Chapter 1

COVID Overview

SymptomsCopy Link!

Common SymptomsCopy Link!

Updated Date: May, 2020
Literature Review:
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Tool:
CDC Symptom Self-Checker

This section covers symptom prevalence, click here for Triage Based on Symptom Questionnaires.

Many patients are asymptomatic. Among patients with symptoms, most present with an influenza-like illness (fevers, myalgias, respiratory symptoms), but many do not present with this classic combination. Some may present with less-usual findings such as perniosis (COVID toes) or anosmia. These ranges are pulled from the following articles, and symptom prevalence varies greatly depending on testing and survey methodology (Arentz et al; Chen et al; Guan et al; Li et al; Wu et al; Zhou et al; WHO-China Joint Mission on COVID-19; Young et al; Yan et al; Jiang et al; Huang et al; Tostmann et al).

  1. Fever, 44-94%
  1. We recommend using >= 38°C to define fever, taking into account the patient’s age, immune status, medications (steroids, chemotherapy, etc.), and recent use of fever-reducing medications.
  2. Children are less likely to have fever or cough (Bialek et al).
  1. Cough, 68-83%
  2. Anosmia and/or ageusia (loss of sense of taste and/or smell) ~70%
  3. Upper respiratory symptoms (sore throat, dripping nose, nasal or sinus congestion), 5-61%
  4. Shortness of breath, 11- 40%
  5. Fatigue, 23-38%
  6. Muscle aches 11-63%
  7. Headache 8-14%
  8. Confusion 9%
  9. Gastrointestinal symptoms (nausea, vomiting, diarrhea), 3-17%

Clinical CourseCopy Link!

Literature Review: University of Washington Literature Report (Clinical Characteristics)

Incubation and Window PeriodCopy Link!

Updated Date: December 19, 2020

Incubation period is the time from exposure to symptom onset. Latency period is the time from exposure to infectiousness (or viral detection, depending on the definition). COVID-19 has a relatively long incubation period, and typically at least 2 days of infectivity before symptoms develop.

IncubationCopy Link!

Time from exposure to symptom onset: mean and median 5 days (common range 2-7 days). (Li et al; Guan et al; Velavan et al; Chan et al; Nie et al).

  • 97.5% of exposed cases will develop symptoms within 11 days and 99% within 14 days. Over 95% of cases develop symptoms within 13 days of infection (Nie et al).
  • Incubation periods of up to 24 days are shown in some reports (Nie et al).

Window PeriodCopy Link!

Samples taken before symptom onset have high false negative rates, as modeled by (Kurcirka et al). 68% false negatives one day before symptoms, compared to 38% false negatives on the first day of symptoms, based on serial testing. They estimated the window period between exposure and detectability of SARS-CoV-2 RNA on nasopharyngeal sampling at 3-5 days, with peak sensitivity 8 days after exposure or 3 days after symptom-onset in their model. As with incubation, individual cases may show longer delays. Asymptomatic patients should still be tested in certain circumstances, but a negative result does not rule out infection.

Duration and Time CourseCopy Link!

Updated Date: May 2020
Literature Review (Clinical Course):
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Median duration of common symptoms (median in survivors only), drawn from (Zhou et al; Young et al):

  1. Fever: 12 days
  2. Shortness of breath: 13 days
  3. Cough: 19 days

Time course from symptom onset to complications (Zhou et al, Feldstein et al):

  1. Multi-System Inflammatory Syndrome in Children (MIS-C): 6 days (range 4-8 days).
  2. Sepsis: Median onset 9 days (range 7-13 days)
  3. Acute Respiratory Distress Syndrome (ARDS): median onset 12 days (range 7-15 days)
  4. Need for Mechanical Ventilation: Median onset 10 days (range 3-12.5 days)
  5. Acute Cardiac Injury: Median onset 15 days (range 10-17 days)
  6. Acute Kidney Injury: Median onset 15 days (range 13-19.5 days)
  7. Secondary Infection: Median onset 17 days (range 13-19 days)
  8. Death: Median 18.5 days, interquartile range 15-22 days (Zhou et al)
  1. Illness severity has been noted to have two peaks at ~14 days and ~22 days (Ruan et al)

SeverityCopy Link!

Updated Date: May, 2020
Literature Review:
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The majority of patients have only mild symptoms; however, the percentage of patients who develop severe or critical disease is far greater than for most other respiratory viruses, including influenza. See how mild, moderate, and severe cases are defined. Assessing the percentage of patients who develop differing severities of illness is fundamentally challenging, due to the widely variable case definitions and severity definitions, as well as the lack of population-level surveillance testing to estimate asymptomatic and minimally symptomatic cases. All of these are estimates and do not apply to all populations or epidemiologic circumstances.

