COVID-19: Infected individuals are most contagious two days before and three days after symptoms develop

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Each wave of the pandemic has underscored just how gravely contagious COVID-19 is, but there is less clarity among experts on exactly when – and to what extent – infected individuals are most likely to spread the virus.

Now, a new study co-led by a Boston University School of Public Health (BUSPH) researcher has found that individuals infected with the virus are most contagious two days before, and three days after, they develop symptoms.

Published in the journal JAMA Internal Medicine, the study also found that infected individuals were more likely to be asymptomatic if they contracted the virus from a primary case (the first infected person in an outbreak) who was also asymptomatic.

“In previous studies, viral load has been used as an indirect measure of transmission,” says Dr. Leonardo Martinez, assistant professor of epidemiology at BUSPH, and who co-led the study with Dr. Yang Ge, research assistant in the Department of Epidemiology & Biostatistics at the University of Georgia College of Public Health.

“We wanted to see if results from these past studies, which show that that COVID cases are most transmissible a few days before and after symptom onset, could be confirmed by looking at secondary cases among close contacts.”

Martinez and colleagues conducted contact tracing and studied COVID-19 transmission among approximately 9,000 close contacts of primary cases in the Zhejiang province of China from January 2020 to August 2020.

“Close” contacts included household contacts (defined as individuals who lived in the same household or who dined together), co-workers, people in hospital settings, and riders in shared vehicles.

The researchers monitored infected individuals for at least 90 days after their initial positive COVID test results to distinguish between asymptomatic and pre-symptomatic cases.

Of the individuals identified as primary cases, 89 percent developed mild or moderate symptoms, and only 11 percent were asymptomatic – and no one developed severe symptoms.

Household members of primary cases, as well as people who were exposed to primary cases multiple times or for longer durations of time, had higher infection rates than other close contacts.

But regardless of these risk factors, close contacts were more likely to contract COVID-19 from the primary infected individual if they were exposed shortly before or after the individual developed noticeable symptoms.

“Our results suggest that the timing of exposure relative to primary-case symptoms is important for transmission, and this understanding provides further evidence that rapid testing and quarantine after someone is feeling sick is a critical step to control the epidemic,” Dr. Martinez says.

In comparison to mild and moderate symptomatic individuals, asymptomatic primary individuals were much less likely to transmit COVID to close contacts – but if they did, the contacts were also less likely to experience noticeable symptoms.

“This study further emphasizes the need for vaccination, which reduces clinical severity among people that develop COVID,” says Dr. Martinez.


MICROBIOLOGY

  • Coronaviruses
    • Positive sense, single-strand enveloped RNA virus belonging to the family Coronaviridae.
    • Coronavirus name derived from the Latin corona, meaning crown. The viral envelope under electron microscopy appears crown-like due to small bulbar projections formed by the viral spike (S) peplomers. Neutralizing antibodies against the S-protein are believed to play an important role in protective immunity.
  • This topic covers the novel coronavirus 2019, 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
    • Remains a pandemic by the WHO. It is 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.
      • Despite mitigation strategies, including facial masks and social distancing, upswings in cases attributed to lack of cohesive public health recommendations, super-spreader events, return to work and school activities, lack of social distancing/wearing face masks (especially younger adults), increased transmissibility of viral variants.
        • Many infections are acquired in homes and congregate living.
      • Rates of infection remain considerable in many countries, with the U.S. accounting for the highest number of both cases and deaths worldwide.
      • The emergence of viral variants continues with rapid change. Most notable for higher transmission rates than the ancestral strain; increased virulence less certain. Leading variants of concern (VOC):
        • B.1.1.7 (Alpha), first described in the UK in fall 2020
        • B.1.357 (Beta) identified first in S. Africa
        • P.1 (Brazil)
        • B.1.617.1 (Kappa)
        • B.1.617.2 (Delta), in August 2021 accounts for >83% of sequenced viruses in the U.S.
  • 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 (per CDC): as determined by types of studies
      • High levels of evidence (meta-analysis, systemic reviews): cancer, cerebrovascular disease, chronic kidney disease, COPD, diabetes (types 1 and 2), cardiovascular disease (CHF, CAD, cardiomyopathies), smoking (current or former), obesity/BMI > 30, pregnancy,
      • Cohort or case-control studies: children with certain health problems, Down syndrome, HIV, neurologic conditions, overweight (BMI 25-30), pulmonary disease, solid organ or blood stem cell transplantation, substance use disorders, use of corticosteroids or immunosuppression.
      • Case series or small sample size: cystic fibrosis, thalassemia
      • Mixed evidence: asthma, hypertension, liver disease, immunodeficiencies
      • 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 are hospitalized at rates greater than expected on a population basis, as well as higher mortality rates.
    • Younger adults are also being hospitalized in the U.S., reflecting increasing percentages in many states, and these cases in the later phases of the pandemic account for an increasing percentage of cases.
    • Children appear less symptomatic with infection and less prone to severe illness, although the Delta variant may change these notions.
      • 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, a higher risk of transmission in some studies than adults.

