Author: Chase Doyle
In less than four months, research scientists and health professionals have identified a novel coronavirus, sequenced its genome, charted the clinical course of disease it causes, and begun trials for investigational vaccines and treatments. Unfortunately, in that same time span, the virus has infected hundreds of thousands around the world, wreaking havoc on health care systems and the global economy.
Thus far, there are no approved therapies for COVID-19, the respiratory illness caused by SARS-CoV-2, but clinicians are exploring a myriad of treatment options, including drugs approved to treat malaria, lupus, rheumatoid arthritis, HIV and Ebola.
Of note, not all people who contract the disease require treatment. According to data presented by Bin Cao, MD, in an American College of Cardiology webinar held in partnership with the Chinese Cardiovascular Association, approximately 80% of confirmed COVID-19 cases involve mild symptoms, ranging from completely asymptomatic disease to mild pneumonia (ACC/Chinese Cardiovascular Association COVID-19 Webinar 1. Presented March 18, 2020).
For the remaining cases that progress to severe (14%) and critically ill (5%) status, however, clinicians must be prepared to treat severe pneumonia, respiratory failure requiring mechanical ventilation, shock, and multiorgan failure requiring admission to the ICU.
COVID-19 Is a Systemic Disease
Dr. Cao, who has been treating patients on the front lines in Wuhan, China, emphasized that COVID-19 is neither a localized disease nor limited to the respiratory tract. Severe and critical cases are not only associated with pneumonia and acute respiratory distress syndrome but also metabolic acidosis, acute kidney injury and acute cardiac injury. He cautioned health care providers to watch for the latter in particular.
“We have to keep in mind that severe and critical cases will have acute cardiac injury, and some of these may be complicated with myocardial infarction,” said Dr. Cao, a professor of pulmonary and critical medicine at the China-Japan Friendship Hospital and Capital Medical University, in Beijing. “Keep a close eye on patients with underlying cardiovascular diseases or hypertension because they’re at risk for cardiac complications.”
Another common finding among severe and critical patients is abnormal coagulation. As Dr. Cao reported, significantly increased levels of D-dimer and fibrinogen/fibrin degradation products have been associated with poor prognosis, and extensive intravascular microthrombosis was discovered in fatal COVID-19 cases on autopsy (Lancet. 2020 Mar 11. [Epub ahead of print]. doi: 10.1016/S0140-6736(20)30566-3). Because vascular endothelial cells express high levels of angiotensin-converting enzyme 2, anticoagulation therapy should be initiated for patients with severe COVID-19 unless otherwise contraindicated, he said.
Peripheral lymphocyte counts, mainly T cells, also were substantially reduced in patients with severe COVID-19, with severe lymphopenia observed until death in nonsurvivors. For survivors, on the other hand, lymphocyte count was lowest on day 7 after onset of illness and improved during hospitalization. In addition, sepsis occurred in more than half of Wuhan inpatients with COVID-19. Although sepsis is usually associated with bacterial infections, no bacterial pathogens were detected in patients on admission, said Dr. Cao, who theorized that sepsis might be directly caused by SARS-CoV-2 infection.
“This is not a lung disease; it’s a whole-body disease,” he explained. “The virus has been detected in nasopharyngeal swabs, sputum, lower respiratory tract secretions, blood and feces using RT-PCR [real-time polymerase chain reaction] and/or NGS [next-generation sequencing] methods. Thus, it’s not surprising that we see viremia in severe cases because this disease can spread from the lungs to other organs, including the heart.” According to Dr. Cao, the median duration of viral shedding was 20 days, but it could be as long as 37 days, which has “never been seen before” in an acute respiratory viral infection.
Isolation and Supportive Care
The approach established by Dr. Cao and his colleagues in Wuhan has been two-pronged: isolation of confirmed patients in a single room to contain the spread of the virus, followed by treatment. Although the disease is not limited to the lungs, severe disease (seen in 14% of patients) is characterized by dyspnea, hypoxia or greater than 50% lung involvement on imaging within 24 to 48 hours. For the 5% of patients who progress to critically ill status, respiratory failure, shock or multiorgan dysfunction are possible clinical outcomes.
According to a primer drafted by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Acute Care Committee, however, early data suggest that the majority of critically ill patients are suffering from only hypoxia and “only require management of hypoxemia using Positive End Expiration Pressure (PEEP), FiO2, and possibly prone positioning.” Although other underlying chronic illnesses must be treated accordingly, the effect of COVID-19 appears to be mostly hypoxemia, albeit profound. Lung lesions also are peripheral and ground glass in appearance, the authors of the primer noted.
For providers with no COVID-19 testing available, chest imaging may help with the diagnosis. However, Dr. Cao cautioned that deterioration can occur rapidly—sometimes within a few hours.