  • Asymptomatic Infection is present in about 20% of cases (Bi et al; Mizumuto et al; Pollan et al). One metanalysis showed asymptomatic infections account for 17% of all infections (Byambasuren et al) but this is difficult to estimate as screenings of entire populations are unavailable.
  • Symptomatic Infection: A Chinese CDC report on approximately 72,000 symptomatic COVID cases (1% of the cases included in the study were asymptomatic), documented the following occurrence rates for mild, severe, and critical symptom presentations (Wu et al):
  • Mild Symptoms to Mild Pneumonia: approximately 81%
  • Severe Symptoms (blood oxygen saturation less than or equal to 93%, respiratory frequency greater than or equal to 30 breaths per minute, and/or lung infiltrates greater than 50% within 48 hours): approximately 14%
  • Critical Symptoms (respiratory failure, shock, multiorgan dysfunction): approximately 5%.
  • Among critically-ill patients, many receive mechanical ventilation. Median time on a ventilator ranges from 11-17 days (Chen et al; Ling et al).
  • Presentation with shock is rare, but vasopressors are eventually used in 67% of critically-ill patients.
  • Cardiomyopathy (Heart Tissue Injury) is noted in 33% of critically-ill patients (Ruan et al).

Prognostic IndicatorsCopy Link!

Updated Date: May, 2020

Demographic and Health FactorsCopy Link!

Literature Review (Comorbidities): Gallery View, Grid View
Literature Review (Sex Differences):
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Multiple factors have been associated with worse prognosis in people infected with SARS COV-2.

  1. Age: increased age is associated with more severe disease and higher rates of death (Wu et al; Chen et al; Yang et al; Qin et al).
  1. Children are less likely to have severe disease, but pediatric deaths have been reported (Bialek et al).
  2. Children appear to be as likely to contract the infection as adults, although symptomatic cases of children are more rare (Bi et al).
  1. Comorbidities and other health factors: Multiple comorbidities and/or health factors are associated with increased risk of severe COVID-19 illness. Evidence-based knowledge on this topic is continuing to develop; for ongoing updates, see the CDC’s living document. The comorbidities and other health factors associated with the strongest bases of evidence for increased risk are listed below. This list is not inclusive of all conditions which may be associated with increased risk; other common conditions which may be associated with increased risk include hypertension, moderate to severe asthma, liver disease, and others (CDC).
  1. Chronic Kidney Disease
  2. Chronic Obstructive Pulmonary Disease (COPD)
  3. Type 2 Diabetes Mellitus
  4. Pregnancy
  5. Sickle Cell Disease
  6. Smoking
  7. Cancer
  8. Down Syndrome
  9. Immunocompromised status associated with solid organ transplant
  10. Obesity (BMI of 30kg/M2 or higher)
  11. Multiple heart conditions, including heart failure, coronary artery disease, and cardiomyopathies
  1. Race: Please see Health Equity for a discussion on racial differences in COVID infection and severity.
  2. Sex: Men appear to be more severely affected by COVID-19 than women. Conclusive evidence related to sex differences is limited by methodology of existing studies (Schiffer et al).
  3. Smoking: Smoking may offer a small risk reduction for COVID infection, though it is not clear why and this finding may be subject to confounding. It does appear to be associated with worse outcomes. See Smoking for more details.

Laboratory IndicatorsCopy Link!

The most significant laboratory abnormalities associated with severe COVID-19 disease and death include the following:

Lab test

Results

Normal Ranges (For many US labs, units and values may vary)

White Blood Cell Count (WBC)

> 10 K/uL (K/uL=10^3/uL)

Male and Female- Adults: 3.4-9.6 x10^3/uL

Lymphopenia

< 1.00 K/uL (K/uL=10^3/uL)

Male and Female- Adults: 0.95-3.07 x10^3/uL

Platelets

< 150 K/uL (K/uL=10^3/uL)

Male Adults: 135-317 x 10^3/uL

Female Adults: 157-371 x10^3/uL

Creatinine

> 1.5 mg/dL

Male Adults: 0.74-1.35 mg/dL

Female Adults: 0.59-1.04 mg/dL

Albumin

< 3 g/dL

3.5-5.0 g/dL

Alanine transaminase (ALT)

> 40 U/L

Males: 7-55 U/L

Females: 7-45 U/L

Creatinine kinase (CK)

> 185 U/L

Males: 39-308 U/L

Females: 26-192 U/L

Troponin T, high-sensitivity (hs-TnT)

> ~20 ng/L

Male <23 ng/L

Female <15 ng/L

C-reactive protein (CRP)

> 125 mg/L

< or =8.0 mg/L

Lactate dehydrogenase (LDH)

> 245 U/L

Adults: 122-222 U/L

Ferritin

> 300 ug/L (Severe Disease); Ferritin > 1000 ug/L (Death)

Males: 24-336 ug/L

Females: 11-307 ug/L

Interleukin 6 (IL-6)

> 10 pg/mL

< or =1.8 pg/mL

D-Dimer

> 1000 ng/mL

< 250 ng/mL

Procalcitonin

> 0.5 ng/mL

< or =0.15 ng/mL

(Zhou et al; Huang et al; Chen et al; Wu et al; Ruan et al)

MortalityCopy Link!

