Coronavirus COVID-19 (SARS-CoV-2)

Updated: September 14, 2020

MICROBIOLOGY

  • Coronaviruses
    • Positive sense, single-strand enveloped RNA virus belonging to the family Coronaviridae.
    • Coronavirus name derived from the Latin corona, meaning crown. Viral envelope under electron microscopy appears crown-like due to small bulbar projections formed by the viral spike (S) peplomers.
  • This topic covers the novel coronavirus 2019 (2019-nCoV) now referred to as SARS-CoV-2.
  • For discussion of other coronaviruses, see individual highlighted modules:
    • Coronavirus for common human respiratory coronavirus infections.
    • SARS for the SARS-CoV virus, not known to circulate since 2002–2003.
    • MERS for the MERS-CoV virus, causing sporadic infections, mostly in the Arabian peninsula since 2012.
    • Coronaviruses also commonly infect birds and mammals causing gastroenteritis and respiratory infections.
  • SARS-CoV-2 appears to be a zoonotic infection that has adapted to humans.
    • Origin is uncertain although bats implicated as this virus most closely related by genetic analysis to bat SARS-like coronavirus (genus Betacoronavirus, subgenus Sarbecovirus). An intermediary, the scaled mammal pangolin, has also been invoked as a potential bridge for the jump to humans.

CLINICAL

  • COVID-19 (novel COronaVIirus Disease-2019) is the disease, SARS-CoV-2 is the virus.

Epidemiology

  • COVID-19 cases
    • Reported worldwide in all continents except Antarctica.
      • Declared a pandemic by the WHO. Unlikely this virus will disappear and may become part of the repertoire of respiratory viruses that infect humans regularly.
    • Real-time global reports available through Coronavirus COVID-19 Global Cases Dashboard by Johns Hopkins CSSE.
    • In the U.S., states with high rates in the early phase of the pandemic, many have low rates now, although exceptions and more localized outbreaks occur, e.g., California. Many other states not greatly impacted earlier are now experiencing high caseloads, including rural regions.
      • Increased cases attributed to lack of cohesive public health recommendations, super-spreader events, return to work and possibly school, lack of social distancing/wearing face masks (especially younger adults).
  • Risk groups
    • Older age, especially > 65 yrs and people with comorbidities appear more likely to develop an infection with severe symptoms and be at risk for death.
      • Age gradient, with > 85 years highest; 80% of U.S. deaths are age > 65 years.
      • CDC reports 94% of COVID-19-related deaths to have at least one comorbidity present.
    • Comorbidity risks:
      • Definite: cancer, chronic kidney disease, COPD, immunocompromise from solid organ transplant, obesity/BMI > 30, serious cardiovascular disease, sickle cell disease, type II diabetes mellitus
      • Possible increased risk (limited data): asthma (moderate-severe), CVA, cystic fibrosis, hypertension, immunocompromise from immunodeficiency/bone marrow transplant, neurological conditions (e.g., dementia), liver disease, pregnancy, pulmonary fibrosis, smoking, thalassemia, type 1 diabetes mellitus.
    • Younger adults are also being hospitalized in the U.S., reflecting increasing percentages in many states, summer 2020.
      • Adults 20–44 account for 20% of hospitalizations, 12% of ICU admissions.
    • In the U.S.:
      • Obesity appears to be emerging as a risk factor, BMI ≥ 30, in nearly half of hospitalized patients.
    • Blacks, Native Americans and Latinx appear to be hospitalized at rates greater than expected on a population basis.
    • Children appear less symptomatic with infection and less prone to severe illness.
      • Children < 1 yr at high risk for severe illness
      • Children 1–10 yrs: low risk of disease and transmission
      • Children 10–18 yrs: higher risk of disease compared to 1–10 yr group; however, higher risk of transmission in some studies than adults.
      • CDC suggests children with medically complex diseases including neurologic, genetic, metabolic conditions, or who have congenital heart disease are at higher risk for severe illness from COVID-19.

