Updated: May 13, 2022
Incubation period and viral shedding, isolation, quarantine or airborne isolation
Symptoms (in the unimmunized): note symptoms of Omicron infection may be milder, resembling a URTI, in both immunized and unimmunized but still capable of producing a severe infection.
Laboratory and imaging findings
Other candidate antiviral therapies: only widely discussed drugs are listed below (see Table for a more complete list and references)
Respiratory Support at Randomization
No oxygen received
Invasive mechanical ventilation*
Other corticosteroids shown to also be potentially beneficial in other trials and meta-analyses had a summary OR 0.66 on 28d all-cause mortality.
Convalescent plasma (CP) or serum-containing neutralizing antibodies against SARS-CoV-2
Monoclonal antibodies (mAbs) specific to SARS-CoV-2 against spike protein, in the U.S. are only offered to outpatients with mild-moderate COVID-19. Trials in hospitalized patients have shown benefit in seronegative patients; however, they do not yet have a EUA by the FDA if hospitalized for COVID-19 pneumonia.
Distribution was paused by HHS due to a lack of activity against the Omicron variant.
The second fully FDA-approved treatment for severe COVID-19 (after remdesivir), it is a selective inhibitor of Janus kinase (JAK) 1 and 2, FDA approved for rheumatoid arthritis, studied for COVID-19 in ACTT-2 studying RDV v. RDV + baricitinib. The drug offered a one-day improvement in symptom resolution, which has led to FDA EUA. Upon subgroup analysis, the drug worked based on the ordinal 6 group (high flow oxygen or non-invasive ventilation). These patients had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The drug might be considered for use in patients who cannot receive dexamethasone but who require high-flow oxygen or non-invasive ventilation. COV-BARRIER RCT with baricitinib vs standard of care (19% received RDV, 79.3% on corticosteroids which differs from ACTT-2 trial). The composite primary endpoint (death, progression to high flow O2, NIMV, MV or ECMO) was not significant. the secondary endpoint 28d all-cause mortality 8.1% v 13.1%, a 38% reduction (HR 0.57 (95% CI 0.41-0.78) was not otherwise explained by the findings specifically, i.e, since the primary endpoint was not reached, no difference in groups regarding clots, MIs, CVA, etc.). Impressive mortality reduction; however, the study was more international than in the US and only a minority received RDV. Recent studies (COV-Barrier subset analysis and Recovery) in critically ill patients also on dexamethasone showed benefits of mortality reduction.
Received EUA in Feb ’22 based on limited clinical data. However, in vitro data suggest it has the most reliable activity against known variants, including the BA.2 subvariant of Omicron. NIH COVID guideline places a lower-tier below remdesivir (RDV) x 3 days in clinical decision-making (similar to molnupiravir). This author’s opinion is that all known mAbs against the spike protein have worked well if they have good in vitro activity, hence would use similarly to how other mAbs were employed especially if logistical issues prevent early administration of RDV.
Distribution was paused by HHS due to a lack of activity against the Omicron variant.
Still waiting for a large RCT to be published to confirm hospital use, however many trials used the agent late (e.g., RECOVERY, others). Convalescent plasma works best as an antiviral. Current FDA EUA for both outpatients and hospitalized patients now enforces the use of high-titer plasma but is only available for immunosuppressed populations. Best used if within 3 days of illness onset or first 3 days of hospitalization. Now indicated only for immunosuppressed populations. High titer units from people who have recovered from COVID-19 and who have been immunized appear to generate the best titers and activity against known circulating variants including Omicron. Outpatient study of early plasma administration showed 54% reduction in hospitalization demonstrating that high-titer units have a role if used early rather than late (in hospital) for average, high-risk patients.
The RECOVERY trial provides the first evidence of therapy that provides a mortality benefit to those who are mechanically ventilated (or who require oxygen, severe COVID-19). In this trial, there was a trend toward increased mortality in those who do not require oxygen, so not recommended in this group usually with early infection. By the numbers, the rate ratio of mortality at 28d was 0.65 (p=0.0003) for those mechanically ventilated, 0.8 (p=0.0021) for severe COVID-19 patients who needed non-invasive supplemental oxygen, but 1.22 (p=0.14; so higher mortality trend) for patients who did not require supplemental oxygen. Some aspects of the RECOVERY trial deserve comment: the UK trial mortality was unusually high if the same benefit would be witnessed in North America is less clear. Also, patients with less than 7d of symptoms appeared to not benefit, suggesting that during the early phase of viral illness there is no impact or potential harm (similar to influenza) but the benefit is seen with the later hyperinflammatory phase. This trial was open-label, but the mortality endpoint would tend to discount bias to a substantial degree. Women appeared to benefit less from dexamethasone than men.
