Updated: August 5, 2020
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Incubation period and viral shedding
Less common symptoms:
Viral kinetics/immunopathogenesis: three scenarios described:
Laboratory and imaging findings
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Dosing and Administration
Receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
10 days (would not continue past 5d if no improvement)
SaO2 ≤94% on room air or supplemental oxygen required
5 days; if no improvement after 5 days, continue for an additional 5 days
Other candidate antiviral therapies: only widely discussed drugs listed below
Respiratory Support at Randomization
No oxygen received
Invasive mechanical ventilation*
Convalescent plasma or serum-containing neutralizing antibodies against SARS-CoV-2
Monoclonal antibodies specific to SARS-CoV-2
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 the during 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 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 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.
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.
Comment: Guidance endorses use of RDV
Among hospitalized patients with severe* COVID-19, the IDSA panel suggests remdesivir over no antiviral treatment. (Conditional recommendation, Moderate certainty of evidence)
Remark: For consideration in contingency or crisis capacity settings (i.e., limited remdesivir supply): Remdesivir appears to demonstrate the most benefit in those with severe COVID-19 on supplemental oxygen rather than in patients on mechanical ventilation or extracorporeal mechanical oxygenation (ECMO).
Recommendation 9. Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir. (Conditional recommendation, low certainty of evidence)
Guidance endorses use of dexamethasone
Among hospitalized patients with severe* COVID-19, the IDSA guideline panel suggests glucocorticoids rather than no glucocorticoids. (Conditional recommendation, moderate certainty of evidence)
Remark: Dexamethasone 6 mg IV or PO for 10 days (or until discharge if earlier) or equivalent glucocorticoid dose may be substituted if dexamethasone is unavailable. Equivalent total daily doses of alternative glucocorticoids to dexamethasone 6 mg daily are methylprednisolone 32 mg and prednisone 40 mg.
Recommendation 5. Among hospitalized patients with COVID-19 without hypoxemia requiring supplemental oxygen, the IDSA guideline panel suggests against the use of glucocorticoids. (Conditional recommendation, low certainty of evidence)
*Severe illness is defined as patients with SpO2 ≤94% on room air, and those who require supplemental oxygen, mechanical ventilation, or ECMO.
Comment: Most important drug recommendations below, but document also handles HCQ, CQ and other issues in care of patients with COVID-19.
NIH panel recommends:
Dexamethasone for mechanically ventilated patients with COVID-19 (A1 recommendation), and for those who require oxygen (B1). It is not recommended based on the RECOVERY trial for hospitalized COVID-19 patients who do not need oxygen (A1). Dose 6 mg/kg/d x 10d.
Remdesivir for hospitalized patients with SpO2 ≤94% on ambient air (at sea level) or those who require supplemental oxygen (AI).
The Panel recommends remdesivir for treatment of COVID-19 in patients who are on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (BI). Duration of Therapy in Patients with Severe COVID-19 Who Are Not Intubated 5d. For mechanically ventilated or ECMO, 10 d.
There are insufficient data on the optimal duration of therapy for mechanically ventilated patients, patients on ECMO, or patients who have not shown adequate improvement after 5 days of therapy. In these groups, some experts extend the total remdesivir treatment duration to up to 10 days (CIII).
Recommendation for Patients with Mild or Moderate COVID-19:
There are insufficient data for the Panel to recommend for or against remdesivir for the treatment of patients with mild or moderate COVID-19.
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.
Comment: Dexamethasone arm of the RECOVERY trial that supports 6mg/kg/d x 10 as a standard of care for severe COVID-19, especially those on mechanical ventilation due to the mortality benefit.
In this trial, there was a trend toward mortality in those who do not require oxygen, so not recommended in this group usually with early infection. 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 the during 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 mortality endpoint would tend to discount bias to a substantial degree.
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: This trial did not yield benefits when given in hospitalized patients with c19. Whether the drug would work if administered earlier is unclear, but has low in vitro activity against this virus compared to HIV.
Comment: Most notable finding is the high rate of cardiac complications that is unclear whether directly viral or related to critical illness. As this is a small series, further reports are needed to confirm.
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: US experience to date differs from China’s experience in that a higher proportion of hospitalizations are among the not elderly.
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: 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: People evaluated as per this report in the US mostly were those with a history of travel/contacts from Wuhan City, China which is the apparent epicenter of this epidemic. Of 210 people, 148 (70%) had travel-related risk only, 42 (20%) had close contact with an ill laboratory-confirmed 2019-nCoV patient or PUI, and 18 (9%) had both travel- and contact-related risks. Eleven of these persons had a laboratory-confirmed 2019-nCoV infection. Given reports now around the globe, it is unclear if testing only those with potential links to China is prudent, but the current availability of test kits from the CDC likely precludes wider testing until either FDA-approved or EUA approval is given to current commercially available respiratory panels to include COVID-19.
Comment: Strain analysis to date of COVID-19 suggests that they are very similar to bat SAR-like 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: 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: These models examine the potential impacts of whether there is short or longer-term immunity to SARS-CoV-2 or seasonality to the virus. These factors will play into whether there is a resurgence of the virus. Additional factors such as social distancing, therapeutic drugs and vaccines will also play a role.
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.
Comment: Unpublished preprint, using an anti-IL6 mab, in 21 patients with advanced COVID-19 pneumonia or ARDS. Following administration, 33% (7/21) improved, 43% (9/21) stabilized without identifiable change, and 24% (5/21) worsened. This uncontrolled study suggests that if such a drug is helpful for cytokine release syndrome from COVID-19, it may be more difficult to improve the sickest, i.e., ill the longest and with most lung damage.
Comment: EUA by the FDA, distribution federally controlled--unclear how much supply available. The drug remains investigational and is not FDA-approved.
Comment: Though observational data though with ~96,000, another report implicating HCQ or CQ in patients ill with COVID-19 with toxicities, mainly cardiac, with no apparent signal of benefit.
Comment: Unpublished, a not yet peer-reviewed report from China on 21 patients in China hospitalized with COVID-19 and received tocilizumab. Most patients had a marked improvement in oxygen needs within 24h of IL6R mab administration. This suggests that interruption of a key cytokine might reverse the "storm" that appears to cause ARDS and further organ injury in a subset of patients.
Comment: Contact tracing has been shortened from 10d to 2d, for operational reasons, and based on data suggesting lower viral shedding in asymptomatic individuals.
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