Symptoms and Management of Coronavirus Disease 2019 (COVID-19) FAQ

Patients with a mild clinical presentation may not initially require hospitalization, but clinical signs and symptoms may worsen, with progression to lower respiratory tract disease in the second week of illness. Risk factors for progressing to severe illness may include, but are not limited to, older age and underlying chronic medical conditions (eg, lung disease, moderate to severe asthma, cancer, heart failure, cerebrovascular disease, renal disease, liver disease, diabetes, immunocompromising conditions, and severe obesity).

Emergency medical attention should be sought if the patient develops trouble breathing, persistent pain or chest pressure, new confusion, inability to awaken or to stay awake, or bluish lips or face.

Most patients with confirmed COVID-19 have developed fever ^[1] and/or symptoms of acute respiratory illness (eg, cough, difficulty breathing).

Signs and symptoms of COVID-19  (not an exhaustive list)

The following symptoms may indicate COVID-19: ^[2]

• Fever or chills
• Cough
• Shortness of breath or difficulty breathing
• Fatigue
• Muscle or body aches
• Headache
• New loss of taste or smell
• Sore throat
• Congestion or runny nose
• Nausea or vomiting
• Diarrhea

Other reported symptoms have included the following:

• Sputum production
• Malaise
• Respiratory distress

Severe COVID-19 may be associated with dyspnea, hypoxia, or greater than 50% lung involvement on imaging. Critical COVID-19 may be associated with respiratory failure, shock, or multiorgan system dysfunction.

Complications may include pneumonia, hypoxemic respiratory failure/acute respiratory distress syndrome (ARDS), sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney injury (AKI), and complications of prolonged hospitalization, including secondary bacterial infections, thromboembolism, gastrointestinal (GI) bleeding, and polyneuropathy/myopathy. ^[3]

Patient counseling

Patients with mild coronavirus disease 2019 (COVID-19) should be counseled regarding the signs and symptoms of complicated disease. If any of these symptoms develop, urgent care should be sought by the patient. ^[4] ​

Home care

• Stay home.
• Limit contact with others through social distancing.
• If cohabitating, infected person(s) should use a separate bedroom and bathroom, if possible.
• Avoid sharing personal items.
• Wear a facemask when around others.
• Wash hands with soap and water for at least 20 seconds.
• Use hand sanitizer with at least 60% alcohol.
• Avoid touching eyes, nose, and mouth.
• Clean surfaces with cleaning sprays or wipes.
• Avoid unnecessary visitors. ^[5]

Home monitoring and resolution of symptoms

• Patients can leave home after 3 things have happened:

  • Fever has been absent for at least 72 hours (ie, 3 full days of no fever without use of fever-reducing medicine plus
  • Other symptoms have improved (eg, cough or shortness of breath have improved) plus
  • At least 10 days have passed since symptoms first appeared.

Exacerbation of symptoms

Emergency medical attention should be sought if the patient develops trouble breathing, persistent pain or chest pressure, new confusion, inability to awaken or to stay awake, or bluish lips or face.

Risk factors for severe COVID-19, regardless of age, include the following: ^{[6, 7, 8, 9]}

• Chronic kidney disease
• COPD
• Immunocompromised state due to solid organ transplant
• Obesity (BMI ≥30)
• Serious heart conditions (eg, heart failure, coronary artery disease, cardiomyopathies)
• Sickle cell disease
• Type 2 diabetes mellitus

The following are underlying conditions that may represent an increased risk of severe COVID-19:

• Asthma (moderate to severe)
• Cerebrovascular disease
• Cystic fibrosis
• Immunocompromised state due to blood or bone marrow transplant, immunodeficiencies, HIV infection, corticosteroid use (or other medications that weaken the immune system)
• Neurologic conditions (eg, dementia)
• Liver disease
• Pregnancy
• Pulmonary fibrosis
• Smoking
• Thalassemia
• Type 1 diabetes mellitus

People who live in a nursing home or long-term care facility are also at a higher risk of severe COVID-19.

Not all patients with coronavirus disease 2019 (COVID-19) will require medical supportive care. Clinical management for hospitalized patients with COVID-19 is focused on supportive care of complications, including advanced organ support for respiratory failure, septic shock, and multiorgan failure. Empiric testing and treatment for other viral or bacterial etiologies may be warranted. ^[10]

Patients with severe or critical COVID-19 are likely to require aerosol-generating procedures, so they should be placed in an airborne infection isolation room (AIIR), if available.

Supplemental oxygen therapy should immediately be administered to patients with severe COVID-19 who have severe acute respiratory infection (SARI) and respiratory distress, hypoxemia, or shock, with the peripheral oxygen saturation target being greater than 94%. ^[4]

Patients with severe COVID-19 should be closely monitored for signs of clinical deterioration (eg, rapidly progressive respiratory failure and sepsis), with supportive care interventions administered immediately. ^[4]

In a case of severe COVID-19, the patient’s comorbid condition(s) should be understood in order to tailor the management of critical illness. ^[4]

Fluid management: When shock is not evident, conservative fluid management should be used in patients with SARI. ^[4]

Empiric antimicrobial therapy should be administered as soon as possible to treat all likely pathogens causing SARI and sepsis, with such treatment provided within 1 hour of initial evaluation for patients with sepsis. ^[4]

Severe hypoxemic respiratory failure must be recognized when standard oxygen therapy is failing in a patient with respiratory distress; prepare for administration of advanced oxygen/ventilatory support. ^[4]

Remdesivir treatment should be administered to hospitalized patients with severe disease.

