Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence

Last Updated on 2022-01-07 © 2022 John Wiley & Sons, Inc.

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Authors:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia
Mindy A. Smith, MD, MS, Clinical Professor, Department of Family Medicine, Michigan State University
Henry C. Barry, MD, MD, MS, Professor Emeritus, Michigan State University
Pete Yunyongying, MD, FACP, Associate Professor, Carle-Illinois College of Medicine, University of Illinois
John Hickner MD, MS, Professor Emeritus, University of Illinois-Chicago

Editor:
Mark H. Ebell, MD, MS, Professor, College of Public Health, University of Georgia

Overall Bottom Line

  • EDITOR'S NOTE: This topic has been made freely available and is being updated regularly. We are at times linking to preprint servers and providing direct links to articles where possible, and most of this literature has been made freely available. As preprint work becomes peer reviewed and formally published, we will update the citations. Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.
  • Suspect COVID-19 when the virus is circulating in the population and a patient reports signs and symptoms of respiratory tract infection, or less commonly fever and neurologic symptoms or thrombosis. Most common symptoms are fever, cough, myalgias, and dyspnea; loss of taste and smell are also common. Approximately 40% of all patients are asymptomatic but appear to be as infectious as symptomatic patients. B
  • • The most appropriate diagnostic test is RT-PCR of multiple specimens carried out according to guidelines. 9 Point-of-care PCR is highly specific, but sensitivity varies by manufacturer; rapid antigen testing has much lower sensitivity (56.2%) and should only be used in symptomatic patients with higher viral loads. 188B
  • Preventive measures include hand washing, surface cleaning, face masks, case isolation, quarantine of contacts for 14 days, school and university closures, social distancing, and sheltering at home. The most effective available face mask should be used when in indoor public spaces to prevent spread. Modeling indicates that only by doing all of these measures can the number of severe cases requiring ventilation not overwhelm hospitals. B
  • Two mRNA vaccines from Pfizer/BioNTech and Moderna have approximately 95% efficacy at preventing symptomatic disease and good safety against SARS-CoV-2. The adenovirus vectored vaccine from Johnson and Johnson/Janssen is 67% effective overall, but 74.4% in the US population that was studied. Vaccine effectiveness for the delta variant is about 87% to 90% overall, but lower among the immunocompromised and elderly. Boosters increase protection about 10-fold and are recommended at least 6 months after the second dose of vaccine. B
  • In patients not requiring oxygen or only requiring low-flow oxygen, remdesivir shortens the duration of hospitalization (11 vs. 15 days) and may reduce mortality slightly. 108B
  • Systemic corticosteroids are highly effective at reducing mortality in patients with COVID-19 who are mechanically ventilated (NNT = 7) or who are on oxygen (NNT = 20) but not in hospitalized patients not requiring oxygen. 161 171B
  • Two studies have found that use of inhaled budesonide in outpatients with early disease results in a shorter duration of symptoms and possibly a lower risk of hospitalization, death, and the need for urgent visits.B
  • A single RCT enrolling 1497 high risk outpatients with symptomatic COVID-19 compared fluvoxamine with placebo and reported a reduced likelihood of hospitalization (11% vs. 16%, NNT = 20, 95% CI 12-61).B 281
  • The monoclonal antibody bamlanivimab and the combination of casirivimab and imdevimab (Regeneron) have been given emergency use authorization for treatment of outpatients not on supplemental oxygen but at high risk for severe disease. A systematic review found an NNT of 21 to 24 to prevent hospitalization. 280B
  • In newly hospitalized patients not requiring mechanical ventilation, the Janus kinase inhibitor tofacitinib 10 mg twice daily reduced the composite of death or respiratory failure (18.1% vs. 29.0%, p = 0.04, NNT = 9). 265B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine (HCQ) is not effective for severe disease, mild disease, early disease, or as post-exposure prophylaxis, and is associated with a higher risk of adverse events. 173 105A