Transmission

  • By respiratory droplets predominantly, but aerosolization possible from speaking or singing (especially indoors/prolonged exposure) > fomite. Virus found in respiratory secretions and saliva.
    • Spread from a fomite, risk considered very low.
  • Viral shedding by asymptomatic people may represent 40–50% of total infections, though some uncertainty remains regarding how much they contribute to totals.
    • Viral shedding may antedate symptoms by up to 3+ days.
    • Viral titers are highest in the earliest phases of infection, 1-2 days before the onset of symptoms, and then in the first 4-6 days of illness in patients without immunosuppression.
  • Why widespread and rapid transmission occurs is not completely understood.
    • Asymptomatically infected people who shed and spread is a likely explanation.
      • People who are not ill will not as carefully take measures to avoid spread.
        • Some are super-spreaders, which may be due to inherent characteristics (e.g., their speech generates aerosol, loud speaking, etc).
      • 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.
      • The amount of airborne transmission frequency is debated, evidence of viral RNA beyond expected droplet range especially indoors if poor ventilation exists.
        • 6-ft distancing remains a routine social distancing recommendation; however, uncovered face/sneezes may generate partial aerosolization with some activities for greater distances.
      • 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 one 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, isolation, quarantine or airborne isolation

  1. Mean incubation 4–5 days, range 2–14
  2. Quarantine and Isolation: some local health departments may have some variation from CDC guidance below.
    1. For COVID-19 illness, the correct term is isolation.
      1. 10d have passed since symptom AND
        1. At least 24 hours with no fever without fever-reducing medication and
        2. Other symptoms of COVID-19 are improving, e.g., loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation​.
      2. A limited number of persons with severe illness or immunosuppression may produce replication-competent virus beyond 10 days that may warrant extending the duration of isolation and precautions for up to 20 days after symptom onset; consider a consultation with infection control experts.
    2. For close contacts with a person with COVID-19, the correct term is quarantine [CDC defined as at least 15 minutes cumulative over 24h, < 6 ft starting two days before illness onset or positive test result if asymptomatic].
      1. 14d observation remains CDC recommended to exclude infection.
      2. Options to decrease to 10d to enhance compliance or 7d if SARS-CoV-2 testing is negative 5-7 after close exposure.
  3. Viral shedding as infectious risk
    • Occurs following recovery but does not appear to play a role in transmission in relatively healthy people >10d following the onset of infection (though some variants may be infectious longer, viral RNA may be detected long after for many weeks; hence, why repeated routine testing for negative SARS-CoV-2 RT-PCR not recommended).
    • In ill hospitalized patients or those with health problems, it may not be so short, but 20-28d is a conservative stance used by some hospitals to remove airborne precautions rather than the two negative nucleic acid amplification tests (NAAT) rule.
      • Rare reports of cultivatable virus > 60 days especially in severely immunocompromised patients.:
        • Low cycle threshold (CT), e.g., < 30 and certainly < 20 may indicate an infectious virus is present.
  4. Some accumulating data suggest that high viral inoculum may lead to increased risk for disease severity.