“You cannot imagine how fast deterioration can occur,” Dr. Cao said. “We have observed patients in stable condition in the morning progress rapidly to respiratory failure by the afternoon. Close monitoring of vital signs and lab work is essential.” Equally essential for providers is personal protective equipment to shield themselves from respiratory droplets spread from patients (www.cdc.gov/coronavirus/2019-ncov/hcp/ppe-strategy/index.html).
According to the SAGES Acute Care Committee, gowns and gloves for contact isolation and face protection will work when intubation is necessary, but patients with COVID-19 often require more than respiratory support. Treating the disease is truly a multidisciplinary effort, said Dr. Cao, who noted that circulatory support, renal replacement therapy, convalescent plasma treatment, blood purification treatment and immunotherapy are commonly used among other therapeutic measures. Most patients hospitalized with COVID-19 are also complicated with hypoproteinemia, he added, so treatment should be complemented with sufficient caloric intake as well as fluid and electrolyte balance.
Dr. Cao also reported that use of corticosteroids is still controversial and should be reserved only for patients with rapid progressive deterioration of oxygenation and excessive inflammation. According to Dr. Cao, corticosteroids should be limited to short-term use (three to five days) and at a low to moderate dosage, and should not be used in patients with the following contraindications: allergy; uncontrolled diabetes; uncontrolled hypertension; glaucoma; gastrointestinal bleeding; immunodepression; a lymphocyte count of less than 300 cells/mcL; and severe bacterial and/or fungal infections.
While various news reports have stated that the use of nonsteroidal anti-inflammatory drugs, such as ibuprofen, could worsen COVID-19 symptoms, the FDA has found no scientific evidence to support these claims.
Finally, for the vast majority of patients who recover from the disease, Dr. Cao recommended the following discharge criteria: resolution of fever for at least 72 hours without the use of fever-reducing medications; improvement in respiratory symptoms; and ensuring that at least seven days have passed since symptoms first appeared. Per the CDC, a test-based strategy for discharge requires two consecutive negative nucleic acid tests for respiratory specimens collected 24 hours apart.
Although clinical trials of investigational vaccines
for COVID-19 have already begun, approval of a vaccine and widespread inoculation could be more than a year away. Finding other medical countermeasures to treat and prevent the disease will thus play a critical role in managing the pandemic.
Chloroquine and Hydroxychloroquine
According to the CDC, there are several hundred clinical trials for COVID-19 underway around the world. Two FDA-approved oral prescription drugs, chloroquine and hydroxychloroquine, have shown activity in vitro against SARS-CoV, SARS-CoV-2 and other coronaviruses, with hydroxychloroquine having relatively higher potency against SARS-CoV-2, the virus that causes COVID-19 (Int J Antimicrob Agents 2020 Mar 4. [Epub ahead of print]. doi: 10.1016/j.ijantimicag.2020.105932).
Although chloroquine has been used for malaria treatment and chemoprophylaxis, hydroxychloroquine is used for treatment of rheumatoid arthritis, systemic lupus erythematosus and porphyria cutanea tarda. In a March 19 press release, the FDA highlighted its collaboration with government agencies and academic centers to determine the effectiveness of chloroquine and hydroxychloroquine in patients with mild to moderate disease to reduce the duration of symptoms and viral shedding. Optimal dosing and duration of either agent for prophylaxis or treatment of SARS-CoV-2 infection have not been identified, but data from multicenter clinical trials conducted in China showed apparent efficacy and safety in treatment of COVID-19-associated pneumonia (Biosci Trends 2020;14:72-73). A small study in France also reported that hydroxychloroquine alone or in combination with azithromycin significantly reduced viral load in nasal swabs compared with a nonrandomized control group (Int J Antimicrob Agents. In press) although clinical benefit was not assessed.
Per the CDC, some U.S. clinicians have reported anecdotally different hydroxychloroquine dosing: 400 mg twice daily on day 1, then daily for five days; 400 mg twice daily on day 1, then 200 mg twice daily for four days; and 600 mg twice daily on day 1, then 400 mg daily on days 2 to 5. In patients with chronic medical conditions such as renal failure or hepatic disease, the CDC advised caution when considering hydroxychloroquine and azithromycin due to association with QT prolongation (Clin Infect Dis 2020 Mar 9 [Epub ahead of print]).
Originally developed to treat the Ebola virus, remdesivir is an investigational IV drug that’s also demonstrated in vitro activity against coronaviruses, including SARS-CoV-2. Although remdesivir was found to have no effect against Ebola, a case report published in The New England Journal of Medicine showed improved clinical condition and subsequent recovery in a critically ill Californian patient with COVID-19 who was administered the antiviral on a compassionate use basis (2020;382(10):929-936). Gilead Sciences, the company that manufactures remdesivir, is developing an expanded access program for the United States to meet what the company described as “overwhelming demand” for the experimental drug.