The antimalarial and antiinflammatory has not been shown in large randomized trials to yield benefit in the treatment of COVID-19 in hospitalized patients (RECOVERY trial), and concerns raised about cardiotoxicities in critically ill patients. It also appears to not offer prevention after exposure. The drug is not recommended by any mainstream experts or authorities.
High hopes for this nucleoside analog; however, the MOVe-OUT trial had only ~ 30% reduction in hospitalization or death within the first month when used in outpatients with fewer than 5 days of symptoms. Concerns about mutagenesis and driving new viral variants with high levels of use have been voiced as concerns by some, although with only a five-day course, the mutagenesis concern seems lower. Regardless, this drug is clearly in a lower tier than PAXLOVID or sotrovimab; however, it is likely the only outpatient drug easily available in early 2022. The drug should not be used in children, adolescents, pregnant and breastfeeding women.
A combination drug is an oral protease inhibitor that has activity against SARS-CoV-2. Results from the outpatient COVID-19 EPIC trial are impressive for treatment of early COVID-19; if given within the first 3 to 5 days of symptoms reduced hospitalization or death by 88-89%. The ease of oral administration will make this the preferred route for many compared to injectable monoclonal antibodies. Problems of limited supply in early 2022 have diminished. The use of ritonavir means that prescribers should take a careful assessment of drug-drug interactions.
The ACTT1 results showed improved LOS by 4 days in patients receiving RDV. The average duration of symptoms prior to enrollment was 9d median with a wide range. The key observation from data is that benefit was derived in patients who were started prior to mechanical ventilation, suggesting that the use of the drug earlier in the disease course has efficacy--consistent with its mechanism of action as an antiviral. Some argue that SOLIDARITY and DisCoVeRy trials show no mortality benefit, although the latter trial did have a similar benefit for patients on oxygen as ACTT-1. Overall, many in the US and NIH guidelines favor continued use for patients with severe COVID-19 requiring oxygen but not admitted to the ICU due to improvement in LOS noted by both prospective and a number of retrospective studies, matched control studies. PINETREE data suggested that early administration (< 5d after symptom onset) in patients at high risk for COVID-19 prevents hospitalization and death. Three-day infusion poses logistical challenges compared to single-dose mAb for outpatients, but may be the treatment of choice for those patients ineligible for Paxlovid and if effective mAb is unavailable. RDV is the first to receive full FDA approval for COVID-19, and use in the outpatient arena often requires financial clearance before receiving since now paid by patient insurance; this may therefore slow the time to first infusion.
Distribution halted and EUA withdrawn due to reduced activity against the BA.2 subvariant (4/5/22).
Better known by its trade name Evusheld, and previously called AZD7422, appears effective PrEP with an 76.7% reduction in symptomatic COVID-19 when alpha and delta variants were commonplace in the PROVENT trial (which was among the unvaccinated with few immunosuppressed in the trial). The monoclonal have an altered Fc that allows for extended half-life and therefore offers protection x 6 months. With BA.2 now dominant in US, the cilgavimab retains significant activity, more so than against early Omicron variant and subvariants. The drug is only for immunosuppressed patients who are expected to not mount adequate vaccine responses or people who cannot receive vaccines due to severe reactions. The drug takes two weeks to have adequate tissue levels and protective effect, so it is not useful for COVID-19 treatment or PEP. There was a signal that administration cause more cardiac events (0.6%) compared to placebo (0.2%) in those with known cardiovascular disease only.
This anti-IL6R mAb has had an up and down and now up history for COVID-19. The drug appears to not work as monotherapy; however, when combined with dexamethasone appears to have an impact on reducing severity and duration of illness as well as reducing mortality in three studies: EMPACTA, REMAP-CAP, and RECOVERY. Endorsed for use by NIH and IDSA for patients on high-flow 02, or first 24h of ICU care--baricitinib is an alternative. Either should be combined with dexamethasone or another corticosteroid. Baricitinib is an alternative, employed by some institutions in the second half of 2021 due to supply shortfalls of tocilizumab.
Comment: Helpful guidance including the suggestion that lower tract specimens (if performed with a validated assay) may be more sensitive than the traditional nasopharyngeal swab, though the evidence is limited. Rapid testing, including antigen and serology also addressed. Also, look at CDC for diagnostic guidance information.