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 and chills (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
    • Sign of early infection that many experience; however, not unique to COVID-19 as may be seen uncommonly with other viral infection
  • Headache
  • Sore throat
  • Sinus congestion, rhinorrhea
  • Nausea, vomiting or diarrhea

Less common symptoms:

  • 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, although Delta variant is prompting greater hospitalizations in younger populations.
  • ~20% develop significant infection (higher risk if elderly or comorbidities).
    • ~15% require hospitalization
    • ~5% require ICU care
    • Lower percentages for those < 50 yrs even with comorbidities.
  • 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 is used in some centers.

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% (e.g., influenza in spring 2020; however, near-zero for the 2021-2022 respiratory season).
      • 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, for those who are hospitalized.
      • 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 the 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.
    • Anosmia and dysgeusia occur at a much high frequency than with other respiratory viruses; studies have cited ranges from 15-48%.
    • Influenza may be more abrupt onset; COVID-19 often with more perturbations of taste and smell.
    • Increasingly, viral multiplex testing incorporating SARS-CoV-2 is available; however, influenza and RSV rates were very low in the 2020-2021 winter respiratory season.
      • Spring/Summer 2021 saw increasing RSV and other routine respiratory viral infections.
  • 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% especially in the critically ill.

COVID-19 testing

  • Testing capacities have improved but in some locations still result in delays in turnaround for molecular testing. Additional information through CDC.
    • Exact sensitivity is not known; however, the general feeling is that they may miss a small percentage depending on technique and timing of illness, so a repeat swab is needed if high suspicion. Lower respiratory tract samples are noted to have higher yields.
    • Detection of viral RNA ≠ infectious virus, necessarily but is true for the first 10d of symptoms in patients who are not severely ill or immunosuppressed.
      • Cycle threshold values are not standardized and vary among platforms, and are not reported as clinical data. However, if values are available, if in the upper 30s, then a low likelihood that the viral shedding correlates with an active, replicating virus.
  • MOLECULAR
    • Nasopharyngeal (NP) swab specimen is the norm, other samples used include nasal, 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 even for molecular assays may range as high as 10-30% 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
    • 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, usually < 15 minutes.
      • Detects high viral loads, typically occurring with the onset of symptoms until day 7.
    • FDA-EUA approval is only for symptomatic early illness of < 1 week as high viral load is needed to generate a positive assay.
      • Role is best for quick assessment in situations of congregate living, need for fast identification of an outbreak.
        • Repeated testing will increase the risk of false positives but generally can trust a positive to indicate infection.
      • Symptomatic people who test negative by antigen still require follow-up molecular testing.
    • Use for the screening of asymptomatic people is increasing but data are limited. CDC has issued an algorithm with interim recommendations.
      • If high pre-test probability, need to confirm antigen negatives with molecular testing.
      • If low pre-test probability, need to confirm antigen positives with molecular testing.
  • 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?”), especially if using anti-nucleoprotein (N) SARS-CoV-2 antibody testing which may cross-react more commonly with common respiratory coronaviruses.
      • Tests have high analytic sensitivity and specificity; however, these are on known or spiked samples. Real-world testing, especially if the low probability of infection, makes these tests much less accurate, prone to false positives.
      • Clinicians should understand if the antibody assessed is against N or S proteins. Many commercial labs use assays against the N protein; these tests will not detect responses to SARS-CoV-2 vaccines (which employ spike protein).
    • Not recommended as the sole basis for diagnosis. Therefore currently available assays do not equate with an “immunity passport” if positive, unclear at what level they may equate with protective immunity.
      • The test may be used to support a clinical diagnosis if a patient has a 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, 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.
      • Many commercial antibody assays assess for antibodies against the N-protein, so they are not useful for assessing response to COVID-19 immunization, which provokes antibodies against the S-protein.
      • Most helpful for epidemiology.
      • Occasionally helpful to investigate recent illness consistent with COVID-19 but without confirmatory molecular determination.
    • 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).[22]
      • 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.[23]
  • 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 as well as a superinfection with bacteria and molds (especially Aspergillus).
  • 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.
    • Liver: increased LFTs common
  • CNS: encephalopathy is 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 recommend those with minor symptoms to stay home and not seek care in health clinics or hospitals and monitor symptoms.
    • Medical care is 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.
    • ICU patients have high rates of clots (DVT, PE and thrombotic events (CVA, MI).
      • Anticoagulation prophylaxis should be pursued in most patients.
  • Secondary infections, especially in severe/critically ill patients:
    • ICU patients: 13–44%
      • Evaluate and treat bacterial or fungal superinfection (especially Aspergillus)
        • Sputum culture, beta-D-glucan and serum or BAL galactomannan are helpful to incorporate into decision-making.
        • Often “nosocomial” pathogens (ESBL, P. aeruginosa, A. baumannii, Aspergillus spp. )
        • Median time from onset of symptoms: 10–17d
        • The median time to death: 19d, terminal events?
    • Factors to consider (mostly China, NY hospital reports)
      • Frequent antibacterial use received in 80–100%
      • Antifungals in 7.5–15