Corticosteroids are not routinely recommended for viral pneumonia or acute respiratory distress syndrome (ARDS) and should be avoided unless indicated for another reason (eg, COPD exacerbation, refractory septic shock). Nonetheless, The UK RECOVERY trial showed that low-dose dexamethasone (6 mg PO or IV daily for 10 days) randomized to 2104 patients reduced deaths by 35% in ventilated patients (P = 0.0003) and by 20% in other patients receiving oxygen only (P = 0.0021) compared with patients who received standard of care (n = 4321). No benefit was seen in patients who did not require respiratory intervention (P = 0.14). ^[11]

Acute respiratory distress syndrome (ARDS)

• Prone ventilation for 12-16 hours per day is recommended in adult mechanically ventilated patients with refractory hypoxemia despite optimized ventilation. ^[4]
• Oxygenation for severe ARDS:

  • Adults: PaO₂/FiO₂ ≤100 mm Hg with PEEP ≥5cmH₂0 or nonventilated (When PaO₂ is not available, SpO₂/FiO₂ ≤315 suggests ARDS);
  • Children: OI ≥16 or OSI ≥12.3
• Cardiologists should prepare to aid other specialists in managing cardiac complications in patients with severe COVID-19. ^[12]

Cardiovascular

• Cardiology and critical-care teams should coordinate management of patients requiring extracorporeal circulatory support with veno-venous (V-V) versus veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). ^[12]
• Obtain echocardiography in the setting of heart failure, arrhythmia, electrocardiographic (ECG) changes, or cardiomegaly. ^[12]
• It is reasonable to triage patients with COVID-19 according to the presence of underlying cardiovascular, diabetic, respiratory, renal, oncologic, and other chronic diseases for prioritized treatment. ^[12]
• Providers are cautioned that classic symptoms and presentation of acute myocardial infarction may be overshadowed in the context of COVID-19, resulting in underdiagnosis. ^[12]

Severe hypoxemic respiratory failure must be recognized when standard oxygen therapy is failing in a patient with respiratory distress; prepare for administration of advanced oxygen/ventilatory support. ^[4]

Prone ventilation for 12-16 hours per day is recommended in adult mechanically ventilated patients with refractory hypoxemia despite optimized ventilation. ^[4]

Oxygenation for severe ARDS:

• Adult: PaO ₂/FiO ₂ ≤100 mm Hg with PEEP ≥5 cm H ₂0 or nonventilated (When PaO ₂ is not available, SpO ₂/FiO ₂ ≤315 suggests ARDS)
• Child: OI ≥16 or OSI ≥12.3

Corticosteroids are not routinely recommended for viral pneumonia or acute respiratory distress syndrome (ARDS) and should be avoided unless indicated for another reason (eg, COPD exacerbation, refractory septic shock). Nonetheless, The UK RECOVERY trial showed that low-dose dexamethasone (6 mg PO or IV daily for 10 days) randomized to 2104 patients reduced deaths by 35% in ventilated patients (P = 0.0003) and by 20% in other patients receiving oxygen only (P = 0.0021) compared with patients who received standard of care (n = 4321). No benefit was seen in patients who did not require respiratory intervention (P = 0.14). ^[11]

Make plans to quickly identify and isolate cardiovascular patients with coronavirus disease 2019 (COVID-19) symptoms from other patients, including in the ambulatory setting. ^[12]

COVID-19–related cardiac complications include arrhythmia and acute cardiac injury. ^[12]

Conditions that can precipitate cardiac complications include acute-onset heart failure, myocardial infarction, myocarditis, and cardiac arrest, as well as any illness that places a higher cardiometabolic demand on patients. ^[12]

COVID-19 cardiac complications appear in line with severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and influenza analogs. ^[12]

Cardiologists should prepare to aid other specialists in managing cardiac complications in patients with severe COVID-19. ^[12]

Cardiology and critical-care teams should coordinate management of patients requiring extracorporeal circulatory support with veno-venous (V-V) versus veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). ^[12]

Obtain echocardiography in the setting of heart failure, arrhythmia, electrocardiographic (ECG) changes, or cardiomegaly. ^[12]

It is reasonable to triage patients with COVID-19 according to the presence of underlying cardiovascular, diabetic, respiratory, renal, oncologic, and other chronic diseases for prioritized treatment. ^[12]

Providers are cautioned that classic symptoms and presentation of acute myocardial infarction may be overshadowed in the context of COVID-19, resulting in underdiagnosis. ^[12]

With the exception of remdesivir, no drugs or biologics have been proven to be effective for the prevention or treatment of COVID-19. Remdesivir gained emergency use authorization (EUA) from the FDA on May 1, 2020, based on preliminary data showing a faster time to recovery of hospitalized patients with severe disease. ^[13] Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and developed as potential therapies. Searching for effective therapies for COVID-19 infection is a complex process. Guidelines and reviews of pharmacotherapy for COVID-19 have been published.