Updated Date: December 16, 2020
Literature Review:
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Cause of DeathCopy Link!

Determining and reporting the cause of death for patients with COVID-related diseases is complex (as it is with any disease).

  • Cause of Death: This is usually the acute medical diagnosis that caused a patient to die, and often relates to a medium-term or long-term diagnosis as well. It will often include other diseases as co-morbid or contributing factors (e.g. pneumonia due to COVID-19 infection or Acute Myocardial Ischemia due to COVID-19 infection and Coronary Artery Disease).
  • Mechanism of Death: Defined as the immediate physiologic issue resulting in death (for example, hypoxemia).

A significant number of COVID-related deaths do not have clear delineation of cause of death (CEBM). The majority of people who die from COVID-19 die from respiratory failure. Because definitions of cause of death are reported differently it can be hard to determine exact numbers, but here are estimates (Ruan et al, 68 cases), (Zhang et al, 82 cases):

  • Respiratory Failure Alone: 53% - 69%
  • Circulatory Failure Alone: 7%-14.6%
  • Mixed Respiratory and Circulatory Failure, Sepsis, or Multiorgan Failure: 28-33%
  • Hemorrhage: 6.1%
  • Renal Failure: 3.1%

Tool: Improving Cause of Death Reporting
Tool: Guidance for Reporting COVID-Related Deaths

Case Fatality RateCopy Link!

Literature Review: Gallery View, Grid View

  • Case Fatality Rate (CFR) is typically the proportion of deaths from a disease relative to the number of people diagnosed with the disease in a specific period of time. Some people define a “case” as showing symptoms.
  • Infection Fatality Rate (IFR) is the proportion of deaths from a disease but relative to all infected individuals including asymptomatic people and infections that were missed. It is harder to measure, and thus most places report CFR.
  • Case Fatality Rate is variable in different countries. Range around the world seems to be between 0-16%, with most countries in the 1-3% range.

Tool: Johns Hopkins Summary of Case Fatality Ratios
Tool: Forecast Hub (Compilations of forecasts by country or state)

PathophysiologyCopy Link!

PathophysiologyCopy Link!

Updated Date: December 16, 2020
Literature Review (ACE2):
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Literature Review (Human Genetics)
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Classification: SARS-CoV-2 is a positive-stranded RNA virus with a nucleocapsid and envelope, belonging to the coronavirus family, of which seven viruses (including the original SARS-CoV in 2003 and MERS in 2013) have crossed from zoonotic origins into humans.

Cell Entry and Replication: For cell entry, the SARS-CoV-2 spike protein binds to the ACE2 receptor, expressed in nasal and bronchial epithelium, pulmonary endothelium, alveolar Type 2 cells, proximal renal tubule cells, cardiac myocytes, gastrointestinal epithelial cells, and others. Cleavage/priming by serine protease TMPRSS2 facilitates SARS-CoV2 cell entry, followed by viral replication using host cell machinery and then exocytosis (Kumar et al).

Cellular Targets and Resulting Lung Injury: The cells that express ACE2 may be the cell populations most injured by infection or targeted by the immune response. Alveolar Type 2 cells secrete surfactant, so injury may result in alveolar collapse at low opening pressures and high PEEP sensitivity, while damage to pulmonary endothelial cells may cause capillary leak and trigger an influx of monocytes and neutrophils, with formation of hyaline membranes. The highly inflamed lung parenchyma can develop microthrombi that help explain some of the thrombotic complications of COVID (Wiersinga et al).

Literature Review (Acute Lung Injury): Gallery View, Grid View

Inflammatory Cascade: Infection with the SARS-Cov-2 virus can cause apoptotic cell death, which triggers an inflammatory cascade of cytokine release, as well as the recruitment of immune cells including macrophages and dendritic cells, and later, antigen-specific T lymphocytes (Bohn et al). If the immune response is not properly checked, a state of hyperinflammation occurs, with the development of Cytokine Storm Syndrome, and sometimes multi-organ failure.