Drug Treatment

  • Caution is advised as to whether proposed drugs that are not sufficiently tested are effective or safe for COVID-19.
    • If a clinical trial is 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 Hospital Therapeutic Guidance(PDF document)(updated 8/6/2021) is available with frequent updates for a more complete discussion of the risks/benefits of FDA-approved, investigational and off-label medications for COVID-19.

Antivirals

  • Remdesivir (RDV)
    • Based on the Adaptive Covid-19 Treatment Trial (ACTT-1[12]), RDV appears most beneficial if given for severe COVID-19 before mechanical ventilation, which reduces the length of hospital stay (from median 15d to 10d). Many institutions limit initiation to those who require oxygen but not ICU care.
    • FDA approved (Oct 2020) for COVID-19 hospitalized patients, ages ≥ 12 yrs or 40 kg.
      • EUA now issued for use in children < 12 yrs, wt 3.5 – 40 kg.
      • Assess sCr, LFTs and PT INR prior to use.
    • Dose: 200 mg IV load on day 1, then 100 mg IV q 24 days 2-5
      • Infuse over 30-120 min.
      • May extend for an additional 5d if no clinical improvement, especially in patients on mechanical ventilation, ECMO or severely immunosuppressed.
      • Carrier may accumulate in renal insufficiency, but not judged to be clinically significant.
    • Warnings:
      • Don’t use if hypersensitivity reactions ensue.
      • Consider d/c if LFTs 10x ULN.
    • Results of an NIH-sponsored clinical trial (ACTT-1) for COVID-19 patients with evidence of lung involvement:
      • The median time to recovery was reduced by 31% (10d v 15d).
        • Median days onset of symptoms (9d) prior to enrollment.
      • The mortality trend suggested (8% v 11.6%) but not statistically significant.
      • The benefit appears derived in this trial in patients started on RDV prior to mechanical ventilation.
        • NIH COVID-19 Guideline states BIIa recommendation for severe COVD-19 requiring oxygen but not 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.
    • Another RCT, from China, did not show a benefit but did note a mortality trend toward benefit.[13]
    • The Solidarity trial (WHO trial, interim results) had RDV as one of four arms but did not find benefit regarding mortality, LOS or decreasing need for mechanical ventilation.
      • Though large trial, as a pragmatic trial there was no placebo comparator. Also, there were problems with selection and assignment bias, missing data.
    • Most in the U.S. continue to use RDV.