Transmission

  • By respiratory droplets predominantly, but aerosolization possible from speaking or singing (especially indoors/prolonged exposure) > fomite. Virus found in respiratory secretions and saliva.
  • Viral shedding by asymptomatic people may represent 30–60% of total infections, though some uncertainty remains regarding how much they contribute to totals.
    • Viral shedding may antedate symptoms by 1–2 days.
    • Viral titers are highest in the earliest phases of infection.
  • Why widespread and rapid transmission occurs is not completely understood.
    • Asymptomatically infected people (an estimated 35% of cases per CDC) who shed and spread is a likely explanation.
      • People who are not ill will not as carefully take measures to avoid spread.
      • Mass gatherings especially indoors in smaller spaces or with poor ventilation appear to enhance transmission.
      • This is in large part the rationale behind universal mask use.
    • Aerosol spread appears possible in some settings.
      • Airborne transmission frequency is debated, evidence of viral RNA beyond expected droplet range especially indoors if poor ventilation exists.
        • Unclear if infectious, and may be due to droplets circulating further than 6 ft or partial aerosolization with some activities.
        • Some widely publicized evidence is based on experimental aerosolization rather than human studies.
      • To date, there has not been a well-documented outbreak traced to aerosol transmission at a distance (e.g., through HVAC ventilatory systems or airplane ventilation).
    • Whether droplet or aerosol, concern for spreading by those ill or not ill but infected is the rationale for the universal wearing of masks while in public or if cannot maintain social distancing, at least six feet.
    • Stool shedding also described later in the disease, but uncertain what role, if any, that plays. Some researchers using as a tool to predict community outbreaks.

Incubation period and viral shedding, quarantine or airborne isolation

  1. Mean incubation 5–6 days, range 2–12
  2. For people quarantined, 14d observation recommended to exclude infection or 10d have passed since symptom onset and 24h without fever or respiratory symptoms.
    • For close contacts, unless person exposed had confirmed COVID-19 within the prior 3 months (assumed to be protected).
  3. Viral shedding as infectious risk
    • Occurs following recovery but does not appear to play a role in transmission in relatively healthy people >10–14d following the onset of infection (though viral RNA may be detected long after).
    • In ill hospitalized patients or those with health problems, it may not be so short, but 28d is a conservative stance used by some hospitals to remove airborne precautions rather than the two negative nucleic acid tests (NAT) rule.
      • CDC has differences that don’t reflect occasional patients noted with cultivable virus > 20 days. Patients with severe to critical illness or who are severely immunocompromised1:
        • At least 10 days and up to 20 days have passed since symptoms first appeared and
        • At least 24 hours have passed since last fever without the use of fever-reducing medications and
        • Symptoms (e.g., cough, shortness of breath) have improved
        • Consider consultation with infection control experts
  4. Some suggest that high viral load may equate with disease severity, but studies to date have not standardized.

Symptoms

  • May occur 2–14 d after exposure (most data are taken from hospitalized patients or presenting for emergency care, less clear about presenting symptoms for the less ill)
  • Fever (44%–98%)
    • Range may be lower at initial hospital presentation or in the outpatient setting.
  • Cough (46–82%, usually dry)
  • Shortness of breath at onset (31%)
  • Myalgia or fatigue (11–44%)
  • Loss of taste or smell
    • Potential sign in early infection, but not unique to COVID-19 as may be seen with other viral infections

Less common symptoms:

  • Pharyngitis
  • Headache
  • Productive cough
  • GI symptoms including diarrhea, nausea, vomiting or abdominal pain
    • Have been described as a presenting symptom and potentially heralding more severe illness
  • Hemoptysis
  • Chest pressure or pain
  • Confusion
  • Cyanosis
  • Skin changes (chilblains or COVID toes)

Disease spectrum

  • Although severe COVID-19 illness is mostly a lower respiratory tract infection, early and mild cases may have features of upper respiratory tract viral infection.
  • ~80% of infections are not severe, and patients recuperate without special treatment.
    • Especially true for children and younger adults
  • ~20% develop respiratory complaints (higher risk if elderly or comorbidities).
    • 12–20% require hospitalization
    • ~2–4% require ICU care
  • Overall mortality risk: 0.5–1.0% (influenza 0.1%), but higher with risk factors and age gradient (highest if > 85 yrs, e.g., 10–27%).
  • For hospitalized patients with pneumonia, limited studies suggest the disease course, true especially of older patients, those with comorbidities:
    • ~50% develop hypoxemia by day 8
      • Severe illness and cytokine release syndrome appear to develop mostly within 5–10d after symptom onset in susceptible patients.
      • Markers of a severe infection include regular high fevers (>39°C), RR > 30, worsening oxygen requirements (4–6L nasal cannula), also elevated IL-6 levels (> 40–100), CRP, ferritin, d-dimer.
      • ARDS develops in 17–29% +/- multiorgan system failure.
    • Patients in the ICU often require mechanical ventilation with prone positions recommended if poor lung compliance; ECMO used in some centers.