Blood type: There is evidence that A blood type is a risk factor for COVID-19 respiratory failure, and O may be protective. This was based on a genome-wide association study (GWAS) of 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain. Respiratory failure was defined as a patient requiring supplemental oxygen or mechanical ventilation (Ellinghaus et al).

Literature Review (ABO): Gallery View, Grid View

Histology and AutopsyCopy Link!

Updated date: December 18, 2020
Literature Review (Autopsy):
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Literature Review (Histology):
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  • Autopsy studies indicate universal damage to pulmonary tissue (Falasca et al; Elsoukkary et al). Pulmonary histology of COVID-19 shows bilateral diffuse alveolar damage, desquamation of pneumocytes, pulmonary edema, hyaline membrane formation, inflammatory cell infiltrates, and multinucleated giant cells, as well as some evidence of direct viral injury (Xu et al; Geng et al). Vascular involvement in the lung is also quite common, with microthrombi, endotheliitis, severe capillaritis, vascular complement deposition, and pulmonary thromboemboli, often in small and mid-sized vessels (Calabrese et al).
  • Cardiac injury and thrombotic complications are widely prevalent, including cardiac inflammatory infiltrates, epicardial edema, and pericardial effusion in some autopsies (Falasca et al; Elsoukkary et al; Geng et al).
  • Acute kidney injury, while common in hospitalized COVID patients, was found to be mild in post-mortem patients with theoretical potential for recovery (Santoriello et al).
  • Neurologic lesions in autopsy series of 43 patients (not necessarily with neurologic manifestations) showed fresh ischemic lesions in 14%, and neuroinflammatory changes with infiltration of cytotoxic T lymphocytes most pronounced in the brainstem (also cerebellum and meninges) (Matschke et al). In patients with significant neurologic decline, more severe findings have been noted including hemorrhagic lesions through the cerebral hemispheres, marked axonal injury, areas of necrosis, and pathology similar to Acute Disseminated Encephalomyelitis (ADEM). (See e.g. Reichard et al).

EpidemiologyCopy Link!

Literature Review: University of Washington Literature Report (Geographic Spread)

Literature Review: University of Washington Literature Report (Modeling and Prediction)

Tool: Outbreak.info (Epidemiology Resources)

Case Counts and PrevalenceCopy Link!

Updated Date: December 19, 2020
Tool: Worldwide case counts are published by teams at the World Health Organization, Johns Hopkins University, and others.

Prevalence estimates depend significantly on testing availability and percentage of the population that has asymptomatic infection as well as on the severity of the epidemic in a specific location. Seroprevalence studies, measuring antibodies across an entire population, can help give a better estimate of true prevalence. In one meta-analysis of 47 studies on seroprevalence covering 399,265 people from 23 countries, the SARS-CoV-2 seroprevalence in the general population varied from 0.37% to 22.1%, with a pooled estimate of 3.38% (Rostami et al). This will no doubt change over time as more people are infected.

OriginsCopy Link!

Updated date: June, 2020
Literature Review:
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Tool: WHO Virus Origin


COVID-19 transmission is primarily human-to-human following a suspected animal-to-human initiating event (Li et al). It is thought that it may have emerged from racoon dogs or civets, but this is still being investigated (Mallapaty). The virus was initially recognized in December 2019 by Chinese authorities in the setting of cases of pneumonia that seemed to be clustered around a seafood market in Wuhan, Hubei Province (Wuhan Municipal Health Commission, 2019). Laboratory samples collected in December 2019 yielded evidence of a novel betacoronavirus, genetically-distinct from previously identified SARS-CoV and MERS-CoV but genetically-similar to previously-published coronavirus strains collected from bats from southwestern China (Zhu et al).

New VariantsCopy Link!

Updated Date: April 23, 2021

Literature Review (Viral Genetics) Gallery View, Grid View
Tool: Viral genomes have been published to GenBank from diverse geographies.
Tool: Reports on real-time phylogenetic tracking of the viral genome can be found at NextStrain (Hadfield et al).
Tool: CDC emerging variants.

Tool: Outbreak.info Mutation Reports (from GISAID data)

Tool: NYT Coronavirus Variants and Mutations

Major New VariantsCopy Link!

Frequency of new mutations: Mutation of RNA viruses is expected and common, though less common in coronaviruses than many other RNA viruses due to “proofreading” capacity (Robson et al). Several new mutations occurred in SARS-CoV-2 in the fall of 2020 (CDC), and more are likely to occur over time. The meaning of these mutations for transmission and severity is as yet unclear, and likely depends on the exact mutation. Many viruses tend to mutate over time to more transmissible but less virulent strains, though this is not always the case.