  • Patients can be considered cured using a test-based strategy (recovery from fever without antipyretics and without respiratory symptoms plus 2 negative PCR tests 24 hours apart). For outpatients in settings where tests are not widely available, the CDC recommends that isolation be maintained for at least 10 days after illness onset and at least 3 days (72 hours) after recovery, defined as: at least 3 days free of fever without antipyretics, 3 days without respiratory symptoms, and at least 7 days after onset of symptoms.Data support that after 10 days, the likelihood of transmission appears negligible. C
  • The overall case fatality rate is estimated to be between 0.5% and 0.9% and is higher in older patients and those with comorbidities. This estimate, from early in the pandemic, is likely lower now due to better treatment and ventilator management. 198 65B

Treatment

Bottom Line

  • Systemic corticosteroids are highly effective at reducing mortality in patients with COVID-19 who are mechanically ventilated (NNT = 7) or who are on oxygen (NNT = 20) but are not recommended for hospitalized patients not requiring oxygen or for outpatients. 161B
  • Two studies have found that inhaled budesonide in outpatients with early disease have a shorter duration of symptoms and may have a lower risk of hospitalization, death, and the need for urgent visits.B
  • A single open-label RCT concluded that remdesivir shortens the duration of hospitalization from 15 to 11 days; there was a non-significant reduction in mortality as well (6.7% vs. 11.9%, p = 0.059, at day 15 and 11.4% vs. 15.2% at day 29). Benefit is greatest in patients requiring only low-flow oxygen. 108B
  • The monoclonal antibody bamlanivimab and the combination of casirivimab and imdevimab (Regeneron) have been given emergency use authorization for treatment of outpatients not on supplemental oxygen but at high risk for severe disease. They somewhat reduce the likelihood for an ED visit or hospitalization. 218B
  • In newly hospitalized patients not requiring mechanical ventilation, the Janus kinase inhibitor tofacitinib 10 mg twice daily reduced the composite of death or respiratory failure (18.1% vs. 29.0%, p = 0.04, NNT = 9). 265B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine (HCQ) is not effective for severe disease, mild disease, early disease, or as post-exposure prophylaxis. 105A

Drug Therapy

  • Sites to link patients with trials have been developed and are active.
  • IDSA guidelines are frequently updated:
    • Strong recommendations against using anti-malarials, alone or in combination with macrolide antibiotics, and lopinavir/ritonavir.
    • Strong recommendation to use dexamethasone (or equivalent dose of other glucocorticoids if dexamethasone is not available) in critically ill hospitalized patients and a conditional recommendation for use in patients hospitalized with severe COVID-19 infections and against its use in hospitalized patients with non-severe illness and who do not need oxygen.
    • Recommends against using tocilizumab in hospitalized patients unless they are severely or critically ill (conditional recommendation).
    • Conditional recommendation in favor of using remdesivir in patients hospitalized with severe illness and those using supplemental oxygen but not on ventilators. The IDSA recommends against using remdesivir in hospitalized patients not needing oxygen.
    • Conditional recommendation when managing hospitalized patients with severe illness who have contraindications to corticosteroids, that patients receive baricitinib with remdesivir rather than remdesivir alone.
    • Conditional recommendation to use casirivimab/imdevimab as post-exposure prophylaxis in exposed persons who are at high risk of progression to severe COVID and to use bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab in ambulatory high-risk persons with mild to moderate COVID.
    • Recommends against using bamlanivimab in hospitalized patients and conditionally recommends against its routine use and against routinely using casirivimab/imdevimab in ambulatory patients (outside of high-risk patients who receive counseling for these agents).
    • Recommends against using the following specific agents except in the context of a clinical trial: convalescent serum, famotidine, baricitinib plus remdesivir plus corticosteroids, and ivermectin.
  • A regularly updated "living" guideline systematic review from the WHO makes a strong recommendation in favor of using Interleukin-6 receptor blockers (tocilizumab and sarilumab) for persons hospitalized with severe and critical covid-19, based on high-certainty evidence of benefit for mortality and mechanical ventilation. They make a strong recommendation for the use of corticosteroids only in patients hospitalized with severe or critical illness.They also make strong recommendations against using hydroxychloroquine (HCQ) and against using lopinavir-ritonavir in patients with COVID, regardless of disease severity. The WHO also recommends against using ivermectin for any patients with COVID except as part of a clinical trial. Additionally, due to low quality evidence, the WHO makes a weak recommendation against using remdesivir. 165
