Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

SymptomsCopy Link!

Common SymptomsCopy Link!

Updated Date: May, 2020
Literature Review: Gallery View, Grid View
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).

2. Cough, 68-83%
3. Anosmia and/or ageusia (loss of sense of taste and/or smell) ~70%
4. Upper respiratory symptoms (sore throat, dripping nose, nasal or sinus congestion), 5-61%
5. Shortness of breath, 11- 40%
6. Fatigue, 23-38%
7. Muscle aches 11-63%
8. Headache 8-14%
9. Confusion 9%
10. 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): Gallery View, Grid View

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: Gallery View, Grid View

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. As vaccines become more common, this percentage of asymptomatic infection is likely to change, as vaccinated patients are less likely to be symptomatic (see Reinfection and Breakthrough Infection).
• 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): Gallery View, Grid View

Multiple factors have been associated with worse prognosis in people infected with SARS COV-2.

1. Viral variant. Certain variants, such as the Delta variant, may be more severe than others. See new variants.
2. 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).

3. 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

4. Race: Please see Health Equity for a discussion on racial differences in COVID infection and severity.
5. 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).
6. 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:

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

MortalityCopy Link!

Updated Date: December 16, 2020
Literature Review: Gallery View, Grid View

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): Gallery View, Grid View
Literature Review (Human Genetics) Gallery View, Grid View

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: October 1, 2021
Literature Review (Autopsy): Gallery View, Grid View
Literature Review (Histology): Gallery View, Grid View

• Histology of COVID-19 associated lung disease most often shows bilateral diffuse alveolar damage with cellular fibromyxoid exudates, desquamation of pneumocytes, pulmonary edema, hyaline membrane formation, microthrombi The prevalence of microthrombi identified in the pulmonary vasculature is similar to that seen in patients with SARS-associated ARDS and higher than that seen during H1N1 influenza-associated ARDS (Hariri et al, 2021)., organizing fibrosis and superimposed pneumonia. There is evidence of direct viral injury to lung tissue, as well as inflammatory sequelae. (Xu et al, Lancet Respir Med, 2020, Hariri et al, Chest, 2021).
• 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: Gallery View, Grid View

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 raccoon 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: December 30, 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

Tool: CDC Delta Variant.

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). Mutations started occurring in SARS-CoV-2 in the fall of 2020 (CDC), and continue to occur over time. The naming system for variants was a letter-and-number system until June 2021, when the WHO created a newer simpler naming system using greek letter names (Nature News).

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

Infectiousness and SeverityCopy Link!

The meaning of these mutations for transmission and severity depends on the exact mutation. In the Summer of 2021, the Delta variantwas identified and appeared to be more transmissible than the ancestral strain (see viral load), and also more severe. One study from the UK of over 43,000 cases showed that Delta patients had twice the risk of hospitalization compared with Alpha patients, despite overall being younger (Twohig et al). On November 26, 2021 the WHO named Omicron a new variant of concern. Omicron is unique because it has 50 new mutations not seen in combination before, with more than 30 mutations located in the spike protein, several of which are believed to make this variant even more infectious than Delta. Though some studies suggest Omicron causes less severe illness, this has not yet been definitively shown. A recent study from South Africa showed that two doses of the Pfizer-BioNTech vaccine was 70% effective against preventing hospitalizations while Omicron was the dominant variant (compared to 93% effectiveness in the period before Omicron was identified).

Infectivity and TransmissionCopy Link!

InfectivityCopy Link!

Updated Date: August 30, 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). Certain viral variants, like Delta, appear to cause higher viral loads (1260 higher, Li et al), and thus be more infectious.

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, viral load does not always correlate perfectly with infectiousness. It is measured by quantitative PCR, which cannot distinguish between a live viable virus or a dead or inactivated virus. 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): Gallery View, Grid View

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 and transmission for all variants. This is an evolving area of research, but the data suggest that at a population-level less transmission occurs between vaccinated people. However, an individual vaccinated person who is experiencing a breakthrough infection (asymptomatic or symptomatic) can certainly transmit to others; For the ancestral strain this was thought to be less common in vaccinated people compared with unvaccinated, but for highly-contagious strains like the delta variant, transmission appears to occur at similar rates regardless of vaccination status. (CDC) Multiple studies have shown that vaccinated and unvaccinated people have similar viral loads/ infectiousness (Brown et al, Riemersma et al), at least in the first six days of infection. After six days, vaccinated people appear to have lower viral loads and be less infectious (Chia et al) 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!

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). As variants of COVID develop, the R0 is likely to change.

The original ancestral strain, pre-control R0 of 2.5 is:

• Roughly comparable with the 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak (Lipsitch et al; Bauch et al; Wallinga et al).
• Higher than the 1918-1919 influenza pandemic (R0 1.5) (Petersen et al).
• Higher than typical seasonal influenza (average R0 1.3) (Coburn et al).

Aerosol, Droplet and Fomite TransmissionCopy Link!

Updated Date: August 30, 2021

Literature Review (Airborne v Droplet): Gallery View, Grid View
Literature Review (Aerosolization): Gallery View, Grid View
Literature Review (Fomites): Gallery View, Grid View

COVID-19 transmission primarily occurs through liquid respiratory particles (droplets, 50-100 micrometers particles) that travel through the air between people who are within a distance of about 2 meters of one another. Early in pandemic there was debate about whether transmission also occurs via aerosols (small particles under <5 micrometers), which can hang in the air for far longer and travel longer distances. Growing evidence indicates that aerosol transmission is possible, especially in poorly-ventilated spaces and with periods of exposure exceeding 30 minutes (Lancet Editorial), and the World Health Organization and US CDC both changed their guidance to include aerosol spread in spring of 2021.

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, 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). See concerns about aerosolization to see a list of procedures and devices and the effect they may have on aerosols. Aerosolized particles appear to remain in the air for at least 3 hours (Van Dorelmalen et al), with some laboratory studies indicating it can be as long as 16 hours (Fears et al)

Fomite (Objects and Surfaces) Transmission: Transmission through touching contaminated objects before touching the mouth, nose, or eyes, is an inefficient mode of transmission (Kampf et al). Mathematical models suggest that the chance of an infection occurring from a contact with a contaminated surface is less than 1 in 10,000. (CDC) While viral RNA has been detectable < 24h on cardboard and < 72h on plastic or steel (Van Dorelmalen et al), attempts to culture virus from surfaces have been unsuccessful (Colaneri et al), suggesting that fomite transmission is unlikely. 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. Having children ages 0-3 is associated with higher secondary attack rates compared with children aged 14-17 (OR 1.43), possibly due to the inability of smaller children to distance and care for themselves. (Paul et al)

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!

Updated Date: January 5, 2022

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).

In the Fall of 2021, to minimize the amount of time students needed to quarantine and miss in-person learning, some schools began implementing a Test To Stay strategy. This involves routine serial testing paired with contract tracing, allowing school-associated close contacts to remain in school during their quarantine period.