The UK RECOVERY trial showed that low-dose dexamethasone (6 mg PO or IV daily for 10 days) randomized to 2104 patients reduced deaths by 35% in ventilated patients (P = 0.0003) and by 20% in other patients receiving oxygen only (P = 0.0021) compared with patients who received standard of care (n = 4321). No benefit was seen in patients who did not require respiratory intervention (P = 0.14). ^[11]

For more information on investigational drugs and biologics being evaluated for COVID-19, see Investigational Drugs and Biologics.

The broad-spectrum antiviral agent remdesivir (GS-5734; Gilead Sciences, Inc) is a nucleotide analog prodrug. On May 1, 2020, The US FDA issued EUA of remdesivir to allow emergency use of the agent for severe COVID-19 (confirmed or suspected) in hospitalized adults and children. ^{[14, 15]}

It was studied in clinical trials for Ebola virus infections but showed limited benefit. ^[16] Remdesivir has been shown to inhibit replication of other human coronaviruses associated with high morbidity in tissue cultures, including severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. Efficacy in animal models has been demonstrated for SARS-CoV and MERS-CoV. ^[17]

Several phase 3 clinical trials are testing remdesivir for treatment of COVID-19 in the United States, South Korea, and China. Positive results were seen with remdesivir after use by the University of Washington in the first case of COVID-19 documented on US soil in January 2020. ^[18] The drug was prescribed under an open-label compassionate use protocol, but the US FDA has since moved to allow expanded access to remdesivir, permitting approved sites to prescribe the investigational product for multiple patients under protocol without requesting permission for each. ^[19] An adaptive randomized trial of remdesivir coordinated by the National Institute of Health (NCT04280705) was started first against placebo, but additional therapies can be added to the protocol as evidence emerges. The first experience with this study involved passengers of the Diamond Princess cruise ship in quarantine at the University of Nebraska Medical Center in February 2020 after returning to the United States from Japan following an on-board outbreak of COVID-19. ^[20] Trials of remdesivir for moderate and severe COVID-19 compared with standard of care and varying treatment durations are ongoing.

EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) was announced April 29, 2020. The analysis included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients who received remdesivir recovered faster than similar patients who received placebo. Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 11 days in patients treated with remdesivir compared with 15 days in those who received placebo. Results also suggested a survival benefit by day 14, with a mortality rate of 7.1% in the remdesivir group, compared with 11.9% in the placebo group, but this was not statistically significant. ^[13]

The ACTT results differ from a smaller randomized trial conducted in China and published hours before the press release by the NIH. Results from this randomized, double-blind, placebo-controlled, multicenter trial (n = 237; 158 to remdesivir and 79 to placebo; 1 patient withdrew) found remdesivir was not associated with statistically significant clinical benefits, measured as time to clinical improvement, in adults hospitalized with severe COVID-19. Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less. The authors concluded that numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies. ^[21]

The open-label phase 3 SIMPLE trial (n = 397) in hospitalized patients with severe COVID-19 disease not requiring mechanical ventilation showed similar improvement in clinical status with the 5-day remdesivir regimen compared with the 10-day regimen on day 14 (OR: 0.75 [95% CI 0.51-1.12]). In this study, 65% of patients who received a 5-day course of remdesivir showed a clinical improvement of at least 2 points on the 7-point ordinal scale at day 14, compared with 54% of patients who received a 10-day course. After adjustment for imbalances in baseline clinical status, patients receiving a 10-day course of remdesivir had a distribution in clinical status at day 14 that was similar to that of patients receiving a 5-day course (P = 0.14). The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir. The trial is continuing with an enrollment goal of 6,000 patients. ^[22]

The first published report with a group of patients receiving remdesivir compassionate use described clinical improvement in 36 of 53 hospitalized patients (68%) with severe COVID-19. At baseline, 30 patients (57%) were receiving ventilation and 4 (8%) extracorporeal membrane oxygenation (ECMO). Measurement of efficacy requires randomized, placebo-controlled trials. ^[23]

Observations during compassionate use follow-up (median of 18 days) included the following:

• Oxygen-support class improved in 36 patients (68%), including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated.
• Twenty-five patients (47%) were discharged.
• Seven patients (13%) died.
• The mortality rate was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

An in vitro study showed that the antiviral activity of remdesivir plus interferon beta (IFNb) for MERS-CoV was superior to that of lopinavir/ritonavir (LPV/RTV; Kaletra, Aluvia; AbbVie Corporation). Prophylactic and therapeutic remdesivir improved pulmonary function and reduced lung viral loads and severe lung pathology in mice, whereas LPV/RTV-IFNb slightly reduced viral loads without affecting other disease parameters. Therapeutic LPV/RTV-IFNb improved pulmonary function but did not reduce virus replication or severe lung pathology in the mice. ^[24]