Comment: Revised regularly with updates. The format includes updated reference tables for some drugs. Informs much of the basis for RDV, dexamethasone, tocilizumab and baricitinib use discussed. Also rates outpatient COVID-19 therapies for early disease. The panel places the only remaining mAb bebtelovimab as a third line (along with molnupiravir) due to limited clinical data to support use while having excellent in vitro activity against Omicron and subvariants.
Comment: Regularly updated, and generally in concert with the NIH GL. One major area where our guide differs is in convalescent plasma use which we believe has a role for early illness in hospitalized patients (< 3d) or in some severely immunosuppressed patients who cannot generate meaningful antibody responses.
Comment: Though convalescent plasma is now limited by the FDA to patients who are immunosuppressed, this RCT of early administration of high-titer convalescent plasma showed a 54% reduction in hospitalization within 28d of symptom onset.
Comment: Trial in unimmunized patients with mild-moderate COVID-19 found 87-88% reduction in hospitalization or death compared to placebo. The drug is relatively well-tolerated. Achilles heel is the co-packaging with ritonavir to boost nirmtrelavir levels which is the SARS-CoV-2 specific protease inhibitor. Ritonavir with its suicide inhibitor impact on CYP3A4 knocks out many patients who are on meds such as tacrolimus. Need to check for drug interactions. Patients on statins can have drug held for the 5 day course.
Comment: It was disappointing that the efficacy fell to 30% from the preliminary 50% impact at reducing hospitalization or death in this study of mild-moderate COVID-19 in unimmunized patients. The drug has a clean slide effect profile. Much has been made of genotoxicity concerns, but the impact is not clear from a 5d course. Check for pregnancy in women of childbearing age. Notably, fewer deaths in the molnupiravir arm, but not statistically significant. Probably worthwhile in patients at high risk for disease progression and at least in early 2022 is the easiest to procure and take compared to other outpatient medications for COVID-19.
Comment: A subset of patients in the expanded access use of COVID-19 convalescent plasma found that high titer recipients who received units before critical illness had a lower risk of death compared to patients who got low titer plasma.
Comment: Small but well done double-blind RCT of patients > 65 yrs with mild COVID-18 and less than three days of symptoms. A total of 160 patients found that severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. The study is the best evidence that you need high titer units and early administration to have an effect.
Comment: Interim results from the ongoing BLAZE-1 trial showing that combination therapy of these mAbs resulted in decreased viral load and less need for hospitalization.
Comment: The use of high-titer convalescent plasma was not helpful in this trial of 511 patients who received it < 7d from the onset of symptoms. The average duration of symptoms in the active arm was 4 days (median IQR).
Comment: This RCT enrolled 12 yrs and older with close household contact with COVID-19 within 96h of the index person receiving the COVID-19 diagnosis. SQ dosing was x one at 600 mg/600 mg. Symptomatic infection was seen in 11/753 (1.5%) vs. 59/752 (7.8%) on the placebo group. The relative risk reduction [1 minus the relative risk], 81.4%; P< 0.001). This appears to be an effective intervention for those at high risk with exposure (unimmunized) but would also consider in the immunized in the advanced elderly, immunosuppressed especially.
Comment: Called a positive trial for tocilizumab, important points are that 1) statistical significance only when the rate of progressing to mechanical ventilation is included (not just mechanical ventilation and death as hard endpoints) and 2) > 80% of patients also received dexamethasone, suggesting that the two drugs need to work together to help patients.
Comment: Helpful data synthesis of major tocilizumab trials. Data overall is mixed, there may be efficacy but nothing like that suggested from observational trials--at least for immunomodulatory monotherapy tocilizumab. The author suggests waiting for more RCT data to determine if the drug is helpful for COVID-19 patients. This paper included EMPACTA; however, not RECOVERY or REMAP-CAP which has defined a difference between dexamethasone + tocilizumab vs. tocilizumab monotherapy.
Comment: 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66). Dexamethasone and hydrocortisone had a similar impact while the single methylprednisolone trial had less effect on mortality.
Comment: The ACTT1 results that showed improved LOS by 4 days in patients receiving RDV. The average duration of symptoms prior to enrollment was 9d median with a wide range. The key observation from data is that benefit was derived in patients who were started prior to mechanical ventilation, suggesting that the use of the drug earlier in the disease course has efficacy--consistent with its mechanism of action as an antiviral. Final results are now available.