Common active variants change incredibly quickly, and are different around the world. Variant trackers can help describe the common variants over time in a specific place. For example, in the USA the UK lineage B.1.1.7 became the dominant strain in the USA in a mere 6 weeks between February and March, 2021.

Tool: Axios Variant Tracker (this outlines the major variants, their relative infectiousness and severity)

Tool: NextStrain Tracker (this gives major strain data globally)

Tool: US CDC Variant Tracker

Testing, Vaccine, and Antibody EfficacyCopy Link!

  • Testing: As new strains emerge, some tests may be able to detect the new strains and some may not: for example, most NAAT testing can be changed rapidly to include novel strains, but some antigen RDTs may not recognize new strains and cannot be altered once they have been manufactured.
  • Vaccines: Most vaccines are targeted at a part of the spike protein that is highly conserved (common between strains) and so vaccination may still provide some protection against many novel strains and complete protection against some strains, but the extent of this protection will depend on the exact mutations in question (which also may evolve over time) and is not yet known. At this point we do not have large-scale trials of vaccines comparing the efficacy in different strains, as strain genetic testing is not always done. For example, Pfizer and Moderna appear to be less effective against the South African variant than the original variants they were tested on, though still very effective against the UK variant (Janssen/Johnson & Johnson was tested in South Africa to begin with, which may explain some of the variance in efficacy).
  • MRNA vaccines are relatively easy to reformulate as new variants emerge, and the both mRNA vaccine companies (Pfizer and Moderna) are suggesting that in the future booster shots may be needed to protect against new variants, similar to how influenza shots are different every year to cover different variants.
  • Prior infection: Similarly, prior infection, convalescent plasma, or monoclonal antibodies may provide partial protection against new strains, but the extent is not yet known and it will depend on the exact variant.

Infectivity and TransmissionCopy Link!

InfectivityCopy Link!

Updated Date: April 23, 2021

Viral Load, PCR Clearance, and Infectiousness TimelineCopy Link!

Literature Review (Viral Shedding): Gallery View, Grid View

Patients who are infected with SARS COV-2 and who have higher levels of virus in their respiratory tracts and oropharynx are the most infectious, regardless of their level of symptoms (Bullard et al). Symptom status does not seem to correlate predictably with viral load (Walsh et al; Lee et al; Zou L et al).

Upper airway viral load peaks within ~5 days of symptom onset, followed by decline (Wölfel et al; Young et al). Consequently, patients appear to be most infectious in the 2-3 days before symptom onset and the 2-3 days after (Ferretti et al). PCR detection continues for a median of 20 days from time of symptom onset, with an interquartile range 17-24 days (Zhou et al). There are rare cases that remain positive up to ~60 days after infection (McKie et al). However, the virus is very rarely culturable (our closest proxy to infectivity) after 9 days (Cevik et al). The culture data underlies the newer guidance (after November 2020) about Quarantine time. See Testing for a diagram of test positivity compared with infectivity and symptoms.

Asymptomatic PatientsCopy Link!

Literature Review (Asymptomatic): Gallery View, Grid View
Literature Review (Presymptomatic):
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Asymptomatic, minimally symptomatic (paucisymptomatic), and pre-symptomatic patients can all transmit the virus (Bai et al; Rothe et al; Furukawa et al), though presence of symptoms is probably associated with increased frequency of transmission. Though it is hard to estimate the prevalence of asymptomatic cases due to testing bias and few population-level studies, one metanalysis found that asymptomatic patients represented 17% or cases, and were 42% less likely to transmit than symptomatic cases (Byambasuren et al). In one study in Beijing, face masks worn by family members of pre-symptomatic COVID-19 patients were shown to be 79% effective (OR = 0.21) at reducing transmission, suggesting that presymptomatic transmission is an important mode of transmission and that masks can be effective at preventing it (Wang et al).

Recovered PatientsCopy Link!

Patients who have recovered from COVID sometimes will have fragments of viral RNA that continue to test positive by PCR. Shedding of viral RNA is longer in more severe disease, or in patients who are immunocompromised. However, recent data shows that this viral RNA does not likely represent infectious virions, but rather parts of the virus that are unable to replicate. As such, the U.S. CDC has changed its recommendations on the duration of isolation and quarantine as well as releasing patients from isolation (Cevik et al).

Vaccinated PeopleCopy Link!

We do not yet know how all available and pending vaccines will perform with respect to asymptomatic infection. This is an evolving area of research, but the data suggests that being vaccinated does NOT preclude asymptomatic infection or transmission from one person to another, but it does greatly reduce rates of transmission.

Epidemiologic suggestions about what protective measures vaccinated people should take vary depending on the type of vaccine in question in that country. Follow local guidance.