Multiple studies have shown that mitigation measures like masks, distancing, and ventilation have a significant impact on reducing transmission in schools (Lessler et al, Doyle et al, Dawson et al, Falk et al). Schools without mask mandates are 3.5 times more likely to have COVID-19 outbreaks than schools with mask mandates based on data from early in the 2021-2022 school year in the USA (CDC). A simulation study indicates that opening windows may significantly reduce transmission, as much as 14 fold, and masks may reduce transmission as much as 8 fold (Villers et al). The exact repercussions of novel variants on these interventions has yet to be determined, but it is likely that they will continue to reduce risk.

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.

Tool: Rockefeller Playbook on Testing in Schools

Tool: New York Times visualization on the Impact of Opening Windows

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).

ImmunityCopy Link!

Antibody ResponseCopy Link!

Updated Date: August 30, 2021

Rates of Antibody ResponseCopy Link!

The majority of patients with RT-PCR-confirmed COVID-19 develop antibodies against the virus within 4 weeks, with most studies ranging from 90-99% (Zhao et al; Wang et al, Arkhipova-Jenkins et al). In most patients these are neutralizing antibodies: over 90% of people seropositive for SARS-CoV-2 appear to have detectable neutralizing antibody responses (Wajnberg et al).

Types of Antibodies and SeroconversionCopy Link!

When assessing research studies, details may depend on exactly which antibodies are being assessed. Generally Seroconversion (detection of circulating antibodies) typically occurs 7-14 days after symptom onset (Deeks et al; Huang et al).

• IgM/IgG or total antibody. 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). A systematic review of 66 studies showed Moderate-strength evidence that IgG levels peak 25 days after symptom onset and are often detectable still at 120 days (many did not do longer followup). IgM levels peak at approximately 20 days and then decline more rapidly. (Arkhipova-Jenkins et al)
• Receptor Binding Domain Antibody. 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).
• 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).
• Neutralizing Antibodies. 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, such as most of those that bind to the nucleocapsid. Understanding which antibodies are neutralizing is critical for Vaccine Development, Monoclonal Antibody Therapy, studying Convalescent Plasma, and determining whether seropositive individuals are Immune from Reinfection. Neutralization assays are not routinely performed clinically. They require testing the antibodies against their intended target in vitro, and are often reported by the Lethal Dose 50 (LD50) or neutralization titer (titer at which the target is inhibited) to determine if the antibody has low, medium, or high neutralizing ability.

Duration of ImmunityCopy Link!

Updated date: August 23, 2021

The duration of immunity after infection or vaccination is not conclusively known, and not consistent between individuals. Relevant host factors may include immune status, age, and severity of initial infection. Studies documenting decay of IgG antibodies or neutralizing titers may underestimate immunity, since both B and T-cell responses likely also play a significant role, and are not reflected in circulating antibody levels (Karlsson et al). Patients with mild infection lose detectable antibodies more quickly but may have an immune memory that allows them to rapidly produce antibodies on re-exposure (Stephens et al). Because of this, this section discusses the duration of antibodies, the relationship of antibodies to immunity and the duration of immunity each separately.

Duration of AntibodiesCopy Link!

The duration of circulating antibodies in the blood is variable between individuals, and likely different in those with natural vs vaccine-induced immunity. We currently have less than a year of data (8 months for vaccines) and thus do not yet know exactly how long circulating antibodies will be detectable after infection or vaccination.

• Infection. Circulating neutralizing antibodies differ significantly in different studies, which may reflect differences in selection criteria, such as differing severity of initial disease.

• In one study of seven month kinetics of antibodies, plasma neutralizing capacity peaked at day 80 after symptom onset and remained stable thereafter up to 250 days. (Ortega et al)
• In a different study, neutralizing antibody titer approached baseline within a 94 day followup in one study (Seow et al.)
• Another kinetic study showed neutralising activity above a titre of 1:40 in 50% of convalescent participants as far as 74 days (Wheatley et al)
• Another study found neutralizing capacity in >70% of patients tested around 6 months (Wu et al)

• Vaccination. The Moderna vaccination thus seems to show persistent antibodies through 6 month, though the meaning of these antibodies are not known (Doria-Rose et al). Pfizer reports waning antibodies after 6 months (Pfizer)

Correlation of Antibodies with ProtectionCopy Link!

Antibodies may reflect some elements of immunity, but do not necessarily reflect immune response on re-exposure (which is largely determined by T cells and memory B cells). One August 2021 study does indicate that waning antibody titers correspond with decreased protection from disease; In one antibody neutralization study of vaccine recipients, Day 57 reciprocal cID50 neutralization titers were compared with cumulative incidence of COVID for 100 days after the titer was drawn (days 57-100). They found that neutralizing titers of undetectable (<2.42), 100, or 1000 vaccine efficacy was 50.8% (−51.2, 83.0%), 90.7% (86.7, 93.6%), and 96.1% (94.0, 97.8%). Therefore, those with a negative titer still have about 50% protection, but less than those with positive neutralizing antibody titers. (Gilbert et al)

Waning Protection from InfectionCopy Link!

Note: this is a rapidly evolving area, and data may change quickly

The effectiveness of vaccine-based immunity at preventing infection may start to wane around 5-6 months, based on data from four studies in the USA which showed a declines in efficacy from 91.7% to 79.8% (Rosenberg et al), 74.7% to 53.1% (Nanduri et al), 91% to 66% (Fowlkes et al) and 86% to 76% (Moderna) 76%-42% (Pfizer) (Puranik et al) across 5-6 month followups. Slide 14 from this CDC summary shows an excellent graphical representation of these trials. The vaccines studied were the ones available in the USA (Pfizer, Moderna, J&J). The decline in efficacy also may correspond somewhat to the emergence of new viral variants like Delta, however the above CDC analysis suggests it is likely a combination of both the new variant and waning immunity. Similarly, the spike of new infections in Israel in August 2021, which has a very high vaccination rate and vaccinated most of its population around February 2021, may be a sign of waning immunity (Goldberg et al).

However, the waning in immunity appears to apply mostly to mild or moderate disease and not severe disease, hospitalization, or death. This CDC study looked at hospitalizations at 21 medical centers in the USA over 24 weeks and found no decline in vaccine effectiveness against COVID-19 hospitalization regardless of time of vaccination or “high risk” status.

Reinfection and Breakthrough InfectionCopy Link!

Updated Date: August 30, 2021
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Reinfection Definition:

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).

• Reinfection is different from (NICE guidelines 2020-12-18, Yahav et al):

• Prolonged symptoms from Post-COVID-19 syndrome or relapse/reactivation (also called recrudescence) of symptoms from initial infection
• Repositivity, or residual shedding of RNA fragments or viral particles (not necessarily infectious; see Infectivity) from the initial infection
• Breakthrough infection, or infection after vaccination in a patient who has not ever had evidence of viral replication

• Conclusive demonstration of reinfection is sometimes difficult, since confirmation requires analysis of paired viral whole genome sequences taken during both initial and subsequent infections to be able to conclusively determine that this is a new virus (ECDC Threat Assessment Brief 2020-09-21).