Comment: Unimpressive trial, but the drug may have been given to late to too ill a population.
N = 237 patients, halted
Confirmed infection, 12d or fewer of symptoms, lung involvement
Remdesivir 200 mg d 1 then 100 mg IV daily vs. placebo
1. No clinical improvement (subgroup < 10d with trend)
2. No difference in mortality (subgroup < 10d with trend)
3. No effect on viral load in upper or lower respiratory tracts
Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain whether this is durable and at what cost to society? It may buy time but effective drugs or vaccines remain in the far future it seems. Authors suggest "the travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid-February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community."
Comment: An early report and these typically have higher rates of infection due to concentrated, very ill patients than later in epidemics. Authors estimate of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system.
Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 detected only in 6 (1.6) of patients. Only 1 of the COVID children required ICU care. Of the COVID patients, fever and cough were common and four had pneumonia.
Comment: A small study of 5 patients who required mechanical ventilation who appeared to benefit from convalescent plasma containing neutralizing antibodies, though also received methylprednisolone and putative antiviral therapies directed against SARS-CoV-2 infection. Authors suggest that many parameters improved including in the 4 ARDS patients.
Comment: Wading into the aerosol v. droplet debate, the suggestion that forceful uncovered sneezes may cause infectious droplets to go beyond the 6 ft range currently advised by the CDC. This concern has prompted universal mask wear for HCWs, but also for the general public. There may be people who are not ill and therefore sneeze or cough, asymptomatic shedding and dispersing virus.
Comment: Paper suggests that some patients presented with GI symptoms as part of COVID-19, 11.4% of 651 in this study from Zheijiang University in Hangzhou. A caveat is their definition of GI included nausea only in addition to diarrhea and vomiting as they only needed one of the three to qualify for GI symptoms. They also suggested that patients who had GI had more severe COVID infection.
Comment: Authors report on patients in earlier phases of COVID-19 infection, 20 (33.9%) reported at least one taste or olfactory disorder and 11 (18.6%) both. This is not unique though as other viral respiratory infections may also cause these symptoms.
Comment: Series of only five patients from France; however, the descriptions of three potential phenotypes may offer insights into different viral- and Immuno-pathogenesis. 1. Paucisymptom patient: nasopharyngeal high viral titer (and virus in feces), 2. Symptoms then decompensation (~day 10, respiratory decompensation): low viral titer compared to earlier in nasopharyngeal samples and 3. Clinical progression/death: high viral titers in upper and lower respiratory samples plus persisting viremia.
Comment: Authors used a nucleocapsid-based antibody for the detection of antibodies against SARS-CoV-2. IgM and IgA antibodies were found 5 days (IQR 3-6) after symptom onset, while IgG was detected on 14 days (IQR 10-18). Positive responses overall were seen as IgM 85.4%, IgA 92.7% and IgG 77.9% respectively. Considering both confirmed and probable cases, the positive rates of IgM antibodies were 75.6% and 93.1%, respectively. The detection efficiency by IgM ELISA is higher than that of qPCR method after 5.5 days of symptom onset. The positive detection rate is significantly increased (98.6%) when combined IgM ELISA assay with PCR for each patient compare with a single qPCR test (51.9%).
Comment: 37 asymptomatic individuals displayed longer viral shedding, less cytokine generation and less serological responsiveness.
Asymptomatic 93.3% (28/30) and 81.1% (30/37) had less IgG and neutralizing Abs
‒In comparison , 96.8% (30/31) and 62.2% (23/37) of symptomatic patients.
-40% asymptomatic seronegative vs. 12.9% of the symptomatic group during convalescence
§Protective immunity may not be long-lived
Comment: HCQ did not appear to prevent illness consistent with COVID-19 in patients with moderate or high-risk exposure to the virus when started within four days of the exposure.
Comment: Pragmatic trial and also important to note the extraordinarily high background mortality in the U.K at the time (~40%). 28-day mortality in the usual care group was highest in those patients receiving IMV (40.7%), intermediate in those receiving oxygen only (25.0%), and lowest among those who were not receiving respiratory support at randomization (13.2%). The greatest absolute reductions in 28-day mortality were seen in the sickest patients, and subgroup analysis suggests in those > 7d of symptoms which would correlate with the inflammatory phase. Dexamethasone improves 28d mortality compared to placebo in patients requiring IMV (NNT = 8.5) and those patients requiring oxygen therapy (NNT = 29). There was no benefit to patients not requiring oxygenation support and even a signal for harm.