  • The European Respiratory Society also has a living guideline for hospitalized patients. They recommend using corticosteroids for patients requiring oxygen, noninvasive ventilation, or mechanical ventilation, and against using them for anyone else. They recommend IL-6 inhibiting monoclonal antibodies for patients requiring oxygen or ventilatory support and not for others (conditional recommendation based on low quality evidence). They recommend anticoagulation for hospitalized patients, and high flow nasal cannula or noninvasive CPAP through a facemask or helmet for patients with hypoxemic respiratory failure not requiring mechanical ventilation. They make no recommendation regarding use of remdesivir for patients not requiring mechanical ventilation due to conflicting evidence from randomized trials, and recommend against offering it for patients requiring mechanical ventilation. Finally, they recommend against use of HCQ, azithromycin, azithromycin + HCQ, colchicine, lopinavir-ritonavir, and interferon-beta. 264
  • Systemic corticosteroids
  • The UK RECOVERY trial randomized over 11,500 hospitalized patients with COVID-19 to one of 6 arms: azithromycin, lopinavir-ritonavir, tocilizumab, convalescent plasma, low dose dexamethasone (6 mg once daily for 10 days), or usual care. This study reports the results for the primary outcome of 28-day mortality between 2104 patients randomized to low dose dexamethasone and 4321 patients randomized to usual care. The primary outcome of 28-day mortality was significantly reduced overall (22.9% vs. 25.7%, rate ratio 0.83, 95% CI 0.75-0.93, NNT = 36). The degree of benefit was strongly associated with the severity of illness. For patients requiring mechanical ventilation mortality reduction was greatest (29.3% vs. 41.4%, RR 0.64, 95% CI 0.51-0.81, NNT = 8), while patients requiring oxygen but not mechanically ventilated benefitted somewhat less (23.3% vs. 26.2%, RR 0.82, 95% CI 0.72-0.94, NNT = 35). No benefit, and in fact a trend toward harm, was observed for hospitalized patients not requiring oxygen or mechanical ventilation (mortality 17.8% vs. 14.0%, RR 1.19, 95% CI 0.91-1.55). 161
  • The efficacy of corticosteroids for reducing mortality in patients requiring mechanical ventilation or oxygen was also supported by a meta-analysis of 7 trials with over 1700 patients. 172
  • The REMAP-CAP trial randomized 384 patients to fixed-dose hydrocortisone, shock-dependent dosing of hydrocortisone, or no cortisone. The mean organ support-free days was 11.5 days for the fixed-dose hydrocortisone group, 9.5 days for the shock-dependent hydrocortisone group and 6 days for the no hydrocortisone group. 171
  • Antiviral drugs
  • Remdesivir
  • The Adaptive COVID-19 Treatment Trial (ACTT) multicenter, multinational study recruited 1063 hospitalized patients with SARS-CoV-2 infection and evidence of lung involvement. They were randomized to remdesivir (200 mg IV on day 1 and then 100 mg IV daily for up to 10 days or hospital discharge) or matching placebo injection. The primary outcome was time to recovery, which was significantly faster in the remdesivir group (11 vs. 15 days, p <0.001). Clinical improvement was also more likely in the remdesivir group using a 7-category ordinal scale. There was also a trend toward lower mortality in the remdesivir group (6.7% vs. 11.9% at 15 days, p = 0.059, NNT = 21). Patients receiving high-flow oxygen, non-invasive mechanical ventilation, or mechanical ventilation did not appear to benefit, and benefit was greatest in those requiring low flow oxygen. Harms or other outcomes such as need for mechanical ventilation were not reported. 108
  • However, the WHO SOLIDARITY trial did not find a benefit to use of remdesivir. This trial took place in 405 hospitals in 30 countries, with 2750 randomized to remdesivir, 651 to interferon + lopinavir, 1412 to interferon only, 1411 to lopinavir + ritonavir, 954 to hydroxychloroquine, and 4088 to no study drug. They found no mortality benefit for any of the drugs. Looking specifically at remdesivir, there were trends toward benefit for non-ventilated patients (RR 0.80, 95% CI 0.63-1.01) and a trend toward harm (RR 1.16, 95% CI 0.85-1.60) for patients on mechanical ventilation. 236