Rates of Reinfection:

Reinfection is uncommon, but appears to be increasing as levels of natural immunity from prior infection wane over time, and new viral variants emerge.

• Comparison of antibody positive and negative cohorts estimated that antibodies from natural infection conferred ~95% protection in one large study (Abu-Raddad et al) Another large study found a lower estimated protection from natural infection of ~81%, dropping to ~47% in those aged 65 years and older (Hansen et al). Dr Jetelina’s table of vaccine efficacy includes multiple studies on the efficacy of natural infection, including against viral variants.
• New viral variants appear to cause more cases of reinfection, with the Delta variant having an Odds Ratio of 1.43 for reinfection relative to ancestral strains (Public Health England)

Clinical Course in Reinfection:

• Symptoms in reinfection tend to be worse than initial infections, especially if the first infection was mild (Cavanaugh et al), however severe disease appears to be less likely (Qureshi et al) There is currently little data about hospitalization and mortality in reinfections.

Rates of Breakthrough Infection:

Given the vaccines are not 100% efficacious, breakthrough infections do occur. The number and severity of breakthrough infections is difficult to definitively track, though it appears rare. Breakthrough infections depend on several things: 1) the person’s immune response to the vaccine (some people are immunocompromised or have lower immune responses to the vaccine, and immunity may wane over time) 2) the variants and their ability to evade vaccination immunity and 3) frequency and nature of exposure to an infected person.

Clinical Course in Breakthrough Infection:

Early data from a study of the 10,262 reported breakthrough cases from January-April 2021 in the USA indicate that breakthrough cases carry about a 10% hospitalization and 2% mortality risk, but a full 27% of recorded cases were asymptomatic. 64% of these breakthrough infections were caused by a variant of concern (MMWR). Preliminary reports suggest that 19% people experiencing breakthrough develop some post-acute COVID (“long COVID”) symptoms (>6wks), which is higher than typical. (Bergwerk et al)

Vaccine vs Natural ImmunityCopy Link!

Updated Date: August 30, 2021

Generally vaccine-based immunity is thought to be more protective than natural immunity. In the case of the Delta variant, it may be about 2 times more protective (Cavanaugh et al). However, this is not universally the case (Gazit et al). For people who have had both the vaccine and natural infection, the natural infection seems to augment immunity similarly to how a booster shot might (Wang et al). For this reason we recommend that people who have had COVID still get fully vaccinated (see vaccination after COVID infection).

The reason for this is that natural infection produces an immune response that is unpredictable relative to vaccination. When infected with the virus, different hosts will develop antibodies to different parts of the virus, whereas with the vaccine antibodies will consistently target the spike protein. Some people with natural immunity will have high neutralizing antibody titers, and others will not. One study found that natural antibodies largely attached to only one region (E484) on the receptor-binding domain, whereas vaccine antibodies attached to many parts of the virus (Greaney et al), meaning that viral mutations may be more likely to escape natural antibodies. Further, the fact that most vaccines are given in 2 doses also likely augments immunity relative to a single infection.

VaccinesCopy Link!

Updated: June 21, 2022
Literature Review: Gallery View, Grid View
Literature Review: University of Washington Literature Report (Vaccines and Immunity)

Tool: Vaccine Allocation Planner (helps states and countries plan vaccine allocation)
Tool: COVID Vaccine Development Tracker
Tool: FDA COVID Vaccine FAQs
Tool: NEJM Vaccine Resources
Tool: NEJM Vaccine FAQ

MechanismsCopy Link!

Most vaccines fall into one of 4 categories. The mechanisms of the commonly available vaccines are listed below in efficacy.

• Genetic Vaccines (typically lipid envelopes carrying SARS-CoV-2 genetic material into cells) including mRNA Vaccines

• Code for the coronavirus “spike” protein to induce an immune response mediated by antibodies and T cells.
• Due to the temperature-sensitivity of genetic material (Simmons-Duffin), these vaccines require very cold storage and transportation environments.
• There is a significant amount of misinformation about mRNA technology:

• The genetic information contained in these vaccines does not integrate with human DNA or change a recipients’ genetic code, nor are they gene therapy. The vaccines do not use nanorobotic technologies. (Reuters Fact Check)
• mRNA does not stay in the body forever, in fact mRNA is degraded rapidly in cell cytoplasm within minutes (Chen et al).
• There is no association with any fertility concerns. There is no effect on sperm paraters (Gonzalez et al) or any female parameters of fertility. The coronavirus’s spike protein and the placental protein syncytin-1 are completely different in structure and the vaccine does not cause immune reactions to syncytin-1 (ASRM)

• Viral Vector Vaccines (repurposed viruses such as adenovirus carrying SARS-CoV-2 genetic material into cells) including Adenovirus-vector Vaccines.

• Use a variety of engineered adenoviruses (common viruses that cause colds and related symptoms) as vectors to expose human cells to the SARS-CoV-2 spike. These are generally cheaper than genetic vaccines (Knoll et al), both due to ease of transport as they only require refrigeration to protect the virus vector, as well as due to less costly supply chains than those required for mRNA vaccine technology.

• Protein-based Vaccines (delivering coronavirus proteins only)
• Traditional “inactivated/attenuated” Coronavirus Vaccines (whole virus that is killed or weakened)

EfficacyCopy Link!

Updated date: August 30, 2021

Tool: Vaccine Table with Efficacy, including Major Variants (Compiled by Dr. Katelyn Jetelina)

Efficacy of vaccines is complex to assess, as it changes as new viral variants emerge and the immunity provided may wane. Further, often they are lumped together in studies that classify people as either vaccinated or unvaccinated and do not differentiate based on the exact vaccine studied. The above table includes data against major variants.

1. Preventing hospitalization, critical illness, and death:

1. All vaccines seem to offer excellent efficacy against hospitalization, critical illness, and death.
2. A large CDC/MMWR study indicated that vaccination was associated with a 29 fold reduction in risk of hospitalization compared with no vaccine.
3. AstraZeneca and Johnson & Johnson appear to be 95-100% effective at preventing severe disease and death.
4. mRNA vaccines (Pfizer and Moderna) have near 100% efficacy at preventing severe disease and death, though case reports of breakthrough, critical illness, and death do occur (US CDC)

2. Preventing all symptomatic infection:

1. The following are the efficacies of the most commonly globally-available vaccines at preventing symptomatic infection at the time of local regulatory authorization, which typically meant with the ancestral strain (not more virulent strains like Delta).