Comment: An early report includes electron microscopy photomicrographs as well as sequence analysis of what is now termed COVID-19 disease and SARS-2-CoV virus.
Comment: Authors have sequenced what is now termed SARS-2-CoV. Its genome 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus.
Comment: One of the initial major reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) affected. Predominant symptoms include fever, fatigue and dry cough. Leukopenia was seen in ~70%. Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]).
Comment: Chest CT shows early ground-glass infiltrates which may offer speedier "diagnosis" than PCR studies in an epidemic setting as a first finding if molecular assays not readily available.
Comment: No surprise, here an infant sheds high levels of the virus but is without symptoms. Children are well known "vectors" of viral infection often without significant disease is well known for regular coronavirus infections, influenza and others.
Comment: Interim analysis of the mAb product studied among 275 outpatients with mild-moderate COVID-19. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11). No differences were seen in the active arm compared to placebo for adverse reactions.
Comment: Though the open-label trial cited as a reason to use 5-day instead of 10-d RDV for severe COVID-19, the fact that the 10-d course did worse without notably more side effects is concerning that the 5d data perhaps not as solid. Also, the FDA cites this trial as a reason (along with ACTT-1) to expand RDV use to those hospitalized but not needing oxygen; however, NNT =~100 and limited patients not requiring oxygen at randomization included.
Comment: A small but well-conducted study looking at 9 cases with most patients on day 1 having mild or prodromal symptoms. Key findings include finding virus in upper respiratory tissues with no difference between nasopharyngeal and oropharyngeal speeding which was very high during the first week of illness, but not in stool. Viral RNA remained in sputum beyond the resolution of symptoms. Seroconversion occurred by day 7 in 50% of patients but by day 14 in 100%. Despite the knowledge gained about viral kinetics, this paper offers proof that illness may also present as a routine upper respiratory tract infection without pneumonia or lower tract symptoms.
Comment: Early experience with this antiviral in severe COVID-19 illness, found that there was an improvement in 36 of 53 patients (68%). Seven patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. The lack of a control arm makes this number difficult to understand whether the drug is helpful. As authors indicate, there is a need to await RCT data.
Comment: Series of 1217 specimens analyzed for respiratory viruses, found 116/1217 specimens (9.5%) were positive for SARS-CoV-2 and 318 (26.1%) were positive for 1 or more non–SARS-CoV-2 pathogens. WIthin the SARS-CoV-2 positive specimens, 24 (20.7%) were positive for 1 or more additional pathogens. The most commonly detected co-infections were rhinovirus/enterovirus (6.9%), respiratory syncytial virus (5.2%), and non–SARS-CoV-2 Coronaviridae (4.3%). This report yielded higher viral co-pathogen rates than earlier COVID-19 studies, but similar to the co-infection rates seen with many standard respiratory viral illnesses. Importantly, this means that finding a virus other than the SARS-CoV-2 should not be grounds for concluding that COVID-19 is not present.
Comment: Syndromic screening that used fever and respiratory symptoms failed to detect SARS-CoV-2 infection (often at high titer) in 17% of HCWs presenting for assessment. While limited testing has forced decisions to screen people at a higher likelihood of infection, the wide range of potential COVID-19 infection means that some may unknowingly work and spread the virus. This no doubt is one reason the virus has spread so rapidly.
Comment: A large critical care experience derived from Northern Italy had 1591 patients who 68% had 1 comorbidity and 82% were male. Mortality as of the 3/25/20 writing date was 26%.
Comment: An entry into the PRO potential for routine aerosolization of SARS-CoV-2. Viral RNA (unclear if infectious) found in toilet areas but not in ventilated isolation words. Levels also seen in areas prone to crowing including medical staff areas.
Comment: High dose CQ suggested to contribute to mortality. 440 patients, 81 were enrolled (41 [50.6%] to a high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instances of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).
Comment: Patients in this Chinese retrospective study were older (median 68 yrs), male (73%) and had cardiovascular disease, including hypertension. While ARDS was common, acute cardiac injury and heart failure were also felt to contribute to high mortality.
Comment: SARS paper that may inform COVID-19 infection. Benefit from convalescent plasma for treatment suggested by earlier discharge.
Official website of the Johns Hopkins Antibiotic (ABX), HIV, Diabetes, and Psychiatry Guides, powered by Unbound Medicine. Johns Hopkins Guide App for iOS, iPhone, iPad, and Android included. Complete Product Information.