  • Another study randomized 397 patients to 5 days or 10 days of therapy and concluded that there was no difference in the likelihood of clinical improvement. The study did not mask or conceal allocation, and as a result a larger number of sicker patients ended up in the 10-day group. In the unadjusted analysis the 5-day group did better, but this difference was no longer significant after adjusting for baseline differences. 118
  • Chinese researchers randomly assigned 237 patients hospitalized with COVID-19 pneumonia and hypoxia who were within 12 days of symptom onset to receive intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) or the same volume of placebo infusions for 10 days in a 2:1 ratio. The treating teams were allowed to administer other therapies. In this study, there was no statistically significant improvement in time to recovery. While about ⅔ of patients in each group reported adverse events, more remdesivir-treated patients stopped treatment early due to adverse events than did placebo-treated patients (12% vs. 5%). They found no difference in mortality (12% vs. 13%). 109
  • A randomized trial in 199 hospitalized patients with severe COVID-19 infection found no benefit from lopinavir-ritonavir. There was no difference in time to clinical improvement (16 days median in both groups. There was a small but non-significant reduction in mortality in the treatment group (19.2% vs. 25.0%, p = NS). 26
  • Lopinavir-ritonavir
  • The RECOVERY trial found that lopinavir-ritonavir was not effective. A total of 1616 patients received daily lopinavir-ritonavir (400 mg and 100 mg, respectively) and 3424 received usual care. The authors report that 23% of the patients allocated to lopinavir-ritonavir died by 28 days compared with 22% of control patients (p = ns). 238
  • Janus kinase inhibitors
  • The Janus associated kinase inhibitor ruxolitinib 5 mg twice daily was studied in a small placebo-controlled randomized trial of 43 patients with severe COVID-19. The time to clinical improvement, assessed in a non-blinded manner, was 12 days in the treatment group and 15 days in the placebo group. There were 3 deaths in the treatment group and 0 in the placebo group. While perhaps promising, the small sample size makes it impossible to draw conclusions about efficacy. 111
  • A trial randomized 1033 hospitalized patients with COVID-19 lower respiratory tract infection to remdesivir alone or remdesivir plus baricitinib, a Janus kinase 1 and 2 inhibitor. Patients who received remdesivir plus baricitinib recovered a median of 1 day faster than those who received remdesivir plus placebo (7 days vs. 8 days; p = .03). The outcome was most prominent in patients with a baseline ordinal score of 6 (those receiving noninvasive mechanical ventilation or high-flow oxygen) with a recovery time of 10 days compared with 18 days (RR 1.51; 1.10-2.08). The odds of improvement in clinical status at day 15 were also greater in the remdesivir plus baricitinib group (odds ratio [OR] 1.3; 1.0-1.6), again more likely in patients with a baseline ordinal score of 6 (OR 2.2; 1.4-3.6). Serious adverse events were less frequently noted in the remdesivir plus baricitinib group and there was no significant mortality difference between the 2 groups. 220
  • A study in Brazil randomized 289 adults with PCR confirmed COVID-19 and radiographic evidence of pneumonia to tofacitinib 10 mg or placebo twice daily for 14 days or until hospital discharge. Those receiving mechanical ventilation or ECMO were excluded. Patients were also receiving glucocorticoids (79%) and all were anticoagulated. Monoclonal antibodies, IL-6 or IL-1 inhibitors, interleukins, and other Janus kinase inhibitors were not allowed. A total of 289 patients were randomized to tofacitinib 10 mg or placebo twice daily for 14 days or until hospital discharge. The primary outcome was the composite of death or respiratory failure at 28 days which was significantly less likely in the tofacitinib group (18.1% vs. 29.0%, p = 0.04, NNT = 9). Deaths were numerically less likely but this was not a statistically significant difference (2.8% vs 5.5%, HR 0.49, 95% CI 0.15-1.63). There was no significant difference between groups in serious adverse events or serious secondary infections. 265
  • Monoclonal antibodies targeting IL-6
  • Monoclonal antibodies targeting IL-6 include tocilizumab, sarilumab, and siltuximab. A systematic review identified 27 good quality RCTs with 10,930 patients (19 with 8048 for tocilizumab, 9 with 2826 of sarilumab, and 1 with 149 of siltuximab). All-cause mortality at 28 days was lower in those receiving IL-6 antagonists (21.8% vs. 25.8%; NNT = 25, 95% CI 18-42). When you look at the specific agents,only tocilizumab significantly decreased 28-day mortality (22.3% vs. 27.3%; NNT = 21, 95% CI 15-33). There was no overall mortality benefit to IL-6 antagonists without corticosteroids. The co-intervention with steroids is probably why the authors report an “association” between IL-6 antagonist use and lower mortality. 275