1. Pfizer/BioNTech (mRNA). FDA EUA cited efficacy of 95% at preventing symptomatic infection. (Pfizer EUA). Full FDA approval on August 23, 2021, cited 91% efficacy (FDA).
2. Moderna (mRNA). FDA EUA cited 94% efficacy against symptomatic infection (Moderna EUA).
3. Oxford/AstraZeneca (viral vector). The Oxford/AstraZeneca vaccine had an initial efficacy of 90% (Ledford; Knoll et al).
4. SinoPharm (whole virus inactivated). 79% effective against symptomatic SARS-CoV-2 infection (WHO)
5. Gam-COVID-Vac aka Sputnik (viral vector). The vaccine is the only vaccine that uses two different serotypes, and it appears to have 91.6% efficacy based on a phase 3 trial (Longunov). It is used in about 70 countries. However, it has yet to gain approval from the EMA or the WHO (as discussed in this Nature article).
6. Covaxin (whole virus inactivated). 77.8% efficacy against symptomatic disease. The vaccine is approved in 15 countries but has yet to gain approval from the WHO (GAVI).
7. Janssen/Johnson & Johnson (viral vector). FDA EUA reports an efficacy of 85% against severe disease, and around 70% for symptomatic disease (Janssen EUA).

3. Preventing asymptomatic infection is incredibly hard to determine, as most studies do not routinely test people without symptoms. However, a few studies indicate effectiveness remains good for most vaccines. Asymptomatic infection appears to be reduced by at least 80% by both of the mRNA vaccines (Tande et al)

Mixing Different VaccinesCopy Link!

Updated date: November 12, 2021

Combining different vaccine types for different shots is an area of active research. On October, 21, 2021, the CDC announced that patients eligible for a booster can choose any of the 3 US COVID vaccines for their booster regardless of what a person received as their primary series

Two major studies have been published on this:

1. A study of 458 individuals were sorted to get the initial full series of J&J, Moderna, or Pfizer vaccinations followed by a booster of one of the three four to six months later (Atmar et al). This study formed the basis of the ACIP recommendation to allow mixing and matching for booster shots. Notably, this study was performed using a 100ug booster for Moderna, not the 50ug booster that is currently recommended.

1. The safety profile appears similar to boosting with the same vaccine, and includes mild reactions like fever, fatigue, and cutaneous reactions.
2. After primary J&J series:

1. Moderna booster gave 56.1 fold increase in IgG and 76.1 fold increase in neutralizing antibodies.
2. Pfizer booster gave 32.8x IgG and 35x neutralizing antibody increases
3. J&J booster gave a 4.2x igG and 4.6x neutralizing antibody increases

3. After a primary Moderna series:

1. Moderna booster gave 7.9 fold increase in IgG and 10.2 fold increase in neutralizing antibodies.
2. Pfizer booster gave 9.7x IgG and 11.5x neutralizing antibody increases
3. J&J booster gave a 4.7x igG and 6.2x neutralizing antibody increases

4. After a primary Pfizer series:

1. Moderna booster gave 17.3 fold increase in IgG and 31.7 fold increase in neutralizing antibodies.
2. Pfizer booster gave 14.9x IgG and 20.1x neutralizing antibody increases
3. J&J booster gave a 6.2x igG and 12.5x neutralizing antibody increases

2. In a UK trial (Com-COV) one dose of AstraZeneca + one dose of Pfizer-BioNTech resulted in higher antibody levels compared with two doses of AstraZeneca, but lower antibody levels compared with 2 doses of Pfizer-BioNTech. (Shaw et al)

Efficacy on New Viral VariantsCopy Link!

Updated date: January 5, 2022

Tool: Vaccine Table with Efficacy, including Major Variants and Natural Infection (Compiled by Dr. Katelyn Jetelina)

Efficacy may change as different viral variants become more predominant, as the antibodies produced by the vaccines may have different neutralizing effects on different strains, especially if the virus mutates the area targeted by the vaccine. However, most vaccines seem to retain at least partial effect against new variants, and most of the time retain excellent protective benefit. Please see this link for a curated chart of the efficacy of six major vaccines or vaccine candidates against major variants, including links to the original literature (compiled by Dr. Katelyn Jetelina). Study estimates for effectiveness against symptomatic disease at the time the Delta variant was most prevalent were around 59% for the Astrazeneca vaccine, 67% for J&J, 66-95% for Moderna, and 39-96% for Pfizer. (Nasreen et al, Sheikh et al, Puranik et al, Pouwels et al, Elliott et al, Fowlkes et al, Sadoff et al, Israel health minister as cited in WSJ). Research on the efficacy of vaccines against the Omicron variant is still emerging but a recent study using serum samples from recipients of the Pfizer-BioNTech vaccine showed that neutralization of Omicron-infected cells was higher in recipients of 3 doses of the vaccine compared to those who had received 2 doses.

neutralization efficiency (by a factor of 100) against the omicron variant after the third dose than after the second dose; however, even with three vaccine doses, neutralization against the omicron variant was lower (by a factor of 4) than that against the delta variant. The durability of the effect of the third dose of vaccine against Covid-19 is yet to be determined.

Booster ShotsCopy Link!

Updated Date: June 21, 2022

Many countries are now recommending booster shots, due to the rise of Delta and Omicron variants as well as due to waning immunity. See Waning Protection from Infection and Breakthrough Infections for summaries of the data driving these decisions. However, even without boosters and even with the emergence of the Delta and Omicron variants, the vaccines remain very highly efficacious at preventing hospitalization and death. This has led the World Health Organization to call for a delay in rolling out booster shots in the name of global equity, as billions of people globally have not yet had the opportunity to have even a first dose (NPR), which would save many more lives.

In places where boosters are being recommended, general guidance includes:

• Boosters for patients with normal immune systems should be lower priority than assuring patients who have not yet had any vaccines get their initial vaccination series
• Mixing different vaccine types is permitted, and may be advantageous for some (especially giving mRNA vaccines to those who received viral vector vaccines). See mixing different vaccines.

In the United States, the CDC has made the following recommendations for booster shots:

• Pfizer BioNTech: single booster for patients ages 5-11 and > 12 years 5 months after primary series has been completed; a second booster is recommended for patients > 50 years or >12 years who are immunocompromised 4 months after the first booster.
• Moderna: single booster for patients > 18 years 4 months after the primary series has been completed; a second booster is recommended for patients > 50 years or >18 years who are immunocompromised.
• Janssen: single booster 2 months after primary vaccination

Dose 3 for Immunosuppressed PatientsCopy Link!

In four recent studies, a subset of 33-50% of immunocompromised patients who did not develop an antibody response to the first two doses did develop a measurable antibody response to a third dose (CDC). A randomized control trial with Moderna found immunocompromised patients with a third dose had better protection compared to the placebo (55% vs. 18%) (Hall et al).

