); 2020 Mar [cited 2020 Jun 17]. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.03.16.20036145
5. 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 Jun 11;382(24):2327–36.
6. Gupta R, Misra A. Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infection with reference to use of therapeutic and other drugs used in Co-morbid diseases (Hypertension, diabetes etc). Diabetes Metab Syndr Clin Res Rev. 2020 May;14(3):251–4.
7. Zhang W, Zhao Y, Zhang F, Wang Q, Li T, Liu Z, et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. Clin Immunol. 2020 May;214:108393.
8. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Jun 18;382(25):2411–8.
9. Chacko J, Brar G, Premkumar R. Hydroxychloroquine in COVID-19: A systematic review and meta-analysis [Internet]. Infectious Diseases (except HIV/AIDS); 2020 May [cited 2020 Jun 23]. Available from: http://medrxiv.org/lookup/doi/10.1101/2020.05.14.20101774
10. Gautret P, Lagier J-C, 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 Mar;105949.