Coronavirus SARS-CoV2 infection (COVID-19)

Essential Evidence

Last Updated on 2020-09-28 © 2020 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 Since preprint servers have not been peer-reviewed, and the data and conclusions may change, information from them should be used with great caution if at all.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
  • Preventive measures include hand washing, surface cleaning, case isolation, quarantine of contacts for 14 days, school and university closures, and general social distancing/sheltering at home. Modeling indicates that only by doing all of these measures can the number of severe cases requiring ventilation not overwhelm hospitals.B
  • Mask and isolate patients on presentation to a healthcare facility and obtain PCR from nasopharynx and oropharynx. Also test for influenza and strep throat if clinically suspected. C
  • The combination of age and CRP can be used to identify patients at low, moderate and high risk of severe illness (see Prognosis section below).B
  • 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. C
  • Treatment is primarily supportive and includes monitoring oxygen saturation.
  • Remdesivir shortens the duration of hospitalization (11 vs. 15 days) and may reduce mortality slightly. 108B
  • Corticosteroids have been shown in a large UK trial with 6425 patients to be 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 Their use also decreases the likelihood of requiring mechanical ventilation. 171B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine 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
  • The overall infection fatality rate is estimated to be 0.5% to 0.9% and is higher in older patients and those with comorbidities. 65 As of September 24th, the Johns Hopkins Center for Health Security reports that there have been 984,813 deaths and 32,356,829 confirmed cases worldwide, 203,147 deaths and 6,997,468 confirmed cases in the US (2.9% case fatality ratio), 9,304 deaths and 151,982 confirmed cases in Canada (6.1% case fatality ratio), and 42,025 deaths and 425,765 confirmed cases in the UK (9.9% case fatality ratio). Mortality rates per 100,000 are 62.0 in the US, 25.1 in Canada, and 63.2 in the UK. These rates are higher than the true case and infected fatality rates due to the large number of undiagnosed mild and asymptomatic cases. B