Tool: Current US CDC guidance on infection prevention and safer activities for vaccinated people. (Includes helpful infographic)

TransmissionCopy Link!

Updated Date: December 18, 2020
Literature Review: University of Washington
Literature Report (Transmission)

Basic Reproduction Number (R0)

Tool: For global estimates of R0, See Here. For the United States, state-by-state estimates of R0 are available Here (Data from The COVID Tracking Project). Please keep in mind these are merely estimates and all models are fallible.

R0 (R-naught) is a measure of transmissibility. It represents the theoretical number of secondary infections from an infectious individual. This is a property both of the infectiousness of the virus and the behaviors of humans to decrease spread.

  • An R0 > 1 is consistent with sustained outbreak.
  • An R0 < 1 means an epidemic is declining.

The R0 for COVID-19 is likely similar to, or slightly higher than, many other respiratory viruses, but because it is so highly influenced by human behavior, it can be changed. The initial R0 of COVID in Wuhan in the absence of containment measures was thought to be about 2.5 (Majumder et al). However, R0 declines with control measures (Zhao et al; Riou et al; Flaxman et al; Read et al; Shen et al).

The pre-control R0 of 2.5 is:

Aerosol, Droplet and Fomite TransmissionCopy Link!

Literature Review (Airborne v Droplet): Gallery View, Grid View
Literature Review (Aerosolization):
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Literature Review (Fomites):
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It is believed that COVID-19 transmission primarily occurs through liquid respiratory particles that travel through the air between people who are within a distance of about 2 meters of one another. Growing evidence indicates that transmission beyond a distance of 2 meters is also possible, especially in poorly-ventilated spaces and with periods of exposure exceeding 30 minutes (Lancet Editorial).

Modes of transmission have been a contested topic. The discussion has been complicated by lack of standardized definitions and usage of terms such as large droplets, small droplets, and aerosols. It is believed that most transmission occurs with droplets produced when a person coughs or sneezes, though other modes also occur.

Droplet Transmission: Liquid respiratory particles vary in size and are produced during breathing, talking, singing, coughing, and sneezing (CDC). Larger particles of 60-100 micrometers typically do not travel through the air farther than 2 meters (Lancet Editorial).

Airborne/Aerosol Transmission: Very small respiratory droplets, often called aerosols, may remain suspended in the air and travel a distance exceeding 2 meters (Lancet Editorial). The risk of producing aerosols is heightened during coughing, sneezing, and certain medical procedures (WHO-China Joint Mission on COVID-19). Aerosolized particles appear to remain in the air for at least 3 hours (Van Dorelmalen et al).

Fomite (Objects and Surfaces) Transmission: Transmission may occur through touching contaminated objects before touching the mouth, nose, or eyes, but this is an inefficient mode of transmission (Kampf et al). While SARS-CoV-2 can persist for days on some surfaces, attempts to culture from surfaces have been unsuccessful. Viral particles have been shown to survive < 24h on cardboard and < 72h on plastic or steel (Van Dorelmalen et al). In cases of suspected transmission through fomites and direct contact, full exclusion of respiratory transmission as the actual mode has not been possible. Transmission through the handling of contaminated objects is presumed to be unusual (Meyerowitz et al). Adherence to standard precautions and disinfection of equipment and surfaces is still indicated (Mondelli et al).

Water and Sewage: Persistence of SARS-CoV-2 virus in drinking-water is possible; indeed, some organizations and public health departments are tracking COVID infection rates by measuring waste-water RNA (see CDC Wastewater Testing, and Larsen et al). There is no evidence to date about survival of the virus in water or sewage, but it is likely to become inactivated significantly faster than non-enveloped human enteric viruses with known waterborne transmission (such as adenoviruses, norovirus, rotavirus and hepatitis A).

Bodily FluidsCopy Link!

  1. Feces and whole blood have been shown to contain viral ribonucleic acid (RNA) on PCR studies (Wölfel et al; Young et al). Significance for transmission is unclear (Chen et al), though in one systematic review of smaller studies, replication-capable virus was found in 35% of samples (van Doorn et al), meaning that fecal transmission may be possible.
  2. Urine does not appear to contain viral ribonucleic acid (Wölfel et al).
  3. Semen and vaginal secretions: COVID-19 virus has not been detected in vaginal secretions (Qiu et al). It is detectable in semen, but transmissibility is unclear. Likelihood of transmission via respiratory secretions during sexual encounters, however, is likely (Sharun et al).
  4. Tears: a few studies have indicated presence of COVID-19 virus in tears, while others have not. Current evidence is limited, but risk of transmission through tears is thought to be low (Seah et al).
  5. Cerebrospinal Fluid: Rarely, CSF has been noted to be positive by PCR (in 2 of 578 samples in one study, but not at levels that are infectious) (Destras et al).

