Potential Therapeutic Options for Coronavirus Disease 2019: Using Knowledge of Past Outbreaks to Guide Future Treatment
In December 2019, the first cases of a novel coronavirus infection, termed coronavirus disease 2019 (COVID-19), were reported in Wuhan, China. This virus, known as 2019-nCoV, has since spread globally, causing significant morbidity and mortality. Human coronaviruses such as 229E, OC43, NL63, and HKU1 typically result in mild, self-limiting upper respiratory tract infections. However, other variants, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the current 2019-nCoV, have higher transmission rates and can cause severe respiratory syndrome and death.
These three coronaviruses share similarities in their genomic, clinical, and pathologic features. They all belong to the beta-coronavirus genus, with MERS-CoV in lineage C and SARS-CoV and 2019-nCoV in lineage B. The origin of these viruses is thought to be zoonotic, with bats as the likely natural reservoir. MERS-CoV uses dipeptidyl peptidase 4 as its primary entry receptor, which is expressed in the human lower respiratory tract, kidneys, and T-cells but not in the upper respiratory tract. This may explain MERS-CoV’s lower transmission rate and higher mortality rate compared to SARS-CoV. In contrast, 2019-nCoV uses angiotensin-converting enzyme 2 (ACE2) as its primary receptor, which is widely expressed in the respiratory tract on epithelial cells, alveolar monocytes, and macrophages. This receptor usage may contribute to 2019-nCoV’s higher transmission rate and lower mortality rate compared to MERS-CoV and SARS-CoV.
COVID-19 symptoms range from fever, cough, myalgia, and fatigue to severe acute respiratory distress syndrome leading to death. The virus spreads through close contact, primarily via respiratory droplets from coughs and sneezes. The World Health Organization (WHO) estimates the mortality rate of COVID-19 to be around 2%, significantly lower than the >10% and >35% rates for SARS and MERS, respectively. As of the current data, over 90,000 people have been infected, and more than 3,000 deaths have been reported, surpassing the numbers seen in SARS and MERS outbreaks.
The WHO recommends supportive therapies for treating COVID-19 symptoms, as specific treatments for the disease are not yet established. However, several direct treatments have been applied in clinics within China, including interferon (IFN)-a, lopinavir/ritonavir, ribavirin, chloroquine phosphate, Arbidol, and traditional Chinese medicine. Clinical experience has shown some benefits from treatments such as chloroquine phosphate and convalescent-phase plasma from recovered patients, but there is no robust evidence from large clinical trials to support the efficacy and safety of these therapies.
Efforts to investigate the history of treatments for similar outbreaks are essential to extrapolate potential direct antiviral therapies for COVID-19. Since 2019-nCoV shares phylogenetic traits with SARS-CoV and MERS-CoV, antiviral treatments used for these viruses may provide insights into future COVID-19 therapies.
Ribavirin, an antiviral drug, was used during the SARS outbreak, but its efficacy remains controversial. Some studies reported that ribavirin, combined with corticosteroids, resolved fever and lung opacities within two weeks. However, significant toxicity was reported in other cases, and ribavirin did not show clinical improvement in MERS-CoV patients. A retrospective cohort study found no difference in survival at 28 days between MERS patients treated with ribavirin and IFN and those who received no treatment. Therefore, ribavirin may not be beneficial for COVID-19 treatment.
Lopinavir/ritonavir, an HIV antiretroviral drug, has shown beneficial effects in SARS and MERS patients. In vitro studies demonstrated that lopinavir/ritonavir inhibits the SARS-CoV protease 3CLPro. Initial treatment with lopinavir/ritonavir in SARS patients was associated with lower intubation rates, fewer adverse clinical events, and reduced mortality compared to ribavirin and corticosteroids. In a single MERS patient, a triple-combination therapy of ribavirin, IFN, and lopinavir/ritonavir resolved viremia within two days. Currently, a placebo-controlled, double-blind randomized controlled trial is ongoing to evaluate the efficacy of lopinavir/ritonavir in MERS. Reports from China and Korea suggest that lopinavir/ritonavir improved recovery and reduced viral load in COVID-19 patients. However, another study found no clinically significant improvement in mild COVID-19 cases treated with lopinavir/ritonavir and Arbidol. These conflicting results indicate that further research is needed to determine the efficacy of lopinavir/ritonavir for COVID-19.
Remdesivir, a broad-spectrum antiviral nucleotide analog, has shown potent activity against diverse RNA viruses, including Ebola virus, SARS-CoV, and MERS-CoV. In a MERS-infected mouse model, a combination of remdesivir and IFN-b was superior to lopinavir/ritonavir in reducing lung viral load and restoring pulmonary function. In vitro studies demonstrated that remdesivir inhibits 2019-nCoV at lower concentrations than ribavirin. The first COVID-19 patient in the United States treated with intravenous remdesivir showed clinical improvement by the next day with no adverse effects. These findings suggest that remdesivir may be effective at controlling viral infections at lower concentrations than existing treatments. Two clinical studies are currently evaluating the efficacy of remdesivir and lopinavir/ritonavir in COVID-19 patients.
Type-I interferons (IFN-a and IFN-b) play key roles in viral innate immunity. Both SARS-CoV and MERS-CoV evade or inhibit IFN signaling, allowing uncontrolled viral replication and systemic inflammation. In vitro studies showed that exogenous IFN-a and IFN-b reduced viral replication in SARS-CoV, with IFN-b being 5 to 10 times more potent than IFN-a. In a MERS-infected rhesus macaque model, IFN-a-2a and ribavirin dual therapy reduced systemic inflammation and viral replication, improving outcomes compared to untreated macaques. IFN-b alone showed more potent inhibition of MERS-CoV in vitro than IFN-a-2a and ribavirin. These findings suggest that type-I IFNs, particularly IFN-b, may be effective in a time-dependent manner in reducing viral replication of SARS-CoV, MERS-CoV, and potentially COVID-19.
Pneumonia and lung inflammation are common clinical features in severe COVID-19, SARS-CoV, and MERS-CoV infections. Higher levels of pro-inflammatory markers were detected in ICU-admitted COVID-19 patients compared to non-ICU patients. Corticosteroids have been used to combat inflammation in SARS, MERS, and COVID-19, but their use is controversial. In SARS and MERS, corticosteroid use was associated with adverse outcomes and delayed viral clearance. In COVID-19, 22% of patients in one cohort received corticosteroid treatment, but the efficacy of corticosteroids in coronavirus infections remains uncertain. Other anti-inflammatory options should be explored.
Artificial intelligence has identified baricitinib, an existing therapy, as a potential host-targeted treatment for COVID-19. Baricitinib is predicted to prevent viral endocytosis in lung cells and could be combined with lopinavir/ritonavir or remdesivir. The integration of new technologies will improve the response to emerging outbreaks like COVID-19.
In the future, efforts to control human-to-human transmission, such as preventing close contact, promoting hygienic practices, and educating the public, should continue. Additionally, measures to strengthen healthcare infrastructure will improve response times and limit the spread of emerging zoonotic diseases.
DOI: 10.1097/CM9.0000000000000816
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