Drug interactions with remdesivir

Coadministration of remdesivir is not recommended with chloroquine or hydroxychloroquine. Based on in vitro data, chloroquine demonstrated an antagonistic effect on the intracellular metabolic activation and antiviral activity of remdesivir. ^[15]

The NIH Panel for COVID-19 Treatment Guidelines recommend against the use of lopinavir/ritonavir or other HIV protease inhibitors, owing to unfavorable pharmacodynamics and because clinical trials have not demonstrated a clinical benefit in patients with COVID-19. ^[25]

In a randomized, controlled, open-label trial of hospitalized adults (n=199) with confirmed SARS-CoV-2 infection, recruited patients had an oxygen saturation of 94% or less on ambient air or PaO₂ of less than 300 mm Hg and were receiving a range of ventilatory support modes (eg, no support, mechanical ventilation, extracorporeal membrane oxygenation [ECMO]). These patients were randomized to receive lopinavir/ritonavir 400 mg/100 mg PO BID for 14 days added to standard care (n=99) or standard care alone (n=100). Results showed that time to clinical improvement did not differ between the two groups (median, 16 days). The mortality rate at 28 days was numerically lower for lopinavir/ritonavir compared with standard care (19.2% vs 25%) but did not reach statistical significance. ^[3] An editorial accompanies this study that is informative in regard to the extraordinary circumstances of conducting such a study in the midst of the outbreak. ^[26]

Another study (n = 86) that compared lopinavir/ritonavir or umifenovir monotherapy with standard care in patients with mild-to-moderate COVID-19 showed no statistical difference between each treatment group. ^[27]

A multicenter study in Hong Kong compared 14 days of triple therapy (n = 86) (lopinavir/ritonavir [400 mg/100 mg q12h], ribavirin [400 mg q12h], interferon beta1b [8 million IU x 3 doses q48h]) with lopinavir/ritonavir alone (n = 41). Results showed that triple therapy significantly shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. ^[28]

Rintatolimod is a TLR-3 agonist (Poly I:Poly C12U; Ampligen; AIM ImmunoTech) (toll-like receptor 3 [TLR-3] agonist) that is being tested as a potential treatment for COVID-19 by the National Institute of Infectious Diseases (NIID) in Japan and the University of Tokyo. ^[29] It is a broad-spectrum antiviral agent. ^[30]

Plitidepsin (Aplidin; PharmaMar) is a member of the compound class known as didemnins. In vitro studies from Spain report plitidepsin potentially targets EF1A, which is key to multiplication and spread of the virus. ^[31]

Favipiravir is an oral antiviral approved for the treatment of influenza in Japan. It selectively inhibits RNA polymerase, which is necessary for viral replication. Japan has commenced with a phase 3 clinical trial. In the United States, a phase 2 trial will enroll approximately 50 patients with COVID-19, in collaboration with Brigham and Women's Hospital, Massachusetts General Hospital, and the University of Massachusetts Medical School. In India, a phase 3 trial combining 2 antiviral agents, favipiravir and umifenovir, started in May 2020. ^{[32, 33]}

IL-6 is a pleiotropic proinflammatory cytokine produced by various cell types, including lymphocytes, monocytes, and fibroblasts. SARS-CoV-2 infection induces a dose-dependent production of IL-6 from bronchial epithelial cells. This cascade of events is the rationale for studying IL-6 inhibitors. As of June 2020, the NIH guidelines note insufficient data to recommend for or against use of IL-6 inhibitors. ^[34]

On March 16, 2020, Sanofi and Regeneron announced initiation of a phase 2/3 trial of the IL-6 inhibitor sarilumab (Kevzara). The United States–based component of the trial will be initiated in New York. The multicenter, double-blind, phase 2/3 trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients. The first part will recruit patients with severe COVID-19 infection across approximately 16 US sites, and will evaluate the effect of sarilumab on fever and the need for supplemental oxygen. The second, larger, part of the trial will evaluate improvement in longer-term outcomes, including preventing death and reducing the need for mechanical ventilation, supplemental oxygen, and/or hospitalization. ^[35]

Based on the phase 2 trial analysis, the ongoing phase 3 design was modified on April 27, 2020, to include only higher-dose sarilumab (400 mg) or placebo in critical patients (ie, requiring mechanical ventilation or high-flow oxygenation or ICU admission). In the preliminary phase 2 analysis, sarilumab had no notable benefit on clinical outcomes when combining the severe (ie, required oxygen supplementation) and critical groups versus placebo. However, there were negative trends for most outcomes in the severe group, while there were positive trends for all outcomes in the critical group. ^[36]

Phase 2 data for critical patients in the 400-mg group (n=145) compared with placebo (n=77), respectively, included the following: ^[36]

• Change from baseline C-reactive protein level: -79% versus -21%
• Died: 23% versus 27%
• Remained on ventilator: 9% versus 27%
• Clinical improvement: 59% versus 41%
• Off oxygenation: 58% versus 41%
• Discharged: 53% versus 41%