According to the FDA, approximately 250 patients have already been granted access to remdesivir, but controlled clinical trials are needed to determine its efficacy and safety. The CDC listed several options for obtaining remdesivir for treatment of hospitalized patients with COVID-19, including a National Institutes of Health–sponsored adaptive double-blind, placebo-controlled trial of remdesivir versus placebo in patients with pneumonia and hypoxia (https://clinicaltrials.gov/ct2/show/NCT04280705) and two phase 3, randomized, open-label trials in patients with severe disease (https://clinicaltrials.gov/ct2/show/NCT04292899) or moderate disease (https://clinicaltrials.gov/ct2/show/NCT04292730).
Lopinavir and Ritonavir
Approved nearly 20 years ago for the treatment of HIV, the combination of lopinavir and ritonavir has been shown to inhibit the protease of viruses, including coronaviruses. Recently published clinical trial data from China, however, have not been promising against COVID-19. In a randomized study of 199 adult patients hospitalized with severe disease, the addition of lopinavir-ritonavir to standard supportive care was not associated with clinical improvement or a reduction in viral loads versus standard care alone (N Engl J Med 2020 Mar 18. [Epub ahead of print]. doi: 10.1056/NEJMoa2001282). Nevertheless, the study authors cautioned that the overall mortality of the trial (22.1%) was substantially higher than rates observed in other studies of hospitalized patients with COVID-19.
What’s more, secondary outcomes demonstrated lower 28-day mortality (19.2% vs. 25.0%) and shorter stays in the ICU (six vs. 11 days) for patients in the lopinavir-ritonavir group versus standard of care. Because the difference in mortality was also greater among patients treated within 12 days after the onset of symptoms compared with those treated later, the investigators hypothesized that utilization of lopinavir-ritonavir at an earlier stage of illness could lead to better responses.
Despite the Chinese study’s negative outcome, lopinavir-ritonavir is still under investigation in a World Health Organization study. Announced on March 18, the large, international SOLIDARITY trial will compare untested treatments in thousands of patients from at least 10 countries. In a media briefing on the pandemic, WHO Director-General Tedros Ghebreyesus, PhD, said, “Multiple small trials with different methodologies may not give us the clear, strong evidence we need about which treatments help to save lives.” As Dr. Ghebreyesus explained, the SOLIDARITY trial is designed to “provide simplified procedures to enable even hospitals that have been overloaded to participate.”
One arm of SOLIDARITY will test lopinavir-ritonavir against standard of care, while another will combine the two antivirals with interferon beta-1b, an anti-inflammatory agent used to treat multiple sclerosis. WHO will also test chloroquine/hydroxychloroquine and remdesivir, although the design of the trial is subject change at any time.
Other Potential Therapies and Drug Safety Information
Time may be of the essence to discover more effective strategies against the virus, but the number of potential therapies is not in short supply. Genomic analysis of SARS-CoV-2 has already generated a list of nearly 70 FDA-approved drugs that target human proteins or host factors associated with its viral replication (BioRxiv [Epub Mar 22, 2020]. doi.org/10.1101/2020.03.22.002386). In the American College of Cardiology webinar, Dr. Cao presented several options that are being employed:
- Interferon alpha: 5 million units, atomization inhalation twice daily.
- Ribavirin: used together with interferon or lopinavir-ritonavir, 500 mg IV injection twice or three times daily, but no longer than 10 days.
- Arbidol: 200 mg three times daily for adults, but no longer than 10 days.
- Convalescent plasma treatment: infusion dose of 200 to 500 mL (4-5 mL/kg), two infusions.
- Favipiravir, a Japanese influenza drug approved by China to treat symptoms of COVID-19. As Dr. Cao acknowledged, there is no solid evidence of efficacy for any of these approaches, and clinicians must be mindful of treatment-related adverse events. Despite the need for more effective therapeutic measures, there is no shortcut for the scientific method.
“Rigorous clinical trials in the setting of COVID-19 will ultimately delineate ‘pearls’ for any drugs that may be considered for this disease,” said Bonnie A. Falcione, PharmD, BCPS (AQ-ID), an associate professor of pharmacy and therapeutics at the University of Pittsburgh School of Pharmacy. “Otherwise, contemporary pearls for agents currently being utilized stem from their recognized safety concerns when they have been used for different diseases. These safety-related pearls cannot be compared without data from well-designed comparative clinical trials, may not be relevant for durations of therapy that differ from the diseases they have historically been used for, and certainly cannot be considered as an all-inclusive list.”
That said, Dr. Falcione noted that providers administering hydroxychloroquine to treat COVID-19 should be aware of the potential for cardiotoxicity, gastrointestinal toxicity and retinopathy, while drug interaction, gastrointestinal toxicity and hepatoxicity have been described with lopinavir-ritonavir.
Experience to derive pearls with remdesivir, however, is limited because of its investigational and compassionate use to date. Lastly, Dr. Falcione said, in some critically ill patients, absorption of any enterally administered drugs may be compromised or unreliable. Hydroxychloroquine and lopinavir-ritonavir do not have parenteral formulations available to avoid this possible problem, she concluded.