• See here for more information on the timing, effect, and monitoring of vaccines in immunosuppressed patients.
• Eligibility criteria for boosters varies by country, so please consult your local health department for guidance. In the USA current guidance includes:

• Moderately to severely immunocompromised individuals. This includes patients with cancer on active or recent chemotherapy, solid or bone marrow transplant, primary immunodeficiencies, HIV with CD4<200, patients on certain immunosuppressive agents, and some other immunocompromised individuals. On January 3, 3022, the FDA approved a third dose of the Pfizer vaccine for children 5-11 years old who are immunocompromised. See full U.S. CDC guidance here.
• Third dose should be >28 days after the last dose.
• Serologic confirmation of antibodies is not yet recommended routinely

Boosters for Patients with Normal Immune SystemsCopy Link!

Countries recommending boosters are largely doing so on the basis of evidence of waning antibody levels and a handful of studies showing reduced vaccine effectiveness over time against mild to moderate disease (but not severe disease). See Waning Protection from Infection for this data.

• Eligibility criteria for boosters varies by country, so please consult your local health department for guidance. In the USA recommendations (see full guidance here) are currently:

• For those who received an initial Pfizer series, a booster is recommended those who are:

1. > 5 months from second dose AND 12+ years old

• For those who received an initial Moderna series, a booster is recommended for those who are:

1. > 6 months from second dose AND 18+ years old

• For those who received an initial J&J vaccine, a booster is recommended >2 months after the initial dose AND 18+ years old
• Note, Moderna boosters are approved for a 50mcg dose, different from the 100mcg initial series dose.

Adverse Events and ReactogenicityCopy Link!

Most observed adverse events during vaccine trials were injection-related or reflected an expected immune response. Many people feel ill following vaccine administration for about 1-3 days, especially after the second dose of the vaccine This is not a sign of infection by the coronavirus.

ContraindicationsCopy Link!

The U.S. CDC considers the following contraindications: severe allergy (e.g. anaphylaxis) to a prior dose of an mRNA COVID vaccine or any of its components, immediate allergic reaction of any severity to a previous dose or any of its components (including PEG), immediate allergic reaction of any severity to polysorbate. (CDC) Reactions to non-COVID vaccines are considered a “precaution” but not a contraindication.

Routine VaccinationsCopy Link!

The CDC now states that COVID-19 vaccines and other vaccines may now be administered without regard to timing. This includes simultaneous administration of COVID-19 vaccine and other vaccines on the same day, as well as co-administration within 14 days. Other public health guidance may vary.

Vaccination Associated Cutaneous ReactionsCopy Link!

Updated Date: October 1, 2021

Cutaneous reactions to vaccination are common with COVID vaccines, as well as other vaccinations. A large red, itchy, painful, and swollen rash at the site of injection is sometimes called COVID-arm, and is a relatively common symptom of vaccination (about 1%, but variable depending on the type of vaccine). It typically occurs about a week after injection (range, 5-10 days). People with these reactions can still receive second and booster doses as they do not lead to serious sequelae (Jacobson et al). Further, many patients who had COVID-arm with a first shot will not have it on the second shot (Blumenthal et al). Pain can be managed with over the counter medications where appropriate.

Other cutaneous reactions can also occur: Amongst 405 cases of cutaneous reactions in one cross-sectional Spanish study (Català et al) of people vaccinated with Pfizer-BioNTech (40.2%), Moderna (36.3%) and AstraZeneca (23.5%), the most common cutaneous reactions were: injection-site (COVID-arm, 32.1%), urticaria (14.6%), morbilliform (8.9%), papulovesicular (6.4%), pityriasis rosea-like (4.9%) and purpuric (4%) reactions.

Vaccine-Induced Immune Thrombotic ThrombocytopeniaCopy Link!

Updated date: May 9, 2021

There have been reports of rare (tens of cases globally) of venous thrombotic disease -- and particularly cerebral venous sinus thrombosis -- in recipients of the widely deployed Oxford/AstraZeneca and Janssen/Johnson & Johnson adenovirus vector vaccines. For both vaccines, the frequency of these events appears to be far lower than the risk of severe thromboembolic complications of COVID-19 itself. As of April 15, 2021, the benefits of both Oxford/AstraZeneca and Janssen/Johnson & Johnson vaccines are thought to outweigh potential risks. From Cines et al:

• Most of the patients are women under 50 years of age, some of whom were on estrogen-based medications.
• Thromboses often occur at unusual sites, such as cerebral venous sinus thrombosis (CVST) or in the portal, splanchnic, or hepatic veins. Cerebral (also “central” or “dural”) venous sinus thrombosis (CVST) refers to a blood clot in the veins that drain blood flow from the brain. Obstruction of outflowing blood can lead to increased intracranial pressure and, depending on the anatomy of the clot, focal neurological symptoms that are a type of stroke.
• At the time of diagnosis, may patients have low platelets: median platelet counts (median, 20,000 to 30,000). High levels of d-dimers and low levels of fibrinogen are common.
• Although the mechanism of this clotting dysfunction is not certain, it appears to be a vaccine cross-reaction that causes an auto-immune thrombocytopenia.

• If you suspect a patient has CVST or other unusual clot due to vaccination, many guidance institutions currently recommend treating that patient similarly to how you would treat a patient with heparin-induced autoimmune thrombocytopenia (HIT).
• This generally involves (where available):

• Close monitoring of blood counts including platelets, sending anti PF-4/heparin antibodies and serotonin release assay or heparin-induced platelet aggregation assay.
• These patients should be treated with non-heparin containing anticoagulants such as Direct thrombin inhibitors (Argatroban, Bivalirudin, Lepirudin) or indirect FXa inhibitors (Danaparoid, fondaparinux).

MyocarditisCopy Link!

Updated Date: October 24, 2021

Receiving the COVID vaccine activates immune activity, which can cause myocarditis in a small subset of patients, particularly adolescent males. However, getting infected with COVID also causes a 16x risk of developing myocarditis (MMWR), among other risks.

• The benefits of vaccination (specifically preventing ICU admission and death) outweigh risks in both girls and boys age 12-17 according to US CDC guidance (CDC update August 2021). See this link for a graphical representation of the CDC’s estimates of risks of myocarditis compared with COVID cases/hospitalizations/deaths for both boys and girls (as of June, 2021). (Mostly mRNA vaccines but also J&J vaccine)
• The UK Joint Committee on Vaccination and Immunization also determined that the benefit of vaccination outweighs the risks in adolescent males, but their statement describes a more marginal difference. The reported risk of myocarditis in the UK is 3 to 17 per million for the first dose; and 12 to 34 per million for the second dose (Astrazeneca vaccine).
• Exact data on the risks of myocarditis differentiated by vaccine type is not yet available. This is an evolving area of research.
• Risk of myocarditis with boosters is actively being studied. Israel has administered 3.7 million boosters and to date their incidence of myocarditis with boosters is lower than with the initial series (presumably as there has been longer between doses).