Household and Community TransmissionCopy Link!

Household contacts of an index case appear more likely to contract the virus than other contacts (Bi et al). Most transmission events occur within households (Luo et al). The household secondary attack rate (e.g. number of people who get infected from an index case) is very variable, thought to be about 17.2% in one meta analysis (Fung et al), though very few studies tested more than once, so many cases may not have been missed The results ranged from 10.3-32.4% when contacts were tested at least twice. One recent study that did daily testing estimated SAR at 35% excluding those who had positive tests at enrollment, 53% including cases positive on enrolment. 75% of secondary cases occurred within 5 days of the index patient’s symptom onset (Grijalva et al). However, when prevalence increases, more community (meaning with no known exposure) transmissions tend to occur, highlighting the necessity of non-pharmaceutical interventions (e.g. masks) coupled with public health strategies such as sentinel and syndromic surveillance.

Super-Spreading Events (SSEs)Copy Link!

Literature Review Gallery View, Grid View

Super-Spreading Events are when an individual directly spreads an infection to an unusually large number of others. Several cases of superspreading have occurred at choirs (Hamner et al), weddings (including a Maine wedding that led to 177 linked cases, including seven deaths), churches Daegu, South Korea, where “Patient 31” infected at least 40 others (Ryall), and even within the White House. SSEs are believed to be disproportionately responsible for COVID-19 cases globally, with several studies suggesting that ≈80% of secondary transmissions have been caused by a small fraction (≈10%) of initially infected individuals. (Althouse et al; Endo et al). SSEs are heavily dependent on sociobiological mechanisms, including individual viral load, numbers of susceptible contacts per person, residence or employment in congregate settings, and ‘opportunistic’ scenarios including temporary clustering of individuals in mass gathering events. Environmental factors also are very important with closed places, crowded places, and poor ventilation playing a significant role in SSEs. Because SSEs play such an outsized role in fueling the pandemic, they amount to a significant concern, but also serve as an opportune area for public health interventions, particularly the prevention of transmission events where over 10 people are infected (Althouse et al).

SchoolsCopy Link!

Schools are unique settings and are likely to contribute to COVID-19 transmission between households and within communities. However, sustained closure of in-person schooling is expected to have an adverse effect on life outcomes for children and to worsen existing inequalities.

The American Academy of Pediatrics advocates that children should be physically present in school where possible (AAP Guidance). In some places, it appears that limited reopening with some precautions has not led to significant numbers of transmission events or large outbreaks (US CDC). However, this may be very location specific: a large-scale study of over 500,000 contacts of 85,000 infected cases in India have noted that children are a significant source of spread, even despite school closures (Laxminarayan et al). This thorough Review of the Literature on School Transmission and Safety summarizes some of the unique challenges and recommendations (Massachusetts General Hospital COVID-19 Resource Library). Decisions on whether or not to open schools depends significantly on local policy and local epidemiology.

Tool: TH Chan School of Public Health at Harvard University Strategies to Minimize Risk
Tool: CDC Guidance on Risk Reduction and Reopening of Schools.

Air TravelCopy Link!

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The risk of contracting COVID-19 on airplanes is low. 50% of the air circulated in the cabin is brought in from the outside, and the remaining 50% is filtered through HEPA filters. Air enters the cabin from overhead inlets and flows downwards toward floor-level outlets. There is relatively little airflow forward and backward between rows, making it less likely to spread respiratory particles between rows (Pombal et al). To avoid transmission, it is advised to avoid moving up and down the aisles as much as possible, and to wear a mask for the duration of the flight. A laboratory study (not real-world) designed to mimic spread within airplanes indicated that the lack of physical distancing when middle seats were permitted for occupancy may increase transmission, but this model did not account for mask wearing or vaccination (CDC).

Pets and AnimalsCopy Link!

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While transmission risk from pets is low, the United States Centers for Disease Control now recommend that social distancing rules should apply to pets as well as to humans (CDC). Dogs showed low susceptibility. Pigs, chickens, and ducks were deemed not susceptible according to early data. Evidence of viral replication was noted in inoculated ferrets and cats, with viral transmission occurring between cats (Chen et al). There is no current evidence of transmission to humans from cats and ferrets, though minks can transmit to humans (Meyerowitz et al). Virologist cited in Nature News suggests cat owners should not yet be alarmed, noting deliberate high-dose inoculation of said cats - unrepresentative of day-to-day pet/owner interactions, and that none of the infected cats developed symptoms in the aforementioned study (Mallapaty et al).

SeasonalityCopy Link!