Another IL-6 inhibitor, tocilizumab (Actemra), is part of several randomized, double-blind, placebo-controlled phase 3 clinical trials to evaluate the safety and efficacy of tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia compared to placebo plus standard of care. The REMDACTA study adds tocilizumab to a regimen of remdesivir in hospitalized patients with severe COVID-19 pneumonia. The COVACTA study is nearing enrollment completion to evaluate tocilizumab plus standard of care versus standard of care alone in patients hospitalized with severe COVID-19. In addition, the EMPACTA study will focus on trials in sites known to provide critical care to underserved and minority populations. ^[37]

A study compared outcomes of patients who received tocilizumab (n = 78) with tocilizumab-untreated controls in patients with COVID-19 requiring mechanical ventilation. Tocilizumab was associated with a 45% reduction in hazard of death (hazard ratio 0.55 [95% CI 0.33, 0.90]) and improved status on the ordinal outcome scale (odds ratio per one-level increase: 0.59 [0.36, 0.95]). Tocilizumab was associated with an increased incidence of superinfections (54% vs 26%; P< 0.001); however, there was no difference in 28-day case fatality rate among tocilizumab-treated patients with superinfection versus those without superinfection (22% vs 15%; P = 0.42). ^[38]

An observational study in New Jersey showed an improved survival rate among patients who received tocilizumab. Among 547 ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend toward an improved survival rate of 54% who received tocilizumab compared with 44% who did not receive the therapy and a propensity adjusted hazard ratio of 0.76. ^[39]

An open label, non-controlled, non–peer reviewed study was conducted in China in 21 patients with severe respiratory symptoms related to COVID-19. All had a confirmatory diagnosis of SARS-CoV-2 infection. The patients in the trial had a mean age of 56.8 years (18 of 21 were male). Although all patients met enrollment criteria of (1) respiratory rate of 30 breaths/min or more, (2) SpO₂ of 93% or less, and (3) PaO₂/FiO₂ of 300 mm Hg or less, only two of the patients required invasive ventilation. The other 19 patients received various forms of oxygen delivery, including nasal cannula, mask, high-flow oxygen, and noninvasive ventilation. All patients received standard of care, including lopinavir and methylprednisolone. Patients received a single dose of 400 mg tocilizumab via intravenous infusion. In general, the patients improved with lower oxygen requirements, lymphocyte counts returned to normal, and 19 patients were discharged with a mean of 15.5 days after tocilizumab treatment. The authors concluded that tocilizumab was an effective treatment in patients with severe COVID-19. ^[40]

A retrospective review of 25 patients with confirmed severe COVID-19 who received tocilizumab plus investigational antivirals showed patients who received tocilizumab experienced a decline in inflammatory markers, radiological improvement, and reduced ventilatory support requirements. The authors acknowledged the study’s limitations and the need for adequately powered randomized controlled trials of tocilizumab. ^[41]

Nonetheless, these conclusions should be viewed with extreme caution. No controls were used in this study, and only one patient was receiving invasive mechanical ventilation. In addition, all patients were receiving standard therapy for at least a week before tocilizumab was started. AWP for 400 mg of tocilizumab is $2765.

Another anti-interleukin-6 receptor monoclonal antibody (TZLS-501; Tiziana Life Sciences and Novimmune) is currently under development. ^[42]

Several studies involving the IL-1 inhibitor anakinra (Kineret) have emerged. A retrospective study in Italy looked at patients with COVID-19 and moderate-to-severe ARDS who were managed with noninvasive ventilation outside of the ICU. The study compared outcomes of patients who received anakinra (5 mg/kg IV BID [high-dose] or 100 mg SC BID [low-dose]) plus standard treatment (ie, hydroxychloroquine 200 mg PO BID and lopinavir/ritonavir 400 mg/100 mg PO BID) with standard of care alone. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein levels and progressive improvements in respiratory function in 21 (72%) of 29 patients; 5 (17%) patients were on mechanical ventilation and 3 (10%) died. In the standard treatment group, 8 (50%) of 16 patients showed respiratory improvement at 21 days; 1 (6%) patient was on mechanical ventilation and 7 (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (P = 0.009). ^[43]

A study in Paris from March 24 to April 6, 2020, compared outcomes of 52 consecutive patients with COVID-19 who were given anakinra with 44 historical cohort patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (hazard ratio [HR] 0.22 [95% CI, 0.11-0.41; P< 0.0001). Similar results were observed for death alone (HR 0.30 [95% CI, 0.12-0.71]; P = 0.0063) and need for invasive mechanical ventilation alone (0.22 [0.09-0.56]; P = 0.0015). ^[44]

On June 15, 2020, the FDA revoked the emergency use authorization (EUA) for hydroxychloroquine and chloroquine donated to the Strategic National Stockpile to be used for treating certain hospitalized patients with COVID-19 when a clinical trial was unavailable or participation in a clinical trial was not feasible. ^[45]

Based on its ongoing analysis of the EUA and emerging scientific data, the FDA determined that hydroxychloroquine is unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other potential serious adverse effects, the known and potential benefits of hydroxychloroquine no longer outweigh the known and potential risks for the EUA.