Symptoms of myocarditis emerged on average 4 days after vaccination. Recovery is hoped to follow a similar course to post-MISC myocarditis patients, who tend to recover within 6 months. One study showed that 86% recovery within 35 days (the length of followup that was published) (Jain et al).

Ability to Transmit to OthersCopy Link!

It is still possible to transmit the virus to others even if vaccinated. This is especially true for highly infectious variants like Delta. It is still true even if asymptomatic. Please see Transmission.

Special PopulationsCopy Link!

Prior Infection or Antibody TherapiesCopy Link!

People who have been previously infected and/or received antibody therapies (monoclonal antibodies, convalescent plasma) can receive the vaccine. Vaccination after infection is covered here.

ObstetricsCopy Link!

Updated Date: August 23, 2021

American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) strongly recommend vaccines for pregnant people. (ACOG) Pregnant women and their doctors may discuss the risks and benefits depending on the individual’s risk of acquiring COVID. Side effects, such as fever, can sometimes cause adverse pregnancy outcomes, but can be treated.

Safety:

• Vaccines are not associated with infertility or pregnancy loss
• In one study of 3,958 pregnant people there were no unexpected outcomes related to COVID-19 vaccination, regardless of trimester. Of the 827 people who completed pregnancy, pregnancy loss, preterm birth, babies size, congenital problems, and death were the same as background rate (Shimabukuro et al). Miscarriage rates are also the same as background rates. (Zauche et al)
• Preliminary findings of the US Vaccine Adverse Events Reporting System (VAERS) find no specific safety concerns to the mRNA vaccines in pregnant and lactating women (Shimabukuro et al).

Efficacy: mRNA vaccines appear to produce a robust humoral immunity in pregnant and lactating women, similar to non-pregnant women, and far greater than the antibody response seen with natural infection. The antibodies appear to transfer to neonates via placenta and breast milk (Gray et al).

PediatricsCopy Link!

Updated Date: June 21, 2022

The Pfizer COVID vaccine received FDA authorization on August 23, 2021 for 16+ in the United States. In addition, the Pfizer vaccine has received Emergency Use Authorization for children ages 6 months - 4 years (3 micrograms) 5-11 (10 micrograms) as well as children ages 12-15 (30 micrograms, same dose as approved 16+ dose). All primary series are 2 doses administered 3 weeks apart. A third primary dose is recommended for patients >6 months who are immunocompromised.

The Moderna COVID vaccine has received Emergency Use Authorization for children ages 6 months - 5 years (0.2mL), 6-11 years (0.5 mL) and >12 years (0.5mL). All primary series are 2 doses 1 month apart. A third primary dose is recommended for patients >6 months who are immunocompromised.

Janssen (J&J) remains restricted to people over 18 years.

In a study of 2260 adolescents aged 12-15, the Pfizer vaccine demonstrated 100% efficacy (Pfizer). The vaccine was well-tolerated in this study, with side effects similar to those seen in people age 16-25.

• A post-market v-safe study of >129,000 vaccinated adolescents eight months after vaccination indicated that the vaccine was very well tolerated. Amongst 8.9 million adolescents, VAERS reports were received for only one per 1,000 vaccines, and 90% were for non serious conditions. (MMWR)
• As described in pediatrics, some immunity for neonates via breast milk likely occurs

Immunosuppressed PatientsCopy Link!

Updated date: May 26, 2021

Immunosuppressed people should get vaccinated against SARS-CoV-2, as all currently approved vaccines do not include live virus. However, vaccination may not be as efficacious as in those who are not immunosuppressed. Guidelines as to timing of vaccination and holding of certain immunosuppressive medications vary among expert panels in different specialties.

• Vaccine Efficacy. Vaccine efficacy varies highly dependent on the type of immunosuppression, the type of vaccine, and local variant epidemiology.

• In a study of 658 solid organ transplant recipients who received both doses of either mRNA vaccine, a month after the second dose 54% of the total cohort and 43% of those taking anti-metabolites (p<.001 for the difference in response rate) had detectable anti-spike antibodies (Boyarsky et al).
• In a prospective study of 133 patients with chronic inflammatory diseases (rheumatologic, IBD, and neuroautoimmune—all but 9 on DMARDs or biologics), compared to 53 healthy controls, after receiving the two-dose series of either mRNA vaccine, most of those with inflammatory diseases developed a robust immune response, but with an overall 3-fold decrease in humoral response compared to the controls (p=.009). Prednisone reduced the humoral response 10-fold, with only 65% seropositivity after the second dose and no clear dose-response relationship, while B-cell depleting agents reduced the humoral response 36-fold. Antimetabolites including methotrexate reduced humoral response 2-3 fold, and JAK inhibitors showed a statistically significant reduction in antibody titers. Other therapies did not have strong impacts on humoral response, with most of these patients taking hydroxychloroquine and/or TNF inhibitors (Deepak et al).
• In a study of IBD patients in which most were on TNF inhibitors or vedolizumab, of the 15 who were studied after receiving both doses of either mRNA vaccine, all seroconverted with robust titers (Wong et al. 2021).
• In a study of 67 patients with hematologic malignancies, 30 of whom were receiving active therapy, 46.3% had developed no anti-spike antibody 16-31 days after the second dose of an mRNA vaccine. There was a non-statistically-significant trend toward worse response among those on active therapy, and a statistically significant worse response among those with CLL compared to other malignancies (76.9% non-response versus 38.9% for the rest of the cohort.) (Agha et al).

• Patient Counseling

• All patients on immunosuppression should be counseled that they potentially remain at elevated risk for SARS-CoV-2 infection compared to the rest of the vaccinated population. This is particularly true for those on glucocorticoids at any dose and/or on B-cell-depleting agents.
• In terms of behavioral practices and masking, patients should behave as though they are unvaccinated.

• Vaccine Timing and Immunosuppression Adjustment

• No modifications for most drugs are suggested at present, though if starting new immunosuppression, vaccination should be completed at least two weeks prior to initiation if possible. The International Organization for the Study of Inflammatory Bowel Disease, as well as the National Psoriasis Foundation, suggest immediate vaccination for all patients currently on immunosuppression, with no alterations in timing and no holding of immunosuppressive medications (Siegel et al; National Psoriasis Foundation 2021). The American College of Rheumatology differs in opinion and makes the suggestions below:

• For anti-CD-20 monoclonals (e.g. rituximab and ocrelizumab), vaccination should occur at the end of the dosing interval, with the second dose for 2-dose vaccines occurring at least 2-4 wks before the next infusion if possible (ACR guidelines).
• Hold treatment for 1 week after each vaccine dose for methotrexate, cyclophosphamide, and JAK inhibitors (ACR guidelines, Feb 2021).
• Hold subcutaneous abatacept for one week before and one week after the first vaccine dose only (ACR guidelines).
• For intravenous abatacept, time COVID vaccination so the first shot occurs 4 weeks after infusion, with the next infusion delayed a week after the shot (ACR guidelines).