  • A trial randomized 377 hospitalized patients on supplemental oxygen (room air O2 saturation <94%) in a 2:1 ratio to 1 or 2 doses of tocilizumab or placebo. More patients in the placebo group received dexamethasone (67.2% vs. 55.4%). For the primary efficacy outcome, significantly fewer patients in the tocilizumab group progressed to mechanical ventilation or death by day 28 (12% vs. 19%; hazard ratio 0.56; 95% CI 0.33-0.97: P = .04) although this was driven entirely by less need for mechanical ventilation. 219
  • Data from the RECOVERY trial support the use of tocilizumab for more severely ill patients. Patients had clinically suspected or laboratory confirmed SARS-CoV-2 infection and evidence of clinical deterioration: O2 <92% on room air or receiving oxygen therapy, and CRP levels ≥75 mg/L). They were randomized to a single weight-based parenteral dose of tocilizumab (n = 2022; dosing: 800 mg if weight >90 kg; 600 mg if weight >65 and ≤90 kg; 400 mg if weight >40 and ≤65 kg; and 8 mg/kg if weight ≤40 kg) or to usual care (n = 2094). Over 80% of these patients were also receiving systemic corticosteroids. The main outcome, 28-day mortality, was lower in tocilizumab-treated patients (30.7% vs. 34.8%; NNT = 25, 95% CI 15-82). Fewer tocilizumab-treated patients required mechanical ventilation (15.1% vs. 19.1%; NNT = 26, 95% CI 16-68). 262
  • Monoclonal antibodies specific to coronaviruses
  • Bamlanivimab is a monoclonal antibody that targets a region of the coronavirus spike protein. Researchers recruited 577 ambulatory patients with confirmed mild to moderate COVID-19 infections. Over the first two months of the study, the researchers randomized patients to a single infusion of placebo or one of three doses of bamlanivimab ranging from 700 to 7000 mg (n = 309) to another wing where patients received a combination of bamlanivimab plus etesevimab (2800 mg each, n = 112) or placebo (n = 156). The secondary outcome of hospitalizations or ED visits occurred in 5.8% of placebo-treated patients and in 1.4% of patients receiving bamlanivimab either as monotherapy or as combination therapy (NNT = 23, 95% CI 11-85). 218 The WHO living systematic review found a similar NNT of 21 to prevent one hospitalization in high risk outpatients. 280 However, it was not effective in hospitalized patients. 232
  • A combination of two monoclonal antibodies, casirivimab and imdevimab (trade name Regeneron) was given emergency use authorization on November 21, 2020 for outpatients 12 years and older with mild to moderate COVID-19 at risk of progression to severe disease. It is given as a single IV infusion. A systematic review found an NNT of 24 to prevent one hospitalization. 280
  • Inhaled corticosteroids
  • In the STOIC trial, researchers identified adults with less than 7 days of cough and either fever or anosmia or both (n = 146), of whom 94% had a positive swab for SARS-CoV-2. They randomized them to budesonide 400 mcg actuations, with two actuations twice daily, or to usual care. In the entire population, the primary outcome of urgent emergency department visit or hospitalization occurred less often in the budesonide group (3% vs. 15%, p = 0.009, NNT = 8). Time to recovery was also about 1 day faster, and symptom resolution was also more rapid. Adverse events (4 with sore throat, 1 dizziness) were minor and self-limited. 256
  • The larger PRINCIPLE trial in the UK randomized (open label) patients to usual care (n = 1988), usual care + inhaled budesonide 800 mcg twice daily for 14 days (n = 1073), or usual care plus other treatments (n = 1639). Time to self-reported recovery was significantly faster in those given budesonide (2.94 days, 95% Bayesian credible interval 1.19-5.12 days). For the outcome of hospitalization or death, the budesonide group showed a trend toward benefit (6.8% vs. 8.8%, absolute difference 2.0%, 95% BCI -0.2%-4.5%). 268
  • Antibiotics
  • There is no evidence to recommend azithromycin for treatment of COVID-19. The RECOVERY trial randomized 2582 patients to receive azithromycin (500 mg once daily for 10 days or until discharge) and 5181 patients to usual care alone. The 28-day mortality was the same (22%) for each treatment group. They also found no significant difference in length of stay or survival to discharge. Additionally, they found no improved outcomes in patients on mechanical ventilation. 213
  • For patients who are mechanically ventilated and in respiratory failure, Surviving Sepsis Campaign guidelines recommend that empiric antimicrobial therapy be considered based on expert opinion.
