EXECUTIVE SUMMARY

There is much more to learn about COVID-19, but from early data, investigators report the illness can cause a spectrum of disease presentations, ranging from no symptoms to severe pneumonia and death.

In a review of 44,000 patients with the disease in China, about 80% were noted to have mild disease, including patients with and without pneumonia. About 20% were classified as severely or critically ill.

The data from China show older patients with COVID-19 are particularly vulnerable to severe outcomes. The mortality rate was about 4% for patients age 60 to 69 years, 8% for patients age 70 to 79 years, and 15% for patients older than age 80 years.

Newer data from a group in the United States show 38% of patients who were sick enough to be hospitalized were younger than age 55 years, although the most severe outcomes occurred in older patients.

While no therapeutics have yet been approved for the treatment of COVID-19 in the United States (as of press time), there are some promising agents under study. These include remdesivir, an antiviral agent originally developed for Ebola, and both hydroxychloroquine and chloroquine, two drugs already approved for use in the treatment of malaria, rheumatoid arthritis, lupus, and some other inflammatory conditions.


While researchers are collecting data on patients in the United States, most information regarding the presentation and management of COVID-19 is from China and is largely limited to patients who were hospitalized with the virus.

Still, more information is coming out regarding patients with milder symptoms and those who are asymptomatic, according to Angela Campbell, MD, MPH, FPIDS, FIDA, a medical officer at the National Center for Immunization and Respiratory Diseases, part of the Centers for Disease Control and Prevention (CDC). Campbell spoke to clinicians as part of an outreach call from the CDC in early March.

“Like most respiratory viruses, the symptoms of COVID-19 are relatively non-specific. We are learning that SARS CoV-2, the virus that causes COVID-19, can really cause a spectrum of disease presentations, ranging from no symptoms to severe pneumonia and death,” reported Campbell, who also is a member of the COVID-19 Response Clinical Team. “In a recent review of all the patients confirmed in China, and that was about 44,000 [patients] ... about 80% were noted to have disease classified as mild, which did include those with and without pneumonia. About 20% were severely or critically ill.”

Among the same group of 44,000 patients with COVID-19 in China, the case mortality rate for patients who reported no underlying medical conditions was 0.9%.

However, the rate was higher for patients with comorbidities and those who were older, Campbell said. In fact, beginning with patients with the virus age 60 years and older, the mortality rate nearly doubled for every 10-year increment.

For example, the mortality rate was about 4% for patients age 60 to 69 years, 8% for patients age 70 to 79 years, and 15% for patients older than age 80 years, Campbell reported. Patients with specific chronic medical conditions were at elevated risk of mortality, too. Campbell noted the mortality rate was about 10% for patients with cardiovascular disease and in the 6% to 7% range for patients with diabetes, chronic respiratory disease, hypertension, and cancer.

But the reports from China did not further break down the age of patients with these chronic diseases. Campbell stressed the case fatality rates from China do not necessarily reflect what clinicians will see in other countries such as the United States. Nevertheless, these statistics are useful in giving providers, epidemiologists, and policymakers an idea of which people are most at risk.

Newer data regarding cases in the United States show the virus is affecting patients across the age spectrum. A CDC analysis of 4,226 cases from Feb. 12 to March 16 showed 38% of patients who were sick enough to be hospitalized were younger than age 55 years, although the most severe outcomes occurred in older patients. The statistics show about 80% of patients who died from the illness were older than age 65 years.

Still, it is clear from the data that the percentage of patients with moderate or severe disease was fairly evenly distributed between younger and older adults: 53% of patients requiring care in an ICU and 45% of patients requiring hospitalization were older than age 65 years.

Notably, the data show that among patients younger than age 19 years, most testing positive for the virus, reported milder symptoms with few hospitalizations. The CDC analysis used early numbers, and experts stress that clinicians should understand that all age groups are at risk.

“We are now starting to see a spectrum of COVID-19 illness in the United States and other countries as well ... among people whom you might predict to be at high risk, but also among some younger and previously healthy adults,” Campbell noted. “At the other end of the spectrum, we are seeing people of all ages with mild upper respiratory symptoms who test positive.”

Clinical manifestations of the virus frequently include fever, but Campbell noted not all patients register a fever when they first present for care. In fact, in published reports, only about half of children with the virus record a fever when they present, she explained. “Other common symptoms for both children and adults include cough, myalgia or fatigue, and shortness of breath at illness onset,” Campbell said.

However, she stressed that most of these reports involve patients who are admitted to the hospital with pneumonia. “Now that we are seeing more mild cases, they are not all going to have shortness of breath,” Campbell shared. “In fact, that varies between 3% and 30%, depending on which population you are looking at. It is not always present at the beginning.”

Campbell said other less commonly reported respiratory symptoms include sore throat, headache, cough, nasal congestion, and rhinorrhea. Reports in the literature and in the United States also show some patients with the virus have experienced gastrointestinal symptoms such as diarrhea and nausea before developing fever or respiratory symptoms.

“Some reports in the literature and [in cases] experienced in the U.S. thus far suggest the potential for clinical deterioration is during the second week of illness,” Campbell observed.

She noted several reports indicate that it was during the second week of illness when dyspnea or labored breathing developed, pneumonia was diagnosed, and hypoxia, or low levels of oxygen in the blood, was observed. “I think this is very important to be aware of,” Campbell added.