• For bone marrow transplant, most institutions are recommending vaccination between 3 months and 12 months after transplant (expert practice).

• Post-vaccination testing

• Antibody testing is not necessarily a reliable indicator for predicting if there has been an immune response, because some antibody tests do not test for antibodies produced by vaccination, and because immune benefit from T cell responses is possible without having circulating antibodies.
• Currently, recommendations do not support testing immune response after vaccination.
• That said, in rare instances, the specialist managing the patient’s immunosuppression may opt to send a quantitative anti-spike antibody, which must be interpreted cautiously. Preliminary data (personal communication) support a strong correlation between B-cell and T-cell responses.

• Revaccination and booster shots are covered here

Tool: ACR COVID Vaccine Clinical Guidance Summary (gives recommendations for multiple clinical scenarios)

Autoimmune Conditions and History of Guillain-BarreCopy Link!

Insufficient data is available on these populations, though people with autoimmune conditions were included in trials and did not seem to have increased symptoms. To date no cases of Guillain Barre have been found with the mRNA vaccines, and it is not a contraindication to vaccination. Very rare cases have been reported in viral vector vaccines (one in the USA as of April 23, 2021).

Vaccine EquityCopy Link!

While approval of the first vaccine marked the culmination of a tremendous scientific effort, the fight against COVID-19 now faces a new challenge: a massive worldwide vaccination campaign. The same embedded structural forces driving inequities in the burden of COVID-19 must also be considered within the context of vaccine access and distribution.

Vaccine Prioritization: It is essential that COVID-19 vaccines be distributed equitably. People who should be prioritized for vaccination include (adapted from the National Academies of Sciences, 2020).

• High-risk of COVID-related Morbidity and Mortality

• Medical Comorbidities
• Over the age of 65

• High-risk of Contracting COVID-19

• Residents of Long-term Care Facilities and Group Homes
• Incarcerated
• Undomiciled
• First-responders
• Healthcare Workers
• Front Line Workers (e.g. Supermarkets, Factories, Schools, Agriculture, and Meat-processing Plants)

Due to generations of structural racism and socioeconomic inequalities, people of color, people with disabilities, immigrants and migrants, indigenous peoples, and the poor are all disproportionately represented in many of these groups.

Global Distribution: The distribution of vaccines among nations should follow similar principles. No country should have enough vaccines to vaccinate their entire population before another country has enough to vaccinate their high-risk populations. As of December, 2020 there is significant imbalance: Canada has ordered enough vaccines to inoculate six-times its population, the United Kingdom and the United States four-times their populations, and the European Union twice its population (New York Times).

COVAX, a global coalition including the WHO to assure vaccination, has proposed that all countries receive an adequate supply to inoculate at least 20% of their population before any nation receives additional vaccines. This will ensure that high-risk groups are vaccinated regardless of where they live. Following this initial roll-out, vaccines should be distributed based on the vulnerability of the country’s health system and the impact of COVID-19 on the country, prioritizing countries most in need (COVAX, 2020).

Vaccine hesitancy: In countries like the US, vaccine hesitancy and distrust of the medical system may further exacerbate inequity (Warren et al). This is shaped by the legacy of exploitation and oppression of marginalized groups in the name of science (for example, the Tuskegee Experiment). Meaningful community engagement and promotion of informed decision-making requires an acknowledgment that these historical and contemporary forces contribute to a rational distrust of the health system among marginalized communities (Burgess et al).

Herd ImmunityCopy Link!

Updated Date: January 24, 2021

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The minimum or critical level of population immunity - acquired either through immunization or previous infection and subsequent recovery - that is required to stymie transmission of a particular communicable disease is colloquially referred to as ‘herd immunity’. When ‘herd immunity’ is achieved, susceptible individuals are indirectly protected from infection because sufficient numbers of immune individuals serve to prevent the circulation of the pathogen to immunologically-naive individuals. The percentage of immune individuals required to achieve ‘herd immunity’ against a particular pathogen varies dramatically depending on factors such as the baseline reproduction rate of the pathogen (R0), the effective reproductive number for a given population (Rt) - which is itself influenced by the efficacy of (and societal adherence to) non-pharmaceutical interventions, population density, therapeutics, immunological factors like the length of immunity, etc.

Current estimates suggest that achieving ‘herd immunity’ against SARS-CoV-2 will not be possible without an absolute minimum of 50% of population immunity (Fonanet et al), and as high as 85% in countries with higher Rt values (On Kwok et al). Because of the significant case fatality rate of COVID, and the ancillary consequences of unnecessary cases and deaths, the WHO recommends that ‘herd immunity’ against SARS-CoV-2 be achieved through immunization campaigns and not by needlessly exposing populations to the pathogen.

Health EquityCopy Link!

What is Health Equity?Copy Link!

Updated Date: December 17, 2020

Equity focuses on the fair and just treatment of all people. By extension, addressing inequities involves eliminating avoidable, unfair or changeable differences among groups, whether these are defined socially, economically, demographically, or otherwise. Upholding equity in health allows prioritization of fair opportunities for everyone to attain their full health potential (WHO Health Systems: Equity).

The COVID-19 pandemic has disproportionately affected historically oppressed populations around the world. Due to long-standing structural inequities, people from these communities are: 1) more likely to be exposed to disease, working essential jobs and living in crowded conditions; 2) less likely have to have access to quality healthcare, including COVID-19 testing and treatment; and 3) more likely to suffer from preexisting health conditions, as a result of adverse social determinants of health, putting them at increased risk of complications and death (Warren et al).

Not all of these can be included here, but we will address several major concerns. Inclusive data collection, while important, needs to be followed by evidence-driven steps to create an inclusive pandemic response and to be the foundation for equitable public health emergency planning (Reed et al).

Providers should screen for and Address Social Determinants of Health (SDOH): SDOH are the conditions under which people are born, grow, live, work, and age (AAFP's The EveryONE Project) which act to shape the health and well-being of people in complex ways. In the context of COVID-19, living situations coupled with job insecurity increase the risk of infection and then make safe isolation and quarantine difficult. In some neighborhoods in the United States, as many as 70% of positive cases required social support to safely isolate and quarantine (Kerkhoff et al).

Resource InequityCopy Link!

Updated Date: January 20, 2021

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Wealth inequality functions as both a cause and effect of health inequity. The global imbalance of wealth among and within nations is the result of historical (and current) forces including colonialism, racism, structural readjustment, and extractive capitalism. This has left many countries with chronically underfunded health systems lacking in infrastructure, equipment, and adequate staffing.

Historically, in the face of these challenges, containment measures are often emphasized over provision of treatment and supportive care. As was seen in the Ebola epidemic, this strategy backfires by ignoring the human toll of weak treatment systems, and downplaying the impact that effective treatment has on containment: When treatment and supportive care are not available or are not high quality, it undermines confidence in public health institutions and messaging; people understandably avoid seeking care when they need it, and may not trust public education campaigns encouraging social distancing, isolation, and other precautionary measures (Farmer).