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Experimental data suggest that the persistence of SARS-CoV-2, either on surfaces or while airborne, is somewhat sensitive to environmental conditions such as temperature, humidity, and ultraviolet radiation. Comparable environmentally-sensitive respiratory viruses often demonstrate seasonality, with greater numbers of infections during winter, and so it seems plausible that SARS-CoV-2 might demonstrate a similar pattern (Carlson et al). However, further studies suggest minimal (≈1%) reductions in SARS-CoV-2 transmission linked to environmental UV radiation (Carleton et al), and the current consensus on such environmental effects is that they are minor in real-world circumstances.

Other respiratory infections such as influenza manifest seasonal oscillations; ‘cold and flu season’ occurs when population susceptibility is high and environmental drivers such as lower temperatures, humidity, and solar radiation conspire to increase transmission, often by changing human behaviors (forcing people indoors). But current levels of immunity to SARS-CoV-2 in most countries are low enough that summer weather is not likely to be protective (Baker et al). If the virus ultimately becomes endemic, it is likely that seasonal oscillations will be observable in temperate regions, with recurrent wintertime outbreaks likely (Kissler et al).

Immunity and VaccinesCopy Link!

Antibody ResponseCopy Link!

Updated Date: December 18, 2020

The majority of patients with RT-PCR-confirmed COVID-19 develop antibodies against the virus (Zhao et al; Wang et al). These two large series of serial samples found antibodies in 161/173 and 308/310 patients respectively. Time to seroconversion, correlation with protection, and durability of immunity, continue to be studied.

When assessing research studies, details may depend on exactly which antibodies are being assessed(e.g,. IgA/IgM/IgG or total antibody, antibodies to the nucleocapsid vs those to the spike protein, or whether the antibodies are “neutralizing” -- for example, antibodies directed against the receptor-binding domain (a component of the spike protein) may appear earlier than antibodies to other antigens (To et al; Okba et al).

Seroconversion (detection of circulating antibodies) typically occurs 7-14 days after symptom onset (Deeks et al; Huang et al). In one study of 173 patients, 100% were seropositive (total antibody) at 15 days (Zhao et al).

  • Although IgM seroconversion is often thought of as occurring before seroconversion for IgG, this has not been consistently observed for SARS-CoV-2 (e.g., Qu et al; Xiang et al; Wang et al; Zhao et al).
  • IgA antibodies are important in mucosal immunity and may play an important role in the response to SARS-CoV-2 (Sterlin et al; Wang et al), but data are currently limited (Deeks et al).
  • The sensitivity of serology (IgM or IgG) may be higher than that of PCR by the second week of illness (day 8 in Zhao et al, day 6 in Guo et al), based on studies with serial samples from individual patients.
  • Antibody detection may identify cases with negative upper airway PCR but high clinical suspicion when timed appropriately found positive IgM in 54 of 58 probable cases without detectable nucleic acid (Guo et al).

Neutralizing antibodies prevent viral replication, usually by binding the spike glycoprotein that SARS-CoV-2 uses to enter cells. Not all antibodies are neutralizing; some bind to the virus but do not stop its activity.

Cross-reactivity occurs when a pre-existing immune response to seasonal human coronaviruses recognizes SARS-CoV-2. It has been seen in both T-cell (e.g., Mateus et al) and humoral (e.g., Ng et al) arms of the immune system. This presence or absence of this response has been hypothesized to contribute to variable outcomes in COVID-19 (Beretta et al). A possible altered immune response due to pre-existing antibodies has also raised the possibility of antibody-dependent enhancement after SARS-CoV-2 vaccination or convalescent plasma therapy. Fortunately, such enhancement has not been reported to date (Wen et al).

Reinfection and Durable ImmunityCopy Link!

Updated Date: April 10, 2021
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Reinfection refers to individuals who have been infected and cleared the original virus, but again show evidence of viral replication after exposure to a new SARS-CoV-2 virus (Falahi et al).

A person who is asymptomatic but tests positive after resolution of COVID-19 may have (1) residual shedding of RNA fragments or viral particles (not necessarily infectious; see Infectivity) from the initial infection, or (2) reinfection after exposure to another SARS-CoV-2 virus. A person who has new or prolonged symptoms and a positive test after resolution of an initial COVID-19 diagnosis could either have (1) ongoing or post- COVID-19 physiological injury in the absence of replicating virus, (2) recrudescence of residual virus not fully cleared after the initial infection, or (3) reinfection after exposure to another SARS-CoV-2 virus.

  • Conclusive demonstration of reinfection is difficult outside of research settings, since confirmation requires analysis of paired viral whole genome sequences taken during both initial and subsequent infections (