  • Anticoagulants and antiplatelet agents
  • In a retrospective cohort study, 4297 patients were hospitalized with COVID-19 between 3/1/20 and 7/31/20 in the US Veterans Affairs health system. The researchers compared patients who had an initial dose of prophylactic anticoagulation in the first 24 hours of hospitalization with those who did not, with a primary outcome of 30 day mortality. The analysis used a propensity score matched approach to adjust for comorbidities, tobacco use, medications, and laboratory results. Overall, 84.4% of patients received anticoagulation within 24 hours of admission; of those receiving it, most received subcutaneous heparin (30%) or enoxaparin (69%). In the propensity score matched analysis, the 30-day mortality was significantly lower in the group receiving early thromboprophylaxis (14.3% vs. 18.7%, NNT = 23). 214
  • A study in 12 US centers randomized patients to standard therapy (prophylactic or intermediate dose LMWH or unfractionated heparin) or therapeutic dose enoxaparin (1 mg/kg twice daily). Patients were at high risk for VTE based on elevated d-dimer or coagulopathy score. The primary outcome of symptomatic venous thromboembolism or arterial thromboembolism or death from any cause within 30 days occurred in less often with therapeutic dose enoxaparin (29% vs. 42%, RR 0.68; 95% CI 0.49-0.96). The incidence of major bleeding was higher with therapeutic dose enoxaparin (4.7% vs. 1.6%). The primary outcome was reduced in non-ICU patients (17% vs. 36.1%, RR 0.46; 95% CI 0.27-0.81) but not in ICU patients (51.1% vs. 55.3%, RR 0.92; 95% CI 0.62-1.39). 279
  • Fluvoxamine
  • An RCT in 11 Brazilian cities randomized high risk outpatient adults with symptomatic COVID to receive 10 days of the SSRI fluvoxamine (100 mg twice daily; n = 741) or placebo (n = 756). The main outcome of hospitalization that could include admissions for observation occurred in 11% of the fluvoxamine-treated participants compared with 16% of the controls (NNT = 20, 95% CI 12-61). There were no significant differences in adverse event rates between the two groups. 281
  • Colchicine
  • In a small Greek trial, 105 hospitalized COVID-19 patients were randomized to receive colchicine or standard medical therapy for up to 3 weeks. The primary clinical outcome was time from baseline to clinical deterioration, defined as a 2-grade deterioration on a 7-point ordinal scale. Mean event-free survival time was 18.6 days in the control group vs. 20.7 in the colchicine group (log rank P = .03). Fewer patients in the colchicine group had clinical deterioration (1.8% vs. 14%, p = 0.02). A larger trial is needed to see if colchicine leads to meaningful clinical benefit for COVID-19 patients. 137
  • The COLCORONA study recruited high-risk patients with COVID who were not yet hospitalized and considered not likely to need hospitalization. They randomized 4488 patients to colchicine (0.5 mg twice daily for the first 3 days followed by once daily) or placebo. 286 Using intention-to-treat, they found the rate of a composite 30-day outcome (death or COVID hospitalization) was similar in both groups of patients (4.7% vs. 5.8%, respectively; p = 0.08). There was also no difference in the rate of each of these events individually. When they restricted their analysis to the 4159 patients with a positive PCR result, the differences became statistically significant for the composite outcome (4.6% vs. 6.0%, respectively; NNT = 71, 95% CI 36-1974), driven mainly by a barely statistically significant reduction in hospitalizations (4.5% vs. 5.9%). In the real world, clinicians seeing a high-risk patient with symptoms and a COVID exposure are more likely to apply data from the main analysis and not this last one. More colchicine-treated patients developed pulmonary emboli (0.5% vs. 0.1%; NNTH = 244, 95% CI 124-1163).
  • Chloroquine and hydroxychloroquine
  • There was initially interest and widespread use of hydroxychloroquine (HCQ) for COVID-19. However, randomized trials to date have all been negative, with no effect on mortality, viral shedding, or symptom duration. 95 and well-designed observational studies have also failed to find any benefit. However, they do find harm, primarily prolonged QT intervals and cardiac arrhythmia and in some cases increased mortality.
  • The UK RECOVERY Trial randomized hospitalized patients to HCQ (n = 1561) or usual care (n = 3155). Patients in the HCQ group got two 800 mg loading doses 6 hours apart, followed by 400 mg twice daily for up to 9 days. There was no difference between groups with regards to 28-day mortality (26.8% HCQ vs. 25.0% usual care, rate ratio 1.09, 95% CI 0.96-1.23). Patients in the HCQ group had a longer time to hospital discharge (16 vs. 13 days) and were less likely to be discharged alive within 28 days (60.3% vs. 62.8%, RR 0.92, 95% CI 0.85-0.99, NNT = 40). Patients in the HCQ group were also more likely to experience the combined outcome of mechanical ventilation or death (29.8% vs. 26.5%, RR 1.12, 95% CI 1.01-1.25, NNT = 30). 246
  • A living systematic review in BMJ confirmed an increased risk of adverse events with HCQ. 165
  • A Brazilian study randomized 665 hospitalized patients to HCQ (400 mg twice daily), HCQ plus azithromycin 500 mg daily, or usual care. Of 665 patients, 504 had confirmed COVID-19 and made up the primary study population. They found no difference between groups for any outcomes including length of stay or mortality (although there were only 2 deaths). 149