Viral kinetics/immunopathogenesis:

  • Uncertainty why

Laboratory and imaging findings

  • In COVID-19 pneumonia
    • Leukopenia in ~70% of hospitalized patients.
    • LDH may be modestly elevated.
    • LFTs elevated more commonly than in typical Community-Acquired Pneumonia cases
    • Note: the detection of other respiratory viruses in COVID-19 may be as high as 20%.
      • Lab detection of viruses such as RSV, influenza, etc. should not result in the conclusion that SARS-2-CoV is not present.
    • Chest CT may show ground-glass opacities that may evolve into consolidation or ARDS.
      • Findings appear to peak at 10d of illness, resolution begins after day 14.
      • CT may show lung findings (such as ground-glass opacities) before the development of symptoms.
    • Among hospitalized patients, about one-third need to be in the ICU/intubated with an ARDS picture.
      • Elevations in IL-6 (> 40–100), CRP (> 10x normal), ferritin (> 1000) suggested correlating with a cytokine release syndrome-like picture and impending ARDS.

Differential diagnosis

  • COVID-19 cannot be easily distinguished from other causes of a viral respiratory infection such as influenza, RSV, other respiratory viruses or community-acquired pneumonia based only on clinical grounds.
    • Influenza may be more abrupt onset; COVID-19 often with more taste and smell perturbations.
    • Multiplex testing will be available for the 2020-2021 respiratory season; however, unclear how many units available to institutions and if used as first-line or tests used in another capacity.
  • Also, consider pulmonary embolus, acute myocardial infection, chest crisis (sickle cell disease), etc.
    • Thromboses complicate critical COVID-19 patients with significant frequency, in some series up to 40%.

COVID-19 testing

  • Testing capacities have improved in many locations, but due to infection control needs, they are usually restricted to certain locations. Additional information through CDC.
    • Exact sensitivity not known; however, the general feeling is that they may miss 20–30% depending on technique and timing of illness, so repeat swab needed if high suspicion. Lower respiratory tract samples are noted to have higher yields.
    • Detection of viral RNA ≠ infectious virus, necessarily but probably so at least the first 10d of symptoms.
  • MOLECULAR
    • Nasopharyngeal (NP) swab specimen is the norm, other samples used include oropharyngeal, saliva, lower respiratory samples.
    • CDC recommends approved assays that detect SARS-CoV-2 nucleic acid or antigen from respiratory tract samples. CDC has further guidance on details for specimen collection, handling and other aspects.
    • Some assays are point-of-care, others may take 1–2 or more days depending on how they are sent and processed.
    • Lower tract specimens may have a higher yield than the upper tract (nasal, oropharyngeal or nasopharyngeal). The false-negative rate is not well known, but may range as high as 30% and depends on when in the course of the disease the testing is done, with later testing having lower rates of detection. The specificity of molecular RNA assays is excellent. Antigen testing has a lower sensitivity than viral RNA assays.
    • Five categories of people with testing recommendations:
      • Signs and symptoms of COVID-19 present
        • Consider testing for other viral infections, e.g., influenza
        • For people with extensive contact with vulnerable populations (e.g., HCWs), even mild symptoms should prompt testing.
      • Asymptomatic but known or suspected exposure to an individual COVID-19 (+)
        • Official CDC guidance changed in August to reflect no need but an option to test close contacts. Stance widely controversial, many advocate testing and contract tracing.
        • Expanded testing in congregate living situations, workplaces, etc. may be indicated to assess/prevent outbreaks.
      • Asymptomatic but without known exposure
        • Testing especially if in close-quarter living or workplaces (correctional facilities, LTACs, homeless shelters, high-density critical infrastructure workplaces)
        • The goal is to ascertain the early identification of cases to prevent spread.
      • Testing to determine the resolution of infection
        • Instead of time and symptom-based resolution, now preferred.
          • Less useful due to prolonged viral RNA detection in many patients following resolution of infectious illness.
          • Situations that may be considered: to discontinue precautions in healthcare settings, to discontinue isolation of patients not in healthcare settings, as part of criteria to return to work in HCWs with suspected or confirmed COVID-19.
      • Public health surveillance
        • Other considerations that may guide testing are epidemiologic factors such as the occurrence of local community transmission of COVID-19 infections in a jurisdiction.
  • ANTIGEN
    • FDA-licensed tests detect viral proteins, e.g., SARS-CoV-2 spike protein.
    • Sensitivity is lower than molecular tests; however, the advantage is a quick turnaround time.
  • SEROLOGIC
    • Antibody-based tests for COVID-19 may have high rates of false-positive testing if used in low-positive-predicative value scenarios (e.g., screening as in "Have I had COVID-19?")
      • Tests have high analytic sensitivity and specificity; however, these are on known or spiked samples. Real-world testing, especially if low probability of infection, makes these tests much less accurate, prone to false positives.
    • Not recommended as the sole basis for diagnosis. Therefore currently available assays do not equate with an "immunity passport" if positive, unclear if they equate with protective immunity.
      • The test may be used to support a clinical diagnosis if a patient has high likelihood of infection but negative viral RNA testing, e.g., patient with fever, cough, ground-glass infiltrates but negative SARS-CoV-2 NAT testing.
      • FDA has warned not to use these tests yet to implicate authentic infection, protective immunity, or to rule out infection.
        • Cannot rule out infection except with molecular respiratory tests
        • Positive results may be due to past or present infection with non-SARS-CoV-2 coronavirus strains, such as coronavirus HKU1, NL63, OC43, or 229E.
      • In the future, with more evaluation against validated banks of sera (positive and negative controls) or multiple antibody-based tests for SARS-CoV-2 may be shown to have higher specificity.
    • Serologic response to SARS-CoV-2
      • One study found the serologic response to a recombinant SARS-CoV-2 nucleocapsid: IgM 85.4%, IgA 92.7% (median 5d after the onset of symptoms), and IgG 77.9% (14d after onset).[18]
      • Another study from China using IgM and IgG SARS-CoV-2-specific antibodies found < 40% seropositive if illness less than 7d, rising to ~100% 15d or more after onset.
      • Asymptomatically infected individuals produce antibodies to lesser levels and may fall below levels of detection within 2–3 months.[19]
  • VIRAL CULTURE
    • Not recommended, except for research purposes (requires BSL-3 lab)