Treatment

Bottom Line

  • Treatment is primarily supportive, with clinical trials of antiviral drugs, anti-malarials, and other drugs ongoing.C
  • Corticosteroids have been shown in the UK recovery trial with 6425 patients to be 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. 161B
  • 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 (7.1% vs. 11.9%, p = 0.059). 108B
  • Multiple randomized controlled trials have confirmed that hydroxychloroquine 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 recommend that chloroquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, tocilizumab, and convalescent plasma only be used in the context of a clinical trial.
  • A regularly updated "living systematic review" concluded (9/11/20) that only glucocorticoids have been shown to reduce mortality and the need for mechanical ventilation, and that remdesivir decreased the duration of symptoms without causing harm. 165
  • Antiviral drugs
  • 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 (7.1% vs. 11.9%, p = 0.059, NNT = 21). Harms or other outcomes such as need for mechanical ventilation were not reported. 108
  • 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
  • A study (preprint, not peer-reviewed) randomized 236 patients to favipiravir or arbidol. There was no difference between groups with regards to need for mechanical ventilation or clinical recovery at 7 days.
  • 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
  • Monoclonal antibodies
  • Studies are underway using tofacitinib, a Janus kinase inhibitor, and other anti-inflammatory drugs, as well as efforts to develop monoclonal antibody-based drugs specific to SARS-CoV2. 147
  • 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
  • A retrospective cohort of patients with ARDS found a lower risk of death with methylprednisolone (46% vs. 62%), but the analysis did not control for possible confounders and only included 84 patients. 20
  • 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
  • WHO suggests that corticosteroids may be considered for patients with COVID-19 and sepsis or septic shock, a conditional recommendation that preceded the results of the RECOVERY trial. 23
  • The Infectious Disease Society of America guidelines do not recommend corticosteroids for treating patients with COVID-19 pneumonia (conditional recommendation based on low certainty evidence). It recommends that their use be considered for patients with COVID-19 and ARDS.
  • Antibiotics
  • There is insufficient evidence to recommend azithromycin for treatment of COVID-19; trials are ongoing.
  • 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
  • Among 2,773 COVID patients hospitalized in New York City, 786 patients received systemic anticoagulation (SAC). After adjusting for important confounders, there was no overall survival benefit of SAC (22.5% vs. 22.8%). However, for patients treated with SAC who required mechanical ventilation (N = 395) receiving SAC was associated with a much lower mortality rate (29.1% vs. 62.7%, p <0.05, NNT = 3). Significant bleeding was slightly more common with anticoagulation (3.0% vs. 1.9%). These results suggest that ventilator-requiring COVID-19 patients may benefit substantially from anticoagulation. 88
  • Another observational study also found an association between heparin use and decreased mortality but only in patients with an elevated sepsis score (40 vs. 64%, p = 0.03, NNT = 4) or d-dimer greater than 6x upper limit of normal (33% vs. 52%, p = 0.02, NNT = 5). 89
  • 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.
  • Randomized trials of HCQ
  • The UK RECOVERY Trial (preprint server, not peer reviewed) 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).
  • 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 Chinese study randomized 150 hospitalized patients with largely mild/moderate COVID-19 to HCQ 1200 mg loading dose on days 1 to 3, followed by 800 mg daily for 11 more days plus usual care or usual care alone. There was no difference in negative seroconversion rates at multiple timepoints, no difference in symptom alleviation at 28 days, and no difference in median time to symptom alleviation (19 vs. 21 days). There were more adverse events in the HCQ group (30% vs. 9%, most commonly diarrhea). 95
  • A pilot study published in the Journal of ZheJiang University (not in PubMed) randomized 30 patients with COVID-19 infection of unknown severity to hydroxychloroquine (HCQ) 400 mg per day for 5 days + usual care versus usual care only. At 7 days, there was no difference in the rates of negative viral swabs by PCR (87% in the HCQ group versus 93% in the control group). There was also no difference regarding incidence of severe disease (1 patient in the HCQ group and none in the usual care group), time to discharge, and time to being afebrile.
  • Observational studies of HCQ
  • A French study evaluated nasal swabs in 11 patients treated with HCQ and azithromycin. One died, and nasopharyngeal swabs remained positive in 8 out of 10 patients 5 to 6 days after treatment initiation. 52
  • A French observational study compared 84 patients receiving HCQ with 89 who did not, adjusting for known confounders using propensity score matching. They found no difference in any clinical outcomes. 96
  • Researchers identified 97 patients who had been given hydroxychloroquine (HCQ), 113 who had been given HCA plus azithromycin (AZ), and 158 who had not received HCQ at US VA hospitals. They used propensity score matching to identify patients who looked similar other than whether or not they received HCQ (or HCQ + AZ) and one had not received HCQ. In the unadjusted analysis, the risk of death was 19.9% in the HCQ alone group, 25.7% in the HCQ+AZ group, 10.0% in the no HCQ group, and 12.7% in those receiving neither drug. After propensity score matching, there was no difference in mortality between groups. There was an association between use of HCQ plus azithromycin with an increased risk of cardiac arrest (adjusted OR 2.13, 95% CI 1.12 - 4.05). 91
  • A large observational study of 1376 patients hospitalized in New York with COVID-19 did propensity score matching to compare those receiving HCQ (59%) with those who did not. They analyzed the data several different ways but found no association between HCQ use and need for intubation or death. 87
  • A multi-center, retrospective observational study included 2,541 hospitalized patients in Detroit with COVID-19. In-hospital mortality was lower among those receiving HCQ + azithromycin (157/783 [20.1%; 95% CI 17.3%-23.0%]) or HCQ alone (162/1202 [13.5%; 95% CI 11.6%-15.5%]) compared to azithromycin alone (33/147 [22.4%; 95% CI 16.0%-30.1%]) or neither drug (108/409 [26.4%; 95% CI 22.2%-31.0%]). The hazard ratio for HCQ alone vs. neither drug was 0.34 (95% CI 0.25-0.46). 148
  • Harms of HCQ
  • 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 to 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
  • A living systematic review in BMJ confirmed an increased risk of adverse events with HCQ. 165
  • Guidance from American College of Cardiology regarding HCQ: withhold if QTc >500 msec or known congenital long QT syndrome; monitor QT interval, withdraw if >500 msec; correct hypokalemia to >4 mEq/L and hypomagnesemia to >2 mg/dl; avoid other QT prolonging agents if feasible. 57
  • Bacillus Calmette-Guerin (BCG) and MMR vaccination
  • In Israel, BCG was no longer routinely administered after 1982. A study compared COVID-19 infection rates in patients born 3 years before and 3 years after this cutoff, and found no difference in infection rates (11.7% vaccinated vs. 10.4% unvaccinated). 90
  • Based on homology of genetic sequences between rubella (and to some extent measles and mumps) viruses, it has been proposed that MMR vaccination may be protective. Ecologic data comparing highly vaccinated populations such as Hong Kong and populations with low rates like Belgium suggest an association. However, this evidence is quite preliminary with no patient level observational data (preprint server, not peer-reviewed).
  • Other medications
  • 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
  • A formulation of vasoactive intestinal peptide (VIP) called aviptadil is in Phase 1 trials for treatment of severe COVID-19, following case reports of benefit.
  • 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. 46 32Current guidance recommends continuing ACE inhibitors and ARBs in patients with COVID-19 infection.
  • A case-control study in Spain matched 1139 patients with COVID-19 taking ACEI or ARB each with 10 controls taking other anti-hypertensives. There was no difference between groups with regards to the likelihood of requiring hospital admission. 101
  • Among 18,472 patients who had COVID-19 testing at the Cleveland Clinic, 1735 (9.4%) tested positive. The researchers performed a propensity-weighted analysis to attempt to adjust for known confounders, comparing those on ACEI/ARB with those not taking one. While patients taking an ACEI had a slightly lower risk of infection and patients taking an ARB had a slightly higher risk of COVID-19, the differences were small and not statistically significant. However, patients on ACEIs were more likely to be hospitalized (OR 1.8, 95% CI 1.2-2.8) or go to the intensive care unit (ICU, OR 1.8, 95% CI 1.1-2.9). While patients taking ARBs were also at higher risk of hospitalization (OR 1.6, 95% CI 1.04-2.5), there was no association with going to the ICU. The use of ACEIs or ARBs was not associated with the use of mechanical ventilation. 119
  • 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
  • In a retrospective, single institution study in Wuhan, China, 126 patients with COVID-19 and preexisting hypertension, of whom 43 were on ARBs/ACEIs, were age- and sex-matched to 125 patients with COVID-19 patients without hypertension. Patients with hypertension appeared to be more likely than those without to have critical illness (18.3% vs. 11.2%) and die in hospital (10.3% vs. 6.4%), but these differences were not statistically significant. Among those with hypertension, the group on ARBs/ACEIs compared to those on other agents had a marginally lower proportion of critical patients (9.3% [4 of 43] vs. 22.9% [19 of 83]; p = 0.061) and a lower but not statistically different death rate (4.7% [2 of 43] vs. 13.3% [11 of 83]; p = 0.283) despite similar blood pressures. Interestingly, patients in the ARBs/ACEIs group had significantly lower concentrations of C-reactive protein and procalcitonin than those with hypertension on other agents. 84