While additional clinical trials may continue to evaluate potential benefit, the FDA determined the EUA was no longer appropriate.

Hydroxychloroquine and chloroquine are widely used antimalarial drugs that elicit immunomodulatory effects and are therefore also used to treat autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis). As inhibitors of heme polymerase, they are also believed to have additional antiviral activity via alkalinization of the phagolysosome, which inhibits the pH-dependent steps of viral replication. Wang et al reported that chloroquine effectively inhibits SARS-CoV-2 in vitro. ^[46] The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2–infected Vero cells. Physiologically based pharmacokinetic models (PBPK) were conducted for each drug. Hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on PBPK models, the authors recommend a loading dose of hydroxychloroquine 400 mg PO BID, followed by 200 mg BID for 4 days. ^[47]

Published reports stemming from the worldwide outbreak of COVID-19 have evaluated the potential usefulness of these drugs in controlling cytokine release syndrome in critically ill patients. Owing to widely varying dosage regimens, disease severity, measured outcomes, and lack of control groups, efficacy data have been largely inconclusive.

The UK RECOVERY Trial randomized 1542 patients to hydroxychloroquine and 3132 patients to usual care alone. Preliminary results found no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs 23.5% usual care; hazard ratio 1.11 [95% CI, 0.98-1.26]; P = 0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes. ^[48]

An observational study of 2512 hospitalized patients in New Jersey with confirmed COVID-19 was conducted between March 1, 2020 and April 22, 2020, with follow-up through May 5, 2020. Outcomes included 547 deaths (22%) and 1539 (61%) discharges; 426 (17%) remained hospitalized. Patients who received at least one dose of hydroxychloroquine totaled 1914 (76%), and those who received hydroxychloroquine plus azithromycin totaled 1473 (59%). No significant differences were observed in associated mortality among patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality rate in patients receiving hydroxychloroquine alone, azithromycin alone, the combination, or neither drug was 25%, 20%, 18%, and 20%, respectively. ^[39]

Because of these findings, the WHO paused the hydroxychloroquine arm of the Solidarity Trial. The FDA issued a safety alert for hydroxychloroquine or chloroquine use in COVID-19 on April 24, 2020. ^[49]

A phase 3 trial is planned to include approximately 440 hospitalized patients at multiple US sites. All patients enrolled in the trial will receive standard of care for COVID-19 and will be randomized into 3 groups—hydroxychloroquine, hydroxychloroquine plus azithromycin, or placebo. ^[50]

An observational study of consecutively hospitalized patients (n = 1446) at a large medical center in the New York City area showed hydroxychloroquine was not associated with either a greatly lowered or an increased risk of the composite endpoint of intubation or death. ^[51]

A retrospective analysis of data from patients hospitalized with confirmed COVID-19 infection in all US Veterans Health Administration medical centers between March 9, 2020, and April 11, 2020, has been published. Patients who had received hydroxychloroquine (HC) alone or with azithromycin (HC + AZ) as treatment in addition to standard supportive care were identified. A total of 368 patients were evaluated (HC n=97; HC + AZ n=113; no HC n=158). Death rates in the HC, HC + AZ, and no-HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC + AZ, and no-HC groups were 13.3%, 6.9%, 14.1%, respectively. The authors concluded that they found no evidence that hydroxychloroquine, with or without azithromycin, reduced the risk of mechanical ventilation and that the overall mortality rate was increased with hydroxychloroquine treatment. Furthermore, they stressed the importance of waiting for results of ongoing, prospective, randomized controlled trials before wide adoption of these drugs. ^[52]

According to a consensus statement from a multicenter collaboration group in China, chloroquine phosphate 500 mg (300 mg base) twice daily in tablet form for 10 days may be considered in patients with COVID-19 pneumonia. ^[53] While no peer-reviewed treatment outcomes are available, Gao and colleagues profess that 100 patients have demonstrated significant improvement with this regimen without documented toxicity. ^[54] It should be noted this is 14 times the typical dose of chloroquine used per week for malaria prophylaxis and 4 times that used for treatment. Cardiac toxicity should temper enthusiasm for this as a widespread cure for COVID-19. It should also be noted that chloroquine was previously found to be active in vitro against multiple other viruses but has not proven fruitful in clinical trials, even resulting in worse clinical outcomes in human studies of Chikungunya virus infection (a virus unrelated to SARS-CoV-2).

A randomized controlled trial in Wuhan, China, enrolled 62 hospitalized patients (average age, 44.7 years) with confirmed COVID-19. Additional inclusion criteria included age 18 years or older, chest CT scans showing pneumonia, and SaO₂/SPOs ratio of more than 93% (or PaOs/FIOs ratio >300 mm Hg). Patients with severe or critical illness were excluded. All patients enrolled in the study received standard treatment (oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids). Thirty-one patients were randomized to receive hydroxychloroquine sulfate (200 mg PO BID for 5 days) in addition to standardized treatment. Changes in time to clinical recovery (TTCR) was evaluated and defined as return of normal body temperature and cough relief, maintained for more than 72 hours. Compared with the control group, TTCR for body temperature and cough were significantly shortened in the hydroxychloroquine group. Four of the 62 patients progressed to severe illness, all of whom were in the control group. ^[55]

The French have embraced hydroxychloroquine as a potentially more potent therapy with an improved safety profile to treat and prevent the spread of COVID-19. ^[56] If it is effective, the optimal regimen of hydroxychloroquine is not yet known, although some experts have recommended higher doses, such as 600-800 mg per day. A study of hydroxychloroquine for postexposure prophylaxis in healthcare workers or household contacts is underway. ^[57]

An open-label multicenter study using high-dose hydroxychloroquine or standard of care did not show a difference at 28 days for seronegative conversion or the rate of symptom alleviation between the two treatment arms. The trial was conducted in 150 patients in China with mild-to-moderate disease. ^[58]

Opposing conclusions by French researchers regarding viral clearance and clinical benefit with the regimen of hydroxychloroquine plus azithromycin have been published. ^{[59, 60, 61]}

A small prospective study found no evidence of a strong antiviral activity or clinical benefit from use of hydroxychloroquine plus azithromycin. Molina et al assessed virologic and clinical outcomes of 11 consecutive patients hospitalized who received hydroxychloroquine (600 mg per day x10 days) and azithromycin (500 mg Day 1, then 250 mg days 2-5). Patient demographics were as follows: 7 men and 4 women; mean age 58.7 years (range: 20-77); 8 had significant comorbidities associated with poor outcomes (ie, obesity 2; solid cancer 3; hematological cancer 2; HIV-infection 1). Ten of the eleven patients had fever and received oxygen via nasal cannula. Within 5 days, 1 patient died, 2 were transferred to the ICU. Hydroxychloroquine and azithromycin were discontinued in 1 patient owing to prolonged QT interval. Nasopharyngeal swabs remained positive for SARS-CoV-2 RNA in 8/10 patients (80%, 95% confidence interval: 49-94) at days 5-6 after treatment initiation. ^[61]

In direct contrast to aforementioned results, another study in France evaluated patients treated with hydroxychloroquine (N=26) against a control group (n=16) who received standard of care. After dropping 6 patients who received treatment from the analysis for having incomplete data, the 20 remaining patients receiving hydroxychloroquine (200 mg PO q8h) had improved nasopharyngeal clearance of the virus on day 6 (70% [14/20] vs 12.5% [2/16]). ^[59] This is an unusual approach to reporting results because the clinical correlation with nasopharyngeal clearance on day 6 is unknown and several patients changed status within a few days of that endpoint (converting from negative back to positive). The choice of that particular endpoint was also not explained by the authors, yet 4 of the 6 excluded patients had adverse outcomes (admission to ICU or death) at that time but were not counted in the analysis. Furthermore, patients who refused to consent to the study group were included in the control arm, indicating unorthodox study enrollment.

This small open-label study of hydroxychloroquine in France included azithromycin in 6 patients for potential bacterial superinfection (500 mg once, then 250 mg PO daily for 4 days). These patients were reported to have 100% clearance of SARS-CoV-2. While intriguing, these results warrant further analysis. The patients receiving combination therapy had initially lower viral loads, and, when compared with patients receiving hydroxychloroquine alone with similar viral burden, the results are fairly similar (6/6 vs 7/9). ^[59]

The French researchers continued their practice of using hydroxychloroquine plus azithromycin and accumulated data in 80 patients with at least 6 days of follow-up. They note that the 6 patients on combination therapy enrolled in their first analysis were also included in the present case series, with a longer follow-up. However, it was not clear from the description in their posted methods when patients were assessed. A favorable outcome was defined as not requiring aggressive oxygen therapy or transfer to the ICU after 3 days of treatment. Sixty-five of the 80 patients (81.3%) met this outcome. One patient aged 86 years died, and a 74-year-old patient remained in the ICU. Two others were transferred to the ICU and then back to the infection ward. Results showed a decrease in nasopharyngeal viral load tested via qPCR, with 83% negative at day 7 and 93% at day 8. Virus culture results from patient respiratory samples were negative in 97.5% patients at day 5. ^[60] This is described as a promising method of reducing spread of SARS-CoV-2, but, unfortunately, the study lacked a control group and did not compare treatment with hydroxychloroquine plus azithromycin to a similar group of patients receiving no drug therapy or hydroxychloroquine alone. Overall, the acuity of these patients was low, and 92% had a low score on the national Early Warning System used to assess risk of clinical deterioration. Only 15% were febrile, a common criterion for testing in the United States, and 4 individuals were considered asymptomatic carriers. In addition, the results did not delineate between asymptomatic carriers and those with high viral load or low viral load.