SITES OF INFECTION

  • Like many severe viral infections, a growing list of potential associations and complications.
  • Progressive illness including the hyperinflammatory phase may cause multi-organ system failure.
  • Pulmonary
    • Pneumonia with characteristic ground-glass infiltrates, later with evolution to ARDS.
    • Co-infection with other viruses described
  • GI
    • Some patients have nausea, vomiting, or diarrhea at the onset.
      • May herald more serious disease
    • The virus has been recovered from stool, but the significance is uncertain.
  • CNS: encephalopathy not uncommon but true encephalitis (abnormal CSF and detection of the virus) appears rare.

TREATMENT

General

  • Location of care
    • Depending on the capabilities of local health systems, public health officials may recommend those with minor symptoms to stay home and not seek care in health clinics or hospitals.
    • Medical care focused on those who are short of breath, have severe symptoms, or require oxygen and supportive care that is only available in a hospital.
  • In-hospital supportive care
    • Oxygen, mechanical ventilation if needed
    • Prone positioning appears helpful if hypoxemia worsens despite intubation and ventilation.
  • Secondary infections, especially in severe/critically ill patients – reports not well described to date but appear to occur:
    • ICU patients: 13–44%
    • Factors to consider (mostly China, NY hospital reports)
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15%
      • Steroids in 25–80% of seriously ill pts

Drug Treatment

  • Many types of drugs are under investigation including antivirals (protease inhibitors, influenza drugs, nucleoside analogs), immunomodulators, and surface protein antagonists such as lecithins.
  • Caution is advised as to whether the proposed drugs are effective or safe for COVID-19.
  • If a clinical trial available, consider enrolling patients rather than prescribing off-label drug use to assist in understanding whether intervention is efficacious for COVID-19.
  • If considering off-label use of available medication, consider data known, risks of drug therapy. Many limit considerations only to patients at high risk for serious COVID-19 disease.
  • Johns Hopkins Medical Institution Guidance Document (PDF document) is available with frequent updates for a more complete discussion of risks/benefits of investigational and off-label medications for COVID-19.