  • A Spanish study randomized 293 outpatients with onset of symptomatic COVID-19 less than 5 days previously to HCQ 800 mg on day 1 and 400 mg once daily for 6 more days. There was no difference in viral loads at 3 and 7 days, or in symptoms or days to resolution. Adverse events were more common in the HCQ group. 157
  • A US study randomized symptomatic outpatients with confirmed or suspected COVID-19 (mostly epidemiologically linked cases) to HCQ 800 mg loading dose followed by 600 mg per day for 4 days or placebo. There was no difference between groups in symptoms duration or severity, hospitalizations, or deaths. 158
  • A Brazilian study randomized 81 patients to high-dose chloroquine (600 mg twice daily for 10 days) or low-dose chloroquine (450 mg twice daily on day 1 and once daily on days 2-5). The high-dose group had a high rate of prolonged QT (25%) and a trend toward higher mortality than the low-dose group and overall mortality similar to historical control rates of death in untreated patients. 141
  • Ivermectin
  • A systematic review identified 24 trials of ivermectin with 3328 participants. The included trials assessed a range of outcomes, such as viral clearance and inflammatory markers. Additionally, the trials used a variety of comparators, including usual care, placebo, hydroxychloroquine, and azithromycin. Overall, the studies were at low to moderate risk of bias. Six trials reported time to clinical recovery, variably defined within the studies. Three of the six trials reported that ivermectin-treated persons recovered more quickly (range = 1-7 days). Seven trials reported hospital length of stay: although the data were heterogeneous, the ivermectin-treated patients had a shorter length of stay by 1.6 days. Eleven trials (2127 participants) reported mortality in persons with moderate to severe infections. The authors report that mortality was lower in the ivermectin-treated patients than in the control patients (3% vs. 8.7%). However, since publication, the authors discovered that 1 of the included studies, with 400 persons (representing 19% of the patients in the studies that reported mortality), has since been withdrawn due to fraudulent data. The authors report they will re-analyze all their data and issue an updated report, so stay tuned. Re-analysis notwithstanding, the messiness of the remaining studies and concerns over fraud indicate that better studies are needed to determine the true role of ivermectin in managing patients hospitalized with COVID-19. 287
  • ACE inhibitor and angiotensin receptor blockers
  • Because the SARS-CoV2 virus binds human angiotensin converting enzyme (ACE)-2 receptors, it has been hypothesized that the increased risk in patients with hypertension may be due to use of ACE inhibitors increasing the number of these receptors. 33 Others hypothesize that ACE inhibitors and angiotensin receptor blockers (ARBs) might be useful as therapy. 4632Current guidance recommends continuing ACE inhibitors and ARBs in patients with COVID-19 infection as the observational studies summarized below found no evidence of harm.
  • Among 12,594 patients in New York who were tested for COVID-19, 5894 (46.8%) were positive and 1002 (17.0%) had severe illness. Antihypertensive medication (ACEI, ARB, beta-blockers, calcium-channel blockers, or thiazide diuretics) use was higher in the COVID-infected patients than in those who tested negative. However, using a propensity analysis to account for known confounders, the authors found no association between any antihypertensive class and contracting COVID-19 or in the risk of having severe disease. 80
  • A Danish cohort study found no difference in COVID-19 mortality among 4480 patients when comparing those taking vs. not taking an ACEI or ARB after adjusting for age and comorbidities. In fact, the non-significant trend was for lower mortality in ACEI/ARB users (hazard ratio 0.83, 95% CI 0.67-1.03). The same researchers also found no difference in the likelihood of becoming infected in a nested case-control study with 571 COVID-19 patients compared to 5710 age and sex matched controls. 131

Other Treatment

  • Guidelines are available from the World Health Organization, Infectious Disease Society of America, and Massachusetts General Hospital.
  • Guidance for using telehealth consultations was published in BMJ and includes a suggested algorithm. 59 CDC also provides guidance for telehealth consultations.
  • Oxygen supplementation
  • Adults: Give supplemental oxygen to patients with severe acute respiratory infection (SARI) and respiratory distress, hypoxemia or shock, with a target O2 of >94% (WHO interim guidance).
  • Children: Give supplemental oxygen with target O2 of >90%. If emergency signs such as obstructed breathing or apnea, severe respiratory distress, central cyanosis, shock, coma or convulsion provide airway management and oxygen to target O2 >94%. (WHO interim guidance).
  • The Surviving Sepsis Campaign Guidelines recommend supplemental oxygen if SpO2 <90% and to maintain it at no higher than 96%. If needed, high flow nasal cannula is recommended over noninvasive positive pressure ventilation depending on availability.