The UK RECOVERY trial showed that low-dose dexamethasone (6 mg PO or IV daily for 10 days) randomized to 2104 patients reduced deaths by 35% in ventilated patients (P = 0.0003) and by 20% in other patients receiving oxygen only (P = 0.0021) compared with patients who received standard of care (n = 4321). No benefit was seen in patients who did not require respiratory intervention (P = 0.14). ^[11]

Corticosteroids are not generally recommended for treatment of COVID-19 or any viral pneumonia. ^[62] The benefit of corticosteroids in septic shock results from tempering the host immune response to bacterial toxin release. The incidence of shock in patients with COVID-19 is relatively low (5% of cases). It is more likely to produce cardiogenic shock from increased work of the heart need to distribute oxygenated blood supply and thoracic pressure from ventilation. Corticosteroids can induce harm through immunosuppressant effects during the treatment of infection and have failed to provide a benefit in other viral epidemics, such as respiratory syncytial virus (RSV) infection, influenza infection, SARS, and MERS. ^[63]

Early guidelines for management of critically ill adults with COVID-19 specified when to use low-dose corticosteroids and when to refrain from using corticosteroids. The recommendations depended on the precise clinical situation (eg, refractory shock, mechanically ventilated patients with ARDS); however, these particular recommendations were based on evidence listed as weak. ^[64] The results from the RECOVERY trial in June 2020 provided evidence for clinicians to consider when low-dose corticosteroids would be beneficial. ^[11]

A study describing clinical outcomes of patients diagnosed with COVID-19 was conducted in Wuhan China (N = 201). Eighty-four patients (41.8%) developed ARDS, and of those, 44 (52.4%) died. Among patients with ARDS, treatment with methylprednisolone decreased the risk of death (HR, 0.38; 95% CI, 0.20-0.72). ^[65]

Researchers at Henry Ford Hospital in Detroit implemented a protocol on March 20, 2020, using early, short-course, methylprednisolone 0.5-1 mg/kg/day divided in 2 IV doses for 3 days in patients with moderate-to-severe COVID-19. Outcomes of pre- and post-corticosteroid groups were evaluated. A composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, or mortality was the primary outcome measure. All patients had at least 14 days of follow-up. They analyzed 213 eligible patients, 81 (38%) and 132 (62%) in pre-and post-corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the post-corticosteroid group than in the pre-corticosteroid group (34.9% vs 54.3%; P = 0.005). This treatment effect was observed within each individual component of the composite endpoint. A significant reduction in median hospital length of stay was observed in the post-corticosteroid group (8 vs 5 days; P< 0.001). ^[66]

The FDA is facilitating access to convalescent plasma, antibody-rich products that are collected from eligible donors who have recovered from COVID-19. Convalescent plasma has not yet been shown to be effective in COVID-19. The FDA states that it is important to determine its safety and efficacy via clinical trials before routinely administering convalescent plasma to patients with COVID-19.

The FDA has posted information for investigators wishing to study convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of single patient emergency Investigational New Drug (IND) applications for individual patients. The FDA also is actively engaging with researchers to discuss the possibility of collaboration on the development of a master protocol for the use of convalescent plasma, with the goal of reducing duplicative efforts. ^[67]

The use of convalescent plasma has a long history in the treatment of infectious diseases. Writing in the Journal of Clinical Investigation Casadevall and Pirofski ^[68] proposed using it as a treatment for COVID-19, and Bloch et al ^[69] laid out a conceptual framework for implementation. To date, two small case series have been published. ^{[70, 71]} These series reported improvement in oxygenation, sequential organ failure assessment (SOFA) scores, and eventual ventilator weaning in some patients. The timelines of improvement varied from days to weeks. Caution is advised, as these were not controlled trials and other pharmacologic methods (antivirals) were used in some patients. ^[71]

An open-label study (n = 103) of patients with laboratory-confirmed COVID-19 in Wuhan, China, given convalescent plasma did not result in a statistically significant improvement in time to clinical improvement within 28 days compared with standard of care alone. ^[72]

A nonrandomized study transfused patients based on supplemental oxygen needs with convalescent plasma from donors with a SARS-CoV-2 anti-spike antibody titer of at least 1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results showed convalescent plasma transfusion improved survival in nonintubated patients (P = 0.015), but not in intubated patients (P = 0.752). ^[73]

Published findings from the 2004 SARS-CoV infection suggest the potential role of inhaled nitric oxide (iNO; Mallinckrodt Pharmaceuticals, plc) as a supportive measure for treating infection in patients with pulmonary complications. Treatment with iNO reversed pulmonary hypertension, improved severe hypoxia, and shortened the length of ventilatory support compared with matched control patients with SARS. ^[74]

A phase 2 study of iNO is underway in patients with COVID-19 with the goal of preventing disease progression in those with severe ARDS. ^[75] A phase 3 study (PULSE-CVD19-001) for iNO (INOpulse; Bellerophon Therapeutics) was accepted by the FDA in mid-March 2020 to evaluate efficacy and safety in patients diagnosed with COVID-19 who require supplemental oxygen before the disease progresses to necessitate mechanical ventilation support. ^[76] The Society of Critical Care Medicine recommends against the routine use of iNO in patients with COVID-19 pneumonia. Instead, they suggest a trial only in mechanically ventilated patients with severe ARDS and hypoxemia despite other rescue strategies. ^[40] The cost of iNO is reported as exceeding $100/hour.