The most common complication of COVID-19 is pneumonia, and reports from China indicate that acute respiratory distress syndrome (ARDS) occurred in 20% to 30% of hospitalized patients with pneumonia, Campbell said.

For critically ill COVID-19 patients who are admitted to the ICU, a broad spectrum of support is required, potentially including both non-invasive and invasive mechanical ventilation. “In China, 3% to 12% of these patients were supported by ECMO [extracorporeal membrane oxygenation],” Campbell noted. “Other reported complications in the literature include cardiac injury, arrhythmia, septic shock, liver dysfunction, acute kidney injury, and multi-organ failure.”

Campbell added that the CDC has heard reports of each of these complications from clinicians caring for COVID-19 patients in the United States, too.

While patients with mild symptoms at presentation may not require hospitalization, follow-up is important as symptoms may worsen in the second week of illness. Consequently, patients at higher risk of complications, such as older patients and those with underlying medical conditions, should be monitored closely.

“For hospitalized patients, clinical management includes prompt implementation of the recommended infection prevention and control measures and supportive management of complications,” Campbell advised. “Both CDC and WHO [the World Health Organization] recommend against the use of corticosteroids unless they are recommended for other reasons [such as] a COPD [chronic obstructive pulmonary disease] exacerbation.”

The reason to refrain from corticosteroids is because experts suggest these drugs could prolong viral replication in patients with COVID-19, Campbell noted.

While research is proceeding on several fronts to find effective therapeutic agents to treat SARS-CoV-2, there is particularly keen interest in the investigational antiviral agent remdesivir, a drug that was first developed as a treatment for Ebola. Since then, this drug has demonstrated antiviral activity against other viruses such as respiratory syncytial virus and Lassa fever. Moreover, researchers have confirmed that the agent inhibits SARS-CoV-2 replication in non-human cells.

“Its clinical impact remains unknown, but it has been given to a small number of patients with COVID-19 both inside and outside the United States,” Campbell explained.

Gilead Sciences, the developer of remdesivir, reportedly provided the drug “for compassionate use” to physicians who were treating the first American patient diagnosed with CoV-2 in Washington state in late January. The drug, which is administered intravenously, was provided to the patient after he developed pneumonia. The patient’s condition improved significantly, according to reports.

On March 23, the Food and Drug Administration (FDA) granted orphan status to remdesivir. This designation is intended to encourage the development of drugs to treat rare diseases, and comes with various tax breaks and a guaranteed seven-year pause on competition.

This designation led to pushback from consumer advocates. In a surprising twist, Gilead asked the FDA on March 25 to rescind that orphan status. In a statement, the company said it was confident remdesivir would receive expedited regulatory review without any other special designations.

Meanwhile, several clinical trials are underway, both in the United States and in China, to test the safety and efficacy of several drugs against COVID-19. For instance, Campbell explained that the National Institutes of Health is running one adaptive randomized, double-blind, placebo-controlled trial that is designed to test several therapeutics as they come into the pipeline. The first drug tested in a randomized clinical trial is intravenous remdesivir vs. intravenous placebo. Clinicians with patients interested in pursuing participation in that trial can obtain more information about that research here.

Gilead Sciences also is operating two additional Phase III clinical trials of remdesivir for the treatment of hospitalized patients. “One [trial] is for moderate COVID-19 disease, and one is for severe COVID-19 disease. Both trials are comparing regimens of five days [of treatment] to 10 days [of treatment],” Campbell explained. “There are several criteria that define moderate and severe [disease]. One of the main [indications] is that if a patient’s oxygen saturation is equal to or less than 94%, it is considered severe.”

More information about both Gilead trials as well as the company’s process for obtaining remdesivir for “compassionate use” can be accessed here. Clinicians also can call the Gilead Medical Resource Center at 1 (866) 633-4474.

There also has been considerable attention paid to hydroxychloroquine and chloroquine, two drugs already used to treat malaria, rheumatoid arthritis, lupus, and some other inflammatory conditions. Both drugs are in use in some other countries to treat COVID-19. However, these agents have not been approved for use against the virus in the United States.

In a statement, FDA Commissioner Stephen Hahn, MD, noted the drugs must be assessed in clinical trials before they can be declared safe and effective against COVID-19. He pledged the agency is moving quickly.

“We understand and recognize the urgency with which we are all seeking prevention and treatment options for COVID-19,” Hahn said. “We must also ensure these products are effective; otherwise, we risk treating patients with a product that might not work when they could have pursued other, more appropriate treatments.”

Notably, while both hydroxychloroquine and chloroquine include safety profiles that are well known, these drugs are not risk-free. Experts have noted these drugs are associated with cardiotoxicity when used for extended periods in patients with hepatic or renal dysfunction, or patients with immunosuppression. Clinical trials are underway to test the efficacy of hydroxychloroquine for pre- and post-exposure prophylaxis of the SARS CoV-2 virus. For example, researchers at the University of Minnesota are testing hydroxychloroquine on 1,500 participants who have been exposed to SARS-CoV-2 to see if the drug can prevent the development of COVID-19, or at least curb the severity of illness. The school notes early results could be available soon. For those interested in learning more information about this trial, send an email to: covid19@umn.edu.

Investigators are testing hydroxychloroquine as a prophylactic at the University of Oxford in the United Kingdom. They plan to enroll healthcare workers and others at high risk of contracting SARS-CoV-2. Much more information about this trial is available here.