Antivirals

  • Much like with influenza, antiviral drugs if effective likely need to be started early in the infection course or used as a preventative.
  • FDA expanded its EUA (8/28/20) to allow use for all patients hospitalized for COVID-19; however, data for patients not requiring oxygen is not supportive, hence this Guide recommends using for severe COVID-19, requiring oxygen.
  • Remdesivir (RDV)
    • Based on the Adaptive Covid-19 Treatment Trial (ACTT), RDV appears most beneficial if given for severe COVID-19 before mechanical ventilation, reduces the length of hospital stay.
    • Remains investigational and is not FDA-approved, but available by emergency use authorization (EUA) by FDA.
      • As of August 2020, the drug may be purchased (instead of the earlier donated drug), but distribution allocated by states to hospitals. Many hospitals developing their own allocation system given the scare resource.
    • Preliminary results of an NIH-sponsored clinical trial (ACTT; NCT04280705) for COVID-19 patients with evidence of lung involvement:
      • The median time to recovery was reduced by 31% (11d v 15d).
        • Median days onset of symptoms (9d) prior to enrollment.
      • The mortality trend suggested (8% v 11.6%) but not statistically significant, but just missed so.
      • The benefit appears derived in this trial in patients started on RDV prior to mechanical ventilation.
      • Investigators concluded that benefit was accrued to patients prior to the need for mechanical ventilation, highly suggestive that this antiviral yields greater benefit the earlier it is initiated.
      • NIH has suggested that this drug will be standard for comparison in adaptive clinical research trials.
    • Another RCT, from China, did not show a benefit but did note a mortality trend toward benefit.[5]Additional trials in progress.
EUA for Use of Remdesivir to Treat Hospitalized Patients with COVID-19[42]

Patient Status

Treatment Duration

Dosing and Administration

Receiving mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

10 days (would not continue past 5d if no improvement)

  • Day 1 (loading dose): Remdesivir 200 mg IV
  • Days 2 through 9: Remdesivir 100 mg IV daily

SaO2 ≤94% on room air or supplemental oxygen required

5 days; if no improvement after 5 days, continue for an additional 5 days

  • Day 1, loading dose: Remdesivir 200 mg IV
  • Days 2 through 5: Remdesivir 100 mg IV daily

Other candidate antiviral therapies: only widely discussed drugs listed below

  • Lopinavir/ritonavir (LPV/RTV)
    • Widely used in China and elsewhere; however, COVID-19 RCT in hospitalized patients who also received other medications yielded no benefit but was given relatively late in the disease course[10]
  • Chloroquine (CQ) or hydroxychloroquine (HCQ)
    • Based on the arm of the RECOVERY trial showing no clinical benefit, and other clinical data with cardiotoxicity concerns
  • Oseltamivir
    • Frequently prescribed because of concern of influenza, which is clinically similar to COVID-19; no known effectiveness against SARS-CoV-2
  • Baloxivir
    • No known activity
  • Favipiravir (aka T-705, Avigan, or favilavir)
    • An anti-influenza drug available in China and Japan; in clinical trials, with preliminary promising results
  • Ribavirin
    • Often proposed along with an interferon product to treat RNA viruses; in clinical trials

Immunomodulators

  • Many agents under consideration in clinical trials or proposed roles
  • Most initial interest regards anti-IL6 agents, to interrupt hyperinflammatory responses that resemble cytokine-release syndromes and cause lung injury.
  • RCTs are in progress to examine the impact on both the early and late use of such drugs.
  • Dexamethasone
    • Preliminary results from the RECOVERY trial showed dexamethasone 6 mg PO or IV daily for up to 10 days reduced 28-day mortality in certain groups of hospitalized COVID-19 patients: recommended for patients with severe COVID-19 (requiring oxygen) including those on mechanical ventilation by the NIH[3] and IDSA[2].
Effect of Dexamethasone on 28−day Mortality by Level of Respiratory Support[21]

Respiratory Support at Randomization

Dexamethasone

Usual Care

*Statistically significant

No oxygen received

17.0%

13.2%

Oxygen only*

21.5%

25.0%

Invasive mechanical ventilation*

29.0%

40.7%

  • 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[4].
  • Tocilizumab
    • An FDA-approved anti-IL6R agent for CAR-T cell cytokine release syndrome; limited supplies in the U.S.
      • Advocated in the Chinese Guidelines; anecdotal reports and case series from large centers with experience suggest some with rapid improvement, with improved oxygenation often within 24–48 hrs of administration.
      • No RCT data yet to show effectiveness, one Phase 3 trial reported in press release (Roche) did not reach primary or secondary endpoints, compared to placebo.
        • Some suggest it may be more effective earlier in the disease course (worsening pulmonary status, peri-intubation) than in ARDS (many days on the ventilator) with lung and organ injury more advanced.
        • Additional trials in progress.
    • Dosing typically 8 mg/kg x single dose
  • Interferon 1b
    • RCT from Hong Kong found when used with lopinavir/ritonavir and ribavirin (triple therapy) versus LPV/RTV alone, the triple therapy yielded quicker clinical improvement and reduced viral shedding.
    • Suspect most of the benefits derived from interferon; however, many hesitant to use since it tends to make people feel terrible
    • Phase II inhaled formulation trial yielded favorable results.
  • Other potential drugs under discussion or study; some use anecdotally reported:
    • Tocilizumab (anti-IL6R) part of initial Chinese COVID-19 guidelines, no supportive RCTs to date. Would not recommend use except in a clinical trial.
    • Sarilumab (anti-IL6R)
      • Failed trial, Phase III.
    • Siltuximab (anti-IL6)
      • 11 mg/kg IV x single dose
    • Anakinra (anti-IL1)
    • anti-GM-CSF
    • GM-CSF
  • Monoclonal antibodies, specific to SARS-CoV-2, in development.