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 March 13, 2020).
  • 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 3/13/2020).
  • 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
  • Use of convalescent plasma from recovered COVID-19 patients has been proposed but remains untested. Studies in patients recovering from MERS-CoV found that they did not have enough antibodies to be useful for therapeutic use. 30
  • An underpowered open-label trial in China randomized 103 hospitalized patients to receive convalescent serum or usual care. The study was terminated after seven days of no new cases in the participating centers. While clinical improvement was observed in 52% of treated patients compared with 43% of controls, this was not statistically significant. Among the 46 patients with severe COVID infections, clinical improvement occurred significantly more often with convalescent plasma (91% vs. 68%, p = 0.03, NNT = 5). Overall, the 28-day mortality rate was lower in the treated patients than in the controls (15.7% vs. 24.0%, respectively) but this relatively large difference was not statistically significant. 120
  • A case series identified 5 patients with severe COVID-19 pneumonia and ARDS who were mechanically ventilated with PaO2/FIO2 <300. They were all given convalescent plasma; fever resolved in 4 of 5 within 3 days, and ARDS resolved in 4 of 5 12 days after the transfusion. At the time of writing, 3 had been discharged from the hospital and 2 were in stable condition. While promising, clinical trials are needed given the small number of patients and uncontrolled design. 70
  • A report on a large series of critically-ill patients who underwent treatment with convalescent sera for COVID-19 found that safety was excellent. In 5000 patients, they found only 36 serious adverse events in the four hours after transfusion (0.7%), including 4 deaths, 11 episodes of transfusion related acute lung injury, and 7 cases of transfusion-associated circulatory overload. Only 2 of the 36 events were definitely felt to be related to the transfusion by the treating physician. 143
  • 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 3/13/2020)
  • Avoid fluid overload by using conservative fluid management in patients with SARI but no evidence of shock. (WHO interim guidance 3/13/2020)
  • 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. (Surviving Sepsis Campaign Guidelines, March 26, 2020)
  • 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.