It should be noted, despite facing significant barriers to containment and treatment, a number of low- and middle-income countries have prevented COVID-19 cases and fatalities from reaching the astronomical levels seen in many wealthier nations.

Economic ConsequencesCopy Link!

The COVID pandemic has led to a global income drop for workers and exacerbated existing health gaps between rich and poor countries (AP News). Disruptions to food supplies and economies risk worsening malnutrition worldwide, and will be a severe setback to the effort to achieve the United Nations Sustainable Development Goals (Ekwebelem et al). Additionally, the pandemic will leave fragile health systems with a legacy of death and attrition in the workforce and shrinking budgets driven by unstable financial outlooks.

Racial DisparitiesCopy Link!

Updated Date: December 17, 2020
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In the United States and United Kingdom multiple sources have demonstrated that Black and Latinx populations are disproportionately likely to be infected and/or die from COVID-19 (Garg; NYSDOH Fatalities, NYC DOH). A systematic review and meta-analysis of over 18 million patients across 50 studies from these two countries found higher COVID infection rates within Black, Latinx, and Asian communities (Sze et al). As of late November, 2020 Black and Latinx Americans have had 1.57 and 1.69-fold, respectively, as many cases as white Americans. Black deaths have been at 2.05-fold the rate of white Americans, and Latinx at 1.38-fold the white case fatality rate (Covidtracking). In the United States, rates of hospitalization among Black and Latinx COVID patients are approximately 4.7 times than among non-Hispanic white patients (Mayo Clinic; Pan et al). In terms of years of potential life lost before age 65, Black Americans are 6.7 times higher, Latinx people 5.4 times higher, Indigenous populations 4.0 times higher, and Asians 2.6 times higher compared to whites (Bassett Working Paper).

Tool: Race Statistics

Systemic health inequities affecting minority racial groups cause increased risk in the following categories:

1. Exposure risk at work: more likely to work in healthcare, education, retail and other jobs that can’t be done from home. In the United States, Latinxs make up 21% of the essential workforce (Economic Policy Institute), but only 18% of the total population (Pew Research). In the United States, 30% of licensed practical and vocational nurses are Black. Close to 25% of the Black workforce in the United States is employed by the service industry (Mayo Clinic).
2. Exposure risk on public transit: more likely to rely on public transport to attend work (Pew Research).
3. Exposure risk in shared living spaces: more likely to cohabitate with others (Census).
4. Comorbid health conditions: Black people in the United States have a significantly elevated risk of hypertension, which is well-documented, and hypertension control rates are significantly poorer in Black, Latinx, and Asian adults (with acknowledgment of heterogeneity between communities included in population groups) (Saeed et al).
5. Access to healthcare and testing: income inequality, lower rates of health insurance, and being situated farther from health centers make it harder for many minority groups to access care.
6. Racism in healthcare delivery: many minority patients experience consciously- and subconsciously-biased health systems and providers when they seek care. Inequitable representation among healthcare leadership and those responsible for healthcare messaging efforts may contribute to reticence from individuals and communities of color. While it is not the sole responsibility of people of color to rectify this, diversifying the types of speakers sharing public health messages may encourage communities of color to more confidently adopt evidence-based public health recommendations (Cooper et al).
7. Chronic stress: stress and allostatic load can affect immune function.
8. Environmental factors: risk for severe COVID has been associated with poorer air quality (Wu et al; Pozzer et al).

Indigenous CommunitiesCopy Link!

Indiginous communities are particularly affected by COVID-19. The cumulative incidence of COVID-19 among American Indian and Alaska Native persons is 3.5 times that among non-Hispanic white persons (CDC) Rates of infection often significantly exceed those in major metropolitan outbreaks (like New York City in April, 2020). As of July, 2020 in New Mexico, American Indians represented 53% of COVID deaths but only 11% of the population (Sequist et al).

Immigrants and MigrantsCopy Link!

Updated Date: December 17, 2020
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Global migration patterns have shifted during the pandemic, decreasing in some areas but increasing in others. Job losses have resulted in a trend of workers attempting to return to countries of origin, and border closures have resulted in ~3 million people left stranded during their return journeys as of October 2020. The pandemic’s longer-term impacts on poverty and food security have yet to be revealed, but it is anticipated that migration of necessity may increase (WFP).

Noncitizens disproportionately experience the health and financial effects of pandemic, but this is often overlooked as national statistics do not always include non-citizens (for example, data is not currently collected for analysis by the USA CDC). Structural factors that shape daily life for noncitizens place these groups at greater risk of becoming infected with COVID (Langellier et al).

• Compared with citizens, noncitizens are more likely to live in larger multi-family households where bedrooms may be shared.
• Non-citizens are also more likely to perform work that cannot be done remotely and depend on public transit.
• Non-citizens are not currently eligible for public financial and food assistance programs such as Social Security, TANF, and SNAP. Paradoxically, eligible documented immigrants who receive support from these public assistance programs are ineligible for citizenship based on the “public charge” test.
• Immigration and Customs Enforcement (ICE) has detained over 50,000 undocumented immigrants in holding facilities in the United States. Detainees in such facilities are subject to all of the same infection risks as prison inmates (see People who are Incarcerated), but may be more prone to poor outcomes since ICE’s operational COVID-19 containment protocols do not consistently reflect evolving CDC recommendations (Openshaw et al; Meyer et al; Keller et al).
• International Medical Graduates (IMGs) make up roughly 25% of the specialist workforce in America but many are serving on H-1B (temporary employment) visas that disqualify them from disability benefits if they were to get COVID at work. This also exposes family members to forcible relocation in the event of their deaths (Tiwari et al).
• Immigrants are also at risk of being systematically overlooked or underserved in public vaccination campaigns (Foppiano et al).

Suggested policy interventions to improve health among non-citizen populations during pandemic include:

• Elimination of citizenship barriers to public assistance programs and elimination of public assistance participation as a barrier to establishing citizenship (Langellier).
• Ensure access to essential resources, such as food, medicine, and legal services (WFP).

Language remains one of the major barriers to quality care. Patients who cannot speak English in the United States are more likely to receive inadequate care (Ross et al). Here are strategies for communication with people with limited proficiency in the language of care providers, shared by the MGH Disparities Solutions Center:

• Create screening and educational materials based on the languages spoken in your population.
• Use interpreting services and tools whenever available (in-person interpreters, bilingual phones, and/or mobile screens such as iPads).
• Use staff hotlines with people who are multilingual.
• Target communication updates in multiple languages and through multiple platforms (posters, email, website, text messaging, etc.)
• Create a registry with clinical staff who are multilingual and deploy them to applicable patient care sites.

People Who Are IncarceratedCopy Link!

Updated Date: November, 2020
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People who are imprisoned are particularly vulnerable to COVID-19 infection due to overcrowding, poor ventilation, