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Transmission & Isolation

Last updated: February 22, 2021

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview

A key intervention to prevent community transmission of SARS-CoV-2 is the prompt isolation of people with active COVID-19 infection. To be most effective at controlling spread, these strategies should be followed with contact tracing and a quarantine period of 14, 10 or 7 days for individuals who have been exposed, based on considerations discussed further below.

As COVID-19 transmission levels rise, the CDC recommends a multi-pronged approach in decreasing transmission, including universal face mask use, physical distancing, avoiding nonessential indoor spaces, increasing testing, prompt quarantine of exposed persons, safeguarding those at increased risk for severe illness or death, protecting essential workers, postponing travel, enhancing ventilation and hand hygiene, and achieving widespread COVID-19 vaccination coverage (Honein, December 2020). 

Healthcare settings use similar mitigation strategies, but with the addition of administrative and engineering controls such as dedicated clinical in-patient units of single negative pressure rooms with frequent air exchanges for patients known or suspected to have COVID-19, personal protective equipment for healthcare workers also plays an important role (CDC, July 2020).   

Transmission-based studies in people with SARS-CoV2 virus provide important information about duration of infectiousness and transmission risk (Wolfel, April 2020; Lu, June 2020; Young, April 2020; Kujawski, April 2020; van Kampen, June 2020; Bullard, May 2020; Zou, March 2020; Cheng, May 2020). In these studies, the highest viral loads are detected in the upper respiratory tract several days before and decrease precipitously after symptom onset. In patients with mild to moderate disease, the virus has not been cultured 10-12 days post symptom onset, even in setting of positive molecular RNA amplification test, indicating viral RNA present but no longer replication competent. In one unpublished study of 129 patients with severe to critical COVID-19, 5 patients had positive cultures at 15 days post symptom-onset or beyond, while one patient had a positive viral culture at 20 days. For additional details about SARS-CoV-2 viral dynamics, see the RT-PCR testing section.  

Based on the evidence, CDC recommends the following symptom- and severity-based strategies for discontinuing isolation and precautions (as opposed to testing-based strategies):   

  • Quarantine can end after Day 10 without testing and if no symptoms have been reported during daily monitoring.  
    • With this strategy, residual post-quarantine transmission risk is estimated to be about 1% with an upper limit of about 10%. 
  • When diagnostic testing resources are sufficient and available, then quarantine can end after Day 7 if a diagnostic specimen tests negative and if no symptoms were reported during daily monitoring. 
    • With this strategy, the residual post-quarantine transmission risk is estimated to be about 5% with an upper limit of about 12%. 
  • In both cases, continued symptom monitoring and masking through Day 14 are recommended. 
  • For most patients, isolation and precautions can be discontinued 10 days after symptom onset, resolution of fever for at least 24 hours (without antipyretics), and improvement in other symptoms.   
  • For some patients with severe disease or severe immunosuppression, consider waiting 20 days after symptom onset to discontinue isolation.   
  • A testing strategy requiring one or two consecutive SARS-CoV-2 PCR tests may be used in severely immunocompromised patients to discontinue or prolong transmission-based precautions. 

CDC guidance states that vaccinated individuals with a suspected or confirmed COVID-19 exposure are not required to quarantine if they meet all of the following criteria:

  • Are fully vaccinated (i.e., ≥2 weeks following receipt of the second dose in a 2-dose series, or ≥2 weeks following receipt of one dose of a single-dose vaccine).
  • Are within 3 months following receipt of the last dose in the series.
  • Have remained asymptomatic since the current COVID-19 exposure.

Individuals who do not meet all three of these criteria should continue to follow current quarantine guidance as discussed above.

Here we describe data on viral RNA shedding of SARS-CoV-2 and contact tracing of known cases; for information on transmission prevention in the healthcare setting, including a discussion of the potential routes of SARS-CoV-2 transmission, please see the Personal Protective Equipment in Medical Settings section. 

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Key Literature

In summary: Knowledge is evolving on the duration of infectivity of patients with COVID-19; current data suggests people begin to transmit SARS-CoV-2 a few days prior to symptom onset, that non-immune-compromised hosts with non-critical illness are unlikely to be infectious 10 days after symptom onset and that individuals with critical illness or significant immune compromise are unlikely to be infectious 15 days after symptom onset. Peak transmission likely occurs around symptom onset, when viral RNA load is at its highest. While prolonged viral RNA shedding can occur, in most cases SARS-CoV-2 cannot be cultured after 8-12 days; whether viral culture directly correlates to a lack of infectivity is not known, but epidemiologic data suggests it may be a reasonable surrogate marker.

The household secondary attack rate of SARS-CoV-2: A rapid review (Fung, October 2020).

Overall, in this review of 22 published and pre-published studies, testing household contacts of COVID-19 cases on multiple occasions may increase the yield for identifying secondary cases.  This suggests that studies with less intensive testing may have missed cases and underestimated the household secondary attack rate.

Study population:

  • 22 published and pre-published studies with data from 20,291 household contacts in 10 countries, 3,151 of whom (15.5%) tested positive for SARS-CoV-2.
  • Household contacts are defined as people living in the same residence as the index case.
  • The household secondary attack rate was defined as the percentage of all household contacts who were reported to have tested positive for SARS-CoV-2 by RT-PCR.

Primary endpoint:

  • To evaluate estimates of the SARS-CoV-2 household secondary attack rate and explore their variation.

Key findings:

  • The number of household contacts per study ranged from 11 to 10,592.
  • 4 of the studies were classified as high quality, 14 as moderate quality and 4 as low quality.
  • The overall pooled random-effects estimate of the household secondary attack rate was 17.1% (95% CI, 13.7-21.2%).
  • In study-level, random-effects meta-regressions stratified by testing frequency (1 test, 2 tests, >2 tests), SAR estimates were 9.2% (95% CI, 6.7-12.3%), 17.5% (95% CI, 13.9-21.8%) and 21.3% (95% CI, 13.8-31.3%), respectively.
  • Household secondary attack rate tended to be higher among older adult contacts and among contacts of symptomatic cases.

Limitations:

  • Household size and composition, contact patterns and testing and isolation practices all vary substantially geographically.

 

Clinical, immunological and virological characterization of COVID-19 patients that test re-positive for SARS-CoV-2 by RT-PCR (Lu, June 2020). 

Overall, 14% of patients in this study were positive for SARS-CoV-2 on RT-PCR.  In a subsample of specimens, viral culture was attempted but not successful.

Study population: 

  •  619 COVID-19 cases who were discharged between 23 January and 19 February, isolated in hotels, and underwent repeat testing on day 7 and 14 after discharge.  

Primary endpoint: 

  • To characterize re-positive patients with COVID-19. 

Key findings: 

  • 87 of the 618 people tested became positive for SARS-CoV-2 on repeat RT-PCR testing. 
  • All re-positive cases had mild or moderate symptoms in initial diagnosis, with a mean age of 30.4 years. 
  • 137 swabs and 59 serum samples from 70 re-positive cases were collected. 
  • Neutralization antibodies (NAbs) titer distributions of the 59 serum samples were similar to other COVID-19 cases (n=150) parallel-tested in the study.  
  • Viral culture was attempted on 33 repeat positive cases; successful isolation did not occur, and no full-length viral genomes could be sequenced.  

Limitations: 

  • Successively collected samples were not collected, resulting in bias towards the summarized duration from the discharge to firstly re-positive result for viral RNA as well as the time of the re-positive RNA to negative.  
  • The corresponding samples were not collected during the acute infection for re-positive cases; therefore, genetic differences remain for SARS-CoV-2 viruses sampled in an acute infection phase and a re-positive phase. 
  • Antibody testing and viral culture was not attempted on the majority of repeat positive cases    

Shedding of infectious virus in hospitalized patients with coronavirus disease-2019 (COVID-19): duration and key determinants (vanKampen, June 2020). 

Overall, in this prospective study, the median duration of shedding of culturable virus was 8 days; after approximately 15 days of viral RNA shedding, the probability of being able to isolate virus on culture dropped below 5%.

Study population: 

  • 129 hospitalized patients with COVID-19 in the Netherlands. 89 (69%) were admitted to the ICU, and 81 required mechanical ventilation. 
  • Neutralizing antibody titers from 112 serum samples from 27 patients were available. 
  • 690 respiratory samples from the 129 patients were tested for viral culture. 

Primary endpoint:  

  • Duration and determinants of infectious virus shedding (defined by positive viral culture). 

Key findings: 

  • 14.7% of patients were moderately or severely immunocompromised. 
  • Infectious virus shedding was present in 23 of the 129 patients (17.8%).  
  • The median duration of infectious virus shedding was 8 days post onset of symptoms (IQR 5-11). 
  • The probability of detecting infectious virus dropped below 5% after 15.2 days post onset of symptoms (95% confidence interval (CI) 13.4-17.2).  
  • Multivariate analyses identified viral loads > 7 log10 RNA copies/mL (odds ratio [OR]; CI 14.7 (3.57-58.1; p<0.001) as independently associated with isolation of infectious SARS-CoV-2 from the respiratory tract.  
  • A serum neutralizing antibody titer of at least 1:20 (OR of 0.01 (CI 0.003-0.08; p<0.001) was independently associated with non-infectious SARS-CoV-2. 

Limitations: 

  • Positive viral culture was used as a marker of infectiousness, but whether this is the best surrogate, given the poor sensitivity of viral culture, is unclear. 
  • The study only included patients with severe disease; the findings may not be generalizable to asymptomatic or mild-moderate patients. 
  • Samples for virologic assessment were not collected at predefined timepoints.  

Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset (Cheng, May 2020). 

Overall, in this prospective study of patients with COVID-19 and their close contacts, the overall clinical secondary attack rate was 0.7%. This increased if the contact occurred within 5 days of symptom onset in the index case, implying increased risk of transmission around the time of symptom onset.  

Study population: 

  • Prospective case-ascertained study of 100 patients in Taiwan with confirmed COVID-19 and 2761 close contacts. 
  • All close contacts were quarantined at home for 14 days after their last exposure to the index case. 
  • During the quarantine period, any relevant symptoms (fever, cough, or other respiratory symptoms) of close contacts triggered RT-PCR testing 
  • For high-risk contacts, including household and hospital contacts, RT-PCR was performed regardless of symptoms (ie, once when they were listed as a close contact). If the initial COVID-19 test result was negative, further testing would only be performed if a close contact developed symptoms during quarantine.

Primary endpoint: 

  • Secondary clinical attack rate (symptomatic cases only) for different exposure time windows of the index cases and for different exposure settings (such as household, family, and health care). 

Key findings: 

  • Of the 2761 close contacts, 22 people became infected; 4 of these were asymptomatic. 
  • The overall secondary clinical attack rate was 0.7% (95% CI, 0.4%-1.0%).  
  • The attack rate was higher among the 1818 contacts whose exposure to index cases started within 5 days of symptom onset (1.0% [95% CI, 0.6%-1.6%]) compared with those who were exposed later (0 cases from 852 contacts; 95% CI, 0%-0.4%).  
  • The 299 contacts with only presymptomatic exposures were also at risk (attack rate, 0.7% [95% CI, 0.2%-2.4%]).  
  • The attack rate was higher among household (4.6% [95% CI, 2.3%-9.3%]) and non-household (5.3% [95% CI, 2.1%-12.8%]) family contacts than that in health care or other settings.  
  • The attack rates were higher among those aged 40-59 years (1.1% [95% CI, 0.6%-2.1%]) and those aged > 60 (0.9% [95% CI, 0.3%-2.6%]). 

Limitations: 

  • Universal testing was performed in high-risk contacts, but not for others; this may have missed some secondary cases. 
  • Contacts were not completely examined prior to symptom onset of the index cases; therefore, there may be an underestimation of early transmission from the index case. In addition, it is possible the contacts were infected from a source other than the index case. 
  • Increased transmissibility in the early stage of COVID-19 may be due to the effect of household and non-household family contacts. 

 

Findings from investigation and analysis of re-positive cases (Korea Centers for Disease Control and Prevention, May 2020). 

Overall, in this unpublished epidemiologic study of re-positive patients with COVID-19 in South Korea, no secondary infections appeared to have occurred. SARS-CoV-2 was unable to be isolated from these patients, supporting the idea that viral RNA shedding was not associated with infectivity (assuming viral culture is a reasonable surrogate for infectiousness. 

Study population: 

  • 477 patients in South Korea with RT-PCR-confirmed SARS-CoV-2 infection who were hospitalized and then discharged with negative RT-PCRs, and then became positive again after isolation was discontinued. 
  • Successful contact tracing and epidemiologic investigation was completed on 285 of the 477 repeat positives. 
  • 790 contacts, including 351 family members, were identified and followed for 14 days from exposure. 

Primary endpoint: 

  • Epidemiological and virological investigation. 

Key findings: 

  • 126 (44.2%) of 285 individuals with re-positive PCR tests had developed new upper respiratory tract symptoms.  
  • On average, it took 44.9 days (range: 8-82 days) from initial symptom onset date to re-testing positive after discharge. 
  • On average, it took 14.3 days (range: 1-37 days) from discharge to testing positive.  
  • Respiratory viral cultures were attempted in 108 of the repeat positive cases; none resulted in isolation of SARS-CoV-2. 
  • Of the 23 re-positive cases from whom the first and the second serum samples were obtained, 96% were positive for neutralizing antibodies. 
  • Three of the 790 contacts developed COVID-19 infection, and none were clearly related to the index case (all 3 infections were traced to the Shincheonji religious group outbreak or a different family member).  

Limitations: 

  • Roughly 40% of the repeat positive patients did not undergo complete contact investigation; whether the findings in the contacts of these patients would have been different is not known. 
  • Contacts were only followed for 14 days from exposure. 
  • Serology was not performed on all patients.   

Prolonged SARSCoV2 RNA shedding: Not a rare phenomenon (Li, April 2020). 

Overall, in this cohort of 378 patients with mild COVID-19, prolonged viral RNA shedding of SARS-CoV-2 for 30 days or more was noted in 36 patients; the median duration of viral RNA shedding was 53.5 days, and IgG and IgM antibodies were detected. Most of these patients had comorbidities.

Study population: 

  • 36 patients with confirmed COVID-19 via RT-PCR on samples collected from the respiratory tract in China who had viral RNA shedding for 30 days or more. 

Primary endpoint: 

  • To describe the clinical characteristics of patients with confirmed COVID-19 who shed viral RNA for 30 days or more. 

Key findings: 

  • The median age of patients was 57.5 years (IQR 52‐65); 11.1% were <40 years old.  
  • Most patients had comorbidities (22 [61.1%]), including cardiovascular diseases (16 [44.4%]), metabolic diseases such as diabetes and gout (7 [19.4%]), and chronic respiratory diseases (3 [8.3%]).  
  • On admission, 33 (91.7%) and 3 (8.3%) patients had mild and severe COVID‐19, respectively. 
  • The median duration of viral RNA shedding was 53.5 days (IQR 47.75‐60.5).  
  • IgG and IgM were detected in the patients, and at week 9 their mean values were 150 and 50 AU/mL, respectively 
  • Compared to patients that had late-onset symptoms, patients with early‐onset symptoms had longer durations of viral shedding and more severe illnesses. 

Limitations: 

  • This was a small sample size from a single center. 
  • Most of the patients received antiviral therapies at different points in their infections; 5.7% received Remdesivir. This may have altered the results. 
  • Most patients had mild COVID-19 and were younger; therefore, these results may not be generalizable to severe patient populations and older individuals.  

Prospective Evaluation of SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients (Zou, March 2020). 

Overall, in this small prospective study of patients with COVID-19, detectable virus was present in an asymptomatic patient at levels similar to his symptomatic family members, suggesting the presence of viral shedding and the potential for transmission in asymptomatic individuals. 

Study population: 

  • 18 patients within 2 family clusters with COVID-19 from China; 1 person was asymptomatic, while 13 had pneumonia on CT.  
  • 72 throat swabs and 72 nasal swabs were collected.  

Primary endpoint: 

  • Viral load measurements via RT-PCR. 

Key findings: 

  • Two family clusters of infections were identified. After returning from Wuhan, 14 individuals contracted COVID-19 determined to be imported. In addition to the asymptomatic transmission, 4 secondary infections developed.    
  • In symptomatic patients, the highest SARS-CoV-2 levels were observed soon after symptom onset, while in the asymptomatic patient the virus was detected for 5 consecutive days.  

Limitations: 

  • Small sample size. 
  • Patients were part of the same family cluster; viral inoculum may have been higher in this group than in patients who are infected outside of the home.   

Additional Literature

Antibody Responses 8 Months after Asymptomatic or Mild SARS-CoV-2 Infection (ChoeDecember 2020). Antibody responses of 58 persons 8 months after asymptomatic (N=7) or mildly symptomatic infection (N=51) with SARS-CoV-2 were investigated at Seoul National University Hospital using 4 commercial immunoassaysRates of antibody positivity according to 3 commercial kits was still high at 8 months after infection, even in asymptomatic or mildly symptomatic participants (69.0%–91.4%)The surrogate virus neutralization test (sVNT) found positive neutralizing activity for 31 (53.4%).

Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence (Hartley, December 2020).  The longevity and immunophenotype of SARS-CoV-2-specific memory T cells and memory B cells (Bmem) in 25 patients with COVID-19 were evaluated using fluorescently-labeled tetramers of the spike receptor binding domain (RBD) and nucleocapsid protein (NCP).  Thirty-six blood samples were obtained between 4 and 242 days post-symptom onset including 11 paired samples. While serum IgG to RBD and NCP was identified in all patients, antibody levels began declining at 20 days post-symptom onset. RBD- and NCP-specific Bmem cells predominantly expressed IgM+ or IgG1+ and continued to rise until 150 days.  Nearly all RBD-specific IgG+ Bmem cells expressed CD27 and their numbers correlated with circulating TFH cells, indicative of long-lived immune memory. 

The Duration of Infectiousness of Individuals Infected with SARS-CoV-2 (Walsh, October 2020). This review summarizes 15 relevant studies, including 13 virus culture and two contact tracing studies. In five of the virus culture studies, the last day on which SARS-CoV-2 was isolated was within 10 days of symptom onset. In another five virus culture studies, SARS-CoV-2 was isolated beyond day 10 for approximately 3% of included patients. The remaining three virus culture studies included patients with severe or critical disease and found that immunocompromised and severe-to-critical patients may be infectious for >10 days. The two contact tracing studies found no evidence of laboratory-confirmed onward transmission of SARS-CoV-2 when close contacts were first exposed more than 5 days after symptom onset in the index case.

Duration of SARS-CoV-2 Infectivity: When is it Safe to Discontinue Isolation? (Rhee, August 2020). In this review summarizing the duration of infectivity of SARS-CoV-2, the authors found the following: median incubation period for SARS-CoV-2 is 5 days, with an IQR of 2-7 days; 98% of patients who develop symptoms do so within 12 days; viral RNA levels peak at symptom onset; asymptomatic and pre-symptomatic individuals transmit prior to symptom onset; sicker patients tend to have detectable RNA for longer periods, but prolonged PCR positivity also occurs in mildly ill and asymptomatic individuals; and persistently positive SARS-CoV-2 RNA PCRs are due to residual viral “debris” rather than replication-competent virus.

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