  • Use of prone positioning appears to improve oxygenation in patients with COVID-19 who are in respiratory distress, preventing the need for intubation and mechanical ventilation in many patients. 142 Randomized trials are lacking. 77 Use of home pulse oximetry should be considered, if available, for patients recovering from COVID-19 at home as hypoxic patients do not always feel dyspneic and may wait too long at home before coming in for help.
  • Clinical trials to evaluate nitric oxide as a treatment for patients with COVID-19 and ARDS are underway, as well as trials to evaluate the efficacy of nitric oxide inhalation for healthcare personnel to prevent infection.
  • Convalescent plasma
  • The UK RECOVERY trial indentified patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection and evidence of clinical deterioration: oxygen saturation <92% on room air or receiving oxygen therapy, and CRP levels ≥75 mg/L. They were randomized to convalescent plasma (n = 5795) or usual care (n = 5763). The protocol called for two units of high-titer convalescent plasma, the first administered as soon as possible after randomization and the second unit the following day. Over 90% of patients in each group also received corticosteroids. The main outcome, 28-day mortality, was the same (24%) in both groups, as was the proportion of those achieving the composite outcome of progression to mechanical ventilation or death (29%). 266
  • An RCT concluded that convalescent plasma can prevent progression of COVID-19 disease in the population of older adults with mild symptoms when administered within 72 hours. They randomized 160 adults aged 65 to 74 with comorbidities or age 75 and older regardless of comorbidities, all of whom had mild symptoms, to convalescent plasma or placebo infusion within 72 hours of onset. The plasma had a high titer of antibodies. The primary endpoint was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an O2 saturation of less than 93% on room air, or both. Fewer patients in the treatment group developed severe respiratory distress (16% vs. 31%, p = 0.03, NNT = 6). 228
  • In a randomized trial of 33 hospitalized patients with severe COVID-19 pneumonia (PlasmAr), there was no benefit of convalescent plasma in this group that was also being treated with corticosteroids. 239
  • In an open label trial in 464 inpatients at 39 Indian hospitals, patients randomized to convalescent plasma were no more or less likely to progress to severe disease or die than those receiving standard care (19% plasma vs. 18% control). 195
  • Stem cell therapy
  • Several companies are investigating stem cell therapy with trials getting underway.
  • Sepsis and shock
  • See detailed recommendations in the WHO interim guidance document and the Surviving Sepsis Campaign Guidelines.
  • Monitor patients for signs of clinical deterioration and sepsis. Monitor hematologic parameters and biochemistries as needed to monitor for complications such as acute hepatic or renal injury, shock, or acute cardiac complications. (WHO interim guidance)
  • Avoid fluid overload by using conservative fluid management in patients with SARI but no evidence of shock. (WHO interim guidance)
  • For acute management of shock, assess fluid responsiveness by measuring dynamic parameters, and use a conservative fluid strategy with balanced crystalloids over colloids or unbalanced crystalloids. Norepinephrine is recommended as the first-line vasopressor, with vasopressin or epinephrine as second line if norepinephrine is not available (SSCG, https://www.sccm.org/SurvivingSepsisCampaign/Guidelines/COVID-19).
  • For patients with severe pneumonia complicated by sepsis, even if suspected of having COVID-19, appropriate empiric antimicrobials should be given promptly.
  • See WHO interim guidance for details regarding management of ARDS in the ventilated patient, including prone ventilation if severe ARDS and using lower tidal volumes (4 to 8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure less than 30 cm H20).
  • The Surviving Sepsis Guidelines generally agree with the WHO interim guidance regarding management of ARDS in ventilated patients, noting that a higher PEEP is recommended over lower PEEP strategy. If severe ARDS and continued hypoxemia, a trial of an inhaled pulmonary vasodilator can be considered, as well as referral to an ECMO center if available.
  • Test of cure
  • For outpatients: When ample testing supplies are available, patients may be considered cured using a test-based strategy: clinically recovered (no fever without use of antipyretics and no cough or dyspnea) plus two negative PCR tests 24 hours apart. A symptom-based strategy omits PCR testing but recommends that isolation be maintained for at least 10 days after illness onset and at least 3 days (72 hours) after recovery. The CDC defines recovery as resolution of fever without the use of fever-reducing medications with progressive improvement or resolution of other symptoms. (CDC interim guidance)
  • For hospitalized patients: A test-based strategy as described above is recommended, with recovery from fever without antipyretics, recovery from respiratory symptoms, and two negative PCR tests at least 24 hours apart. (CDC interim guidance)
  • A briefing paper from the National Academies of Medicine and Sciences suggested two sequential negative PCR tests be used to indicate that virus is no longer being shed.