Convalescent plasma or serum; or IVIG

Convalescent plasma (CP) or serum-containing neutralizing antibodies against SARS-CoV-2

  • Proposed as a useful treatment, no large RCT yet to show benefit.
    • NIH Guidelines say there is neither strong data for or against its use.
    • FDA EUA (8/23/20) approved the use of convalescent plasma and replaces the previous expanded access program.
      • High- or low-titer convalescent plasma to be used; however, a 90-day grace period to use existing non-titered supply issued by the FDA (9/2/30) and includes details for use of the investigational agent under the EUA.
      • Single-patient eIND also remains available.
  • RCTs for prophylaxis, early and late COVID-19 treatment are in progress.
    • Mostly observational, matched cohort trials suggest benefit, especially if used early.
    • Though no placebo is cited in the data, experience under the expanded-access program suggests few side effects, suggesting adequate safety.
  • Prior treatment studies
  • Studies in COVID-19
    • Pre-print of expanded-access CP upon which FDA based EUA suggested a subgroup benefited if < 80 years, ≤ 3 days of hospitalization; those who received high titer CP (compared to low titer), had a mortality benefit[43].
    • RCTs (mostly small, underpowered) have not shown mortality benefit to date, although a meta-analysis of observational studies suggests early use does have an impact[44].
  • Risks
    • Pathogen transmission (~1 per 2 million transfusions for HIV/HBV/HCV)
    • Allergic transfusion reactions
    • Transfusion-associated circulatory overload (TACO)
    • Transfusion-related acute lung injury (TRALI)
      • Risk < 1 per 5000, potentially higher in COVID-19 due to pulmonary epithelial injury
      • Risk lower if routine donor screening includes HLA antibody screening of female donors with a history of pregnancy.

Intravenous immunoglobulin (IVIG)

  • Proposed as an intervention in the setting of viral-induced lung injury/ARDS that appears to be due to disordered regulatory T cells with a hyperimmune response
  • Better characterized in influenza-related ARDS, but COVID-19 appears similar.
  • Pooled IVIG reduces immune responses through multiple mechanisms including lessening interrupting complement cascade, lessening activated CD4+ and cytotoxic CD8+ T cells.
  • No clinical trial data to back use

Monoclonal antibodies specific to SARS-CoV-2

  • May become an alternative to convalescent plasma or serum when available. Studies are in progress.

Prevention

  • No vaccine is currently available.
    • Multiple candidate vaccines are in development.
    • Convalescent plasma or serum has been proposed; studies are underway.
  • As a newly described virus, much remains to be learned.
    • Travel restrictions, quarantines, school/work closings, social distancing are helpful to lower Ro (contagiousness of infection), but whether to loosen or lift is a considerable debate among public health officials and politicians.[7]
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season
  • Healthcare workers and health systems in the U.S.
    • Recommend following CDC Guidance for Risk Assessment and Public Health Management of SARS-CoV-2[41]
    • Debate exists whether standard contact and respiratory droplet precautions are sufficient (as with SARS, MERS) versus aerosol/airborne precautions.
      • Current CDC recommendations are for aerosol (e.g., use of negative pressure isolation) airborne precautions.
  • General measures recommended:
    • Avoid sick individuals.
    • Wash hands with soap and water x 20 seconds before eating, after cough/sneezing or bathroom visits.
    • Social distancing maneuvers include keeping spacing >6 feet from other people.
    • Masks now universally recommended when in public.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.

Complications

  • Thrombosis: increasing reports of substantial rates of DVT and PE in critically ill patients. Some centers using low-molecular-weight heparin for prevention; others calling against, citing paradoxical clotting.
    • MI, CVA also appear with unusual frequency.
    • Unclear if COVID-19-associated incidence of venous thromboembolism higher than what is reported customarily in ICU populations despite prophylaxis (~8-9%) as only "high incidence" centers reporting.
  • HLH-like changes described in a subset of patients who died, autopsy findings.
  • CNS: Encephalitis (rare) or encephalopathy
  • Secondary infection
    • Limited data on incidence because many COVID-19 patients are treated empirically with antibacterials for pneumonia.
    • Appears particularly in critically ill patients and those with prolonged hospitalizations.
    • Wuhan experience suggested a 10–20% incidence of bacterial and fungal infections, with a higher percentage in patients who died.
    • Anecdotal experiences growing regarding concern for the development of pulmonary aspergillosis.

Selected Drug Comments

Drug

Recommendation

Dexamethasone

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.

Hydroxychloroquine

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.[20] Drug is not recommended by any mainstream experts or authorities.

Remdesivir

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. Although August FDA EUA expanded use to all hospitalized patients, there is no compelling data to use it in patients without oxygen needs are who are critically ill at the start of therapy.

FOLLOW UP

  • Case fatality rates highly variable in regions, different countries. Unclear why and may be multifactorial.
  • Preliminary evidence in humans and SARS-CoV-2 infected rhesus macaques suggest that reinfection does not occur.
  • Recovery from COVID-19 produces antibodies, but the response is heterogeneous, especially lower in asymptomatic infected patients, and measurable responses may diminish significantly in as little as 2–3 months. The protective immunity duration is unclear. T cell responses also likely important. Not yet clear what is required to prevent a second infection.
  • Advice for COVID-19 (+) patients and self-isolation/quarantine: further details, CDC.
    • Inpatients:
      • Healthcare settings: no longer a requirement for 2 sequential negative COVID-19 RT-PCR tests before airborne precautions can be lifted, as viral RNA has been detected (so-called re-positives), for up to 12 weeks or longer.
      • CDC (7/17/20) changed from a testing alogrithm to a time-based assessment.
        • Except for rare situations, a test-based strategy is no longer recommended to determine when to discontinue transmission-based Precautions.
        • For patients with severe to critical illness or who are severely immunocompromised, transmission-based precautions are extended to 20 days after symptom onset (or, for asymptomatic severely immunocompromised patients, 20 days after their initial positive SARS-CoV-2 diagnostic test).
    • Outpatients:
      • CDC (7/17/20 update), also time-based, no less than 10d after symptom onset.
        • Changed from “at least 72 hours” to “at least 24 hours” have passed since
          • The last fever without the use of fever-reducing medications.
          • Also changed from “improvement in respiratory symptoms” to “improvement in symptoms” to address the expanding list of symptoms associated with COVID-19.
        • Patients who have impaired ability to make antibodies (e.g., immunosuppressed patients) are likely to shed virus longer.

OTHER INFORMATION

  • Testing for viral RNA now may include asymptomatic in addition to symptomatic patients.
  • Severe illness strikes much the same populations at high risk for complications of seasonal influenza (e.g., elderly, immunosuppressed, obesity and comorbidities).
  • The case fatality rate is probably higher than seasonal influenza (≤0.1%) but may be lower than initially reported (~ 2–4%), but careful epidemiology surveys in progress; it may be different in some countries as social distancing interventions and other factors differ.
    • Current estimates suggest COVID-19 is ~6–12x worse than seasonal influenza but has a steep age gradient.

See also

Basis for recommendation

  1. Hanson KE. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, last updated 5/6/20, [accessed 7/31/20]. [https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostic...]

    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.

  2. Bhimraj A, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 [last updated 9/4/20]

    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.

  3. NIH COVID-19 Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/ (last updated 9/4/20 accessed 9/13/20)

    Comment: The most important drug recommendations below, but document also handles HCQ, CQ and other issues in the 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.
    Convalescent Plasma: insufficient information for or against use. Should not be a standard of care. RCTs needed.
    IL-6 inhibitors (e.g., tocilizumab): recommended against use except in a clinical trial. RCTs to date have not shown efficacy.

References

  1. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020.  [PMID:32876694]

    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.

  2. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.  [PMID:32423584]

    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
    Findings:
    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

  3. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32445440]

    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.

  4. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020.  [PMID:32144116]

    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."

  5. Mizumoto K, Chowell G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6).  [PMID:32168464]

    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.

  6. Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020.  [PMID:32163697]

    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.

  7. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020.  [PMID:32187464]

    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.

  8. Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020.  [PMID:32191259]

    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.

  9. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020.  [PMID:32219428]

    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.

  10. CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346.  [PMID:32214079]

    Comment: US experience to date differs from China’s experience in that a higher proportion of hospitalizations are among the not elderly.

  11. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA. 2020.  [PMID:32215590]

    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.

  12. Jin X, Lian JS, Hu JH, et al. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut. 2020.  [PMID:32213556]

    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.