Other candidate antiviral therapies: only widely discussed drugs listed below (see Table for more complete list and references)

  • Fluvoxamine
    • Phase 2 data suggested benefit, unclear mechanism. Awaiting a larger, well-designed trial to evaluate. Insufficient data to recommend for or against.
  • Ivermectin
    • Double-blind, RCT of mild COVID-19 treatment x 5d, without efficacy. Not recommended.
  • Lopinavir/ritonavir (LPV/RTV)
    • COVID-19 RCT in hospitalized patients (RECOVERY) who also received other medications yielded no benefit but was given relatively late in the disease course,
  • Chloroquine (CQ) or hydroxychloroquine (HCQ)
    • Based on the arm of the RECOVERY trial showing no clinical benefit, and other clinical data with cardiotoxicity concerns
  • Among other investigational agents in trials of note: molnupiravir (formerly EIDD-2801) oral antiviral with preliminary evidence of reduced viral shedding, AT-527 (oral).

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
    • 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].
Respiratory Support at RandomizationDexamethasoneUsual Care
No oxygen received17.0%13.2%
Oxygen only*21.5%25.0%
Invasive mechanical ventilation*29.0%40.7%
*Statistically significant

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[11].

  • Two studies suggest preliminary potential benefits with inhaled budesonide:
    • STOIC: Phase 2 trial found a reduced need for medical care and improved time to recovery.
    • PRINCIPLE (preprint): Early interim analysis suggested shorter illness duration by 3d.
  • Baricitinib: an oral JAK1/JAK2 inhibitor that is FDA approved for the treatment of rheumatoid arthritis.
    • FDA EUA approved for ages ≥ 2 yrs COVID-19 in hospitalized adults and pediatric patients requiring supplemental oxygen, invasive mechanical ventilation, or ECMO.
    • ACTT-2 trial compared RDV + baricitinib vs. RDV + placebo
      • The primary endpoint was median time to recovery (defined as discharged from hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care)
        • 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir
          [hazard ratio: 1.15 (95% CI 1.00, 1.31); p=0.047].
      • Most benefit in patients on high-flow oxygen not requiring mechanical ventilation.
    • COV-BARRIER (preprint): 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) not significant.
      • 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 primary endpoint not reached, no difference in groups regarding clots, MIs, CVA, etc.).
    • Dosing:
      • Adults and pediatric patients 9 years of age and older: 4 mg PO once daily
      • Pediatric patients 2 years to less than 9 years of age: 2 mg PO once daily
    • Duration: 14 days or until hospital discharge.
  • 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.
  • Tocilizumab
    • An FDA-approved anti-IL6R agent for CAR-T cell cytokine release syndrome and rheumatoid arthritis.
      • RCTs performed early in the pandemic as monotherapy have not had positive results.
      • More recent studies with high percentages of patients also on dexamethasone have shown benefit.
        • EMPACTA found less progression to ventilation or death if used prior to mechanical ventilation.
        • REMAP-CAP found that patients on high flow oxygen or within the first 24 hours of ICU care contributed most significantly more days of organ-free survival (10d compared to placebo) and decreased mortality.
        • RECOVERY found patients who were on oxygen with evidence of systemic inflammation (e.g., CRP > 7.5), had improved survival, and more likely to be discharged by day 28.
      • IDSA and NIH Guidelines not yet recommended use except in a clinical trial.
    • Dosing typically 8 mg/kg x single dose
  • Lenzilumab (anti-GM-CSF): LIVE-AIR study (preprint), n = 520, severe COVID-19, (69% on RDV, 94% on corticosteroids)
    • Primary endpoint (survival w/o mechnical ventilation): mITT, 16% v. 22%, 54% decrease (HR 1.54, 95% CI, 1.02-2.31)
    • Subgroup < 85 yrs and CRP < 150, 9% vs. 21%, 92% reduction, HR 1.92 (95% CI, 1.20-3.07)
    • Dosed as 600 mg IV q 8h x 3 doses
  • Anakinra (anti-IL1): SAVE-MORE RCT (preprint), 100 mg SQ daily x 10 vs standard of care, hospital stay was shorter and 28-day mortality decreased (hazard ratio: 0.45; P: 0.045).

Antibody-based therapies

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 (revised 2/4/21) now approves the use of only high-titer convalescent plasma.
      • See the FDA fact sheet for healthcare providers for detailed information.
      • Many RCTs remain in progress, but no large trials have yet confirmed benefit although substantial observational data points to subsets of COVID-19 patients who may benefit
        • The subset derived from the expanded access use earlier in 2020 found that the use of high-titer plasma within three days of hospitalization conferred a mortality benefit if received before intubation[4].
        • A small RCT in patients older than 65 years with mild to moderate COVID-19 reduced progression to severe COVID-19 if received within 3 days of onset of illness[5].
        • Retrospective matched cohort study (preprint): CP within 3 days after admission, but not 4-7 days, was associated with a significant reduction in mortality risk (aHR = 0.53, 95% CI 0.47-0.60, p< 0.001).
        • Many RCTs published in 20202 were mostly small, underpowered) have not shown mortality benefit to date, although a meta-analysis of observational studies suggests early use does have an impact.
        • RECOVERY trial yielded no 28d mortality benefit; NIH and IDSA Guidance no longer recommends for hospitalized patients.
          • However, positive data suggest early use (< 3d of symptoms or hospitalization), as well as case reports in immunosuppressed illness suggest there remains a role.
      • Single-patient eIND (updated 11/16/20) also remains available.
      • This author favors use in patients with risk factors for severe COVID-19 if early in illness course or if patients are immunosuppressed (especially with impaired B-cell responses).
  • RCTs for prophylaxis, early and late COVID-19 treatment are in progress.
  • Prior treatment studies
    • Suggest an impact on influenza, SARS, and Middle East respiratory syndrome (MERS)
    • In the largest treatment study against SARS, 80 patients in Hong Kong who were treated prior to d14 had a shorter length of stay defined as discharge before d22.[41]
  • 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

Monoclonal antibodies specific to SARS-CoV-2, in the U.S. only offered to outpatients with mild-moderate COVID-19. Trials in hospitalized patients have not yielded benefits to date.

  • EUAs issued by the FDA for outpatient therapy of COVID-19.
    • Bamlanivimab and bamlanivimab/etesevimab: single or two neutralizing mAbs against the surface spike protein of SARS-CoV-2.
      • Paused distribution until further notice of BAM/ETE by HHS as of 6/25/21, due to less effectiveness against variants of concern (P.1, B.1.356).
    • Casirivimab and imdevimab: two neutralizing mAb against the surface spike protein of SARS-CoV-2. Appears to maintain activity against variants of concern (VOC).
      • Only offered to patients ≥ 12 yrs at high risk for COVID-19 hospitalization or complications.
      • Dose:600 mg of casirivimab and 600 mg of imdevimab administered together (EUA dose change 6/2/21 from 1200/1200).
        • Dosing for treatment may be given either IV or SC.
      • Benefits cited are decreased need for hospitalization or ED visits (6% placebo, 3% in mAb arm)[31].
      • RECOVERY trial (preprint) in hospitalized patients using 4g/4g dose found mortality benefit in patients who were seronegative at the time of administration.
        • As of June 30, 2020, FDA EUA only authorizes treatment for mild-moderate COVID-19 in outpatients, not hospitalized patients.
    • Sotrovimab: single mab that has activity against VOCs. EUA granted 5/21/21 for outpatients with risk factors based on 1% vs 7 % placebo hospitalization or death (85% reduction).

Prevention

  • As a newly described virus, much remains to be learned.
    • Travel restrictions, quarantines, school/work closings, social distancing are helpful to lower R(contagiousness of infection), but the degree of mitigation remains a source of considerable debate among public health officials and politicians.[14]
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season. Co-infections are possible (viral, bacterial, fungal).
  • Healthcare workers and health systems in the U.S.
    • Recommend following CDC Guidance for Risk Assessment and Public Health Management of SARS-CoV-2[42]
    • 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 in healthcare settings.
  • Casirivimab/imdevimab received EUA for prevention of COVID-19 in patients at high risk after close contact (15 minutes cumulatively in a confirmed case over 24h)
    • Dosing is the same as treatment (600mg/600mg) but can be given SQ (requires four 2.5 mL injections) or IV infusion.
  • 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 are now universally recommended when in public, indoors.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.

Vaccines

  • Multiple candidate vaccines are in development.
    • Preliminary data from mRNA vaccines are highly promising (94-95% efficacy including avoiding severe COVID-19) and have led to the FDA EUAs for two vaccines: Pfizer/BioNTech and Moderna COVID-19 vaccines.
      • Both appear to retain excellent protection against variants of concern including P.1, B.1.357, B.1.617.2 (delta).
    • mRNA vaccines in the U.S. with Emergency Use Authorizations (see individual modules for details):
      • Pfizer/BioNTech
      • Moderna
  • Select other vaccines in use in other countries or under consideration by the FDA
    • AstraZeneca/Oxford ChAD vaccine with inadvertent lower half-dose as dose #1 followed by full dose = 90% efficacy, whereas designed dosing yielded 62% percent efficacy, though recent 1-dose efficacy x 3 months is cited as 76% effective.
      • Appears to not work well against the viral variant identified in S. Africa (B.1.357).
    • JNJ/Janssen adenovirus vaccine with FDA EUA also appears protective against severe COVID-19.
      • One-dose vaccine
      • Cited as 66% overall effective
        • 72% in the U.S., 66% in Latin America, 57% in S. Africa.
        • 85% effective at preventing severe COVID-19.
      • Rare clots described, with pause suggested by FDA/CDC (4/12/21, subsequent resumption)
    • Other vaccines have been employed in countries such as China, UAE, Brazil.
      • Multiple sources for updates include WHO and ACIP.

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 it, 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 (uncommon, more in elderly)
  • Cardiac: myocarditis (transient and also more severe)
  • 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’s 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

DrugRecommendation
Bamlanivimab/etesevimabDue to insufficient in vitro activity (by pseudoneutralization assay), the distribution of this combination by HHS has been halted as of 6/25/21.
BaricitinibA 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). However, place in treatment uncertain and is the focus of the ACTT-4 trial starting in Jan 2021, RDV + barcitinib vs. RDV + dexamethasone. The drug might be considered for use in patients who cannot receive dexamethasone but who require high-flow oxygen or non-invasive ventilation. Recent COV-BARRIER (preprint) 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 primary endpoint 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.
Casirivimab imdevimabTwo monoclonal antibodies have a similar FDA EUA indication for mild-moderate outpatient COVID-19. The published trial suggested a decrease in medical visits with use, which was the basis for emergency approval. In the overall trial population of 275 patients, 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). Adverse reactions were not notably different in the arms. This combination cocktail appears to retain activity against all VOCs. Recent RECOVERY trial (preprint) suggests mortality benefit in hospitalized patients who are seronegative at the time of administration.
COVID-19 Convalescent PlasmaStill waiting for large RCT to confirm use, however many trials used the agent late (e.g., RECOVERY, others). Convalescent plasma works best as an antiviral. Current FDA EUA for hospitalized patients now enforces the use of high-titer plasma. Best used if within 3 days of illness onset or first three days of hospitalization. May also have a role in immunosuppressed populations.
DexamethasoneThe 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.
HydroxychloroquineThe 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.[24] The drug is not recommended by any mainstream experts or authorities.
RemdesivirThe 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. 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.
SotrovimabSingle mAb that preliminary data showing 85% reduction in death or hospitalization for patients receiving it for mild-moderate COVID-19 as outpatients prompted the FDA to issue EUA (5/24/21).
TocilizumabThis 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 reduced 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.

FOLLOW UP

  • Case fatality rates are 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.
    • Outpatients:
      • CDC (July 2020), 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 the virus longer, 20d recommended as a minimum including for those with severe COVID-19 or immunosuppression.

reference link https://www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ABX_Guide/540747/all/Coronavirus_COVID_19__SARS_CoV_2_


More information: Yang Ge et al, COVID-19 Transmission Dynamics Among Close Contacts of Index Patients With COVID-19 A Population-Based Cohort Study in Zhejiang Province, China, JAMA Intern Med (2021). DOI: 10.1001/jamainternmed.2021.4686

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