  13. Giacomelli A, Pezzati L, Conti F, et al. Self-reported olfactory and taste disorders in SARS-CoV-2 patients: a cross-sectional study. Clin Infect Dis. 2020.  [PMID:32215618]

    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.

  14. Lescure FX, Bouadma L, Nguyen D, et al. Clinical and virological data of the first cases of COVID-19 in Europe: a case series. Lancet Infect Dis. 2020.  [PMID:32224310]

    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.

  15. Guo L, Ren L, Yang S, et al. Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19). Clin Infect Dis. 2020.  [PMID:32198501]

    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%).

  16. Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020.  [PMID:32555424]

    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

  17. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020.  [PMID:32492293]

    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.

  18. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32678530]

    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.

  19. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.  [PMID:31978945]

    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.

  20. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.  [PMID:32015507]

    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.

  21. Bajema KL, Oster AM, McGovern OL, et al. Persons Evaluated for 2019 Novel Coronavirus - United States, January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(6):166-170.  [PMID:32053579]

    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.

  22. Benvenuto D, Giovanetti M, Salemi M, et al. The global spread of 2019-nCoV: a molecular evolutionary analysis. Pathog Glob Health. 2020.  [PMID:32048560]

    Comment: Strain analysis to date of COVID-19 suggests that they are very similar to bat SAR-like coronavirus.

  23. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.  [PMID:32031570]

    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%]).

  24. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020.  [PMID:32101510]

    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.

  25. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020.  [PMID:32112082]

    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.

  26. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020.  [PMID:32821939]

    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.

  27. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020.  [PMID:32235945]

    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.

  28. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32275812]

    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.

  29. Kim D, Quinn J, Pinsky B, et al. Rates of Co-infection Between SARS-CoV-2 and Other Respiratory Pathogens. JAMA. 2020.  [PMID:32293646]

    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.

  30. Chow EJ, Schwartz NG, Tobolowsky FA, et al. Symptom Screening at Illness Onset of Health Care Personnel With SARS-CoV-2 Infection in King County, Washington. JAMA. 2020.  [PMID:32301962]

    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.

  31. Kissler SM, Tedijanto C, Goldstein E, et al. Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science. 2020.  [PMID:32291278]

    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.

  32. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020.  [PMID:32250385]

    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%.

  33. Liu Y, Ning Z, Chen Y, et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature. 2020.  [PMID:32340022]

    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.

  34. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857.  [PMID:32339248]

    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%).

  35. Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.  [PMID:32217556]

    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.

  36. Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis. 2005;24(1):44-6.  [PMID:15616839]

    Comment: SARS paper that may inform COVID-19 infection. Benefit from convalescent plasma for treatment suggested by earlier discharge.

  37. Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons Under Investigation for COVID-19 in Healthcare Settings. U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov/coronavirus/2019-ncov/infection-control/control-recomm...]
  38. Interim U.S. Guidance for Risk Assessment and Public Health Management of Healthcare Personnel with Potential Exposure in a Healthcare Setting to Patients with Coronavirus Disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html](accessed 6/26/20, last updated 7/31/20]

    Comment: Contact tracing has been shortened from 10d to 2d, for operational reasons, and based on data suggesting lower viral shedding in asymptomatic individuals.

  39. COVID-19 Update: FDA Broadens Emergency Use Authorization for Veklury (remdesivir) to Include All Hospitalized Patients for Treatment of COVID-19 (8/28/20)

    Comment: FDA broadens use of RDV for all hospitalized patients based on ACTT-1 and the SIMPLE trial. However, there is little data to support use in patient who do not require oxygen.


  40. Joyner M, et al Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience; MedRxIV
    accessed 9/13/20

    Comment:

    In this trial without placebo, a dose-response analysis suggested such that the pooled relative risk of mortality among patients transfused with high antibody level plasma units was 0.65 [0.47-0.92] for 7 days and 0.77 [0.63-0.94] for 30 days compared to low antibody level plasma units.

  41. Joyner M, et al. Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy. Medrxiv (accessed 9/13/20)



    Comment:

    Aggregating available trial data, authors argue that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001)

  42. Joyner M, et al. Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy. Medrxiv (accessed 9/13/20)



    Comment:

    Aggregating available trial data, authors argue that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43, P < 0.001). Note that no RCT performed to date has shown such benefit.

  43. Gritti G, Raimondi F, Ripamonti D, et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support, https://www.medrxiv.org/content/10.1101/2020.04.01.20048561v1 (accessed 9/14/20)

    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.

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Last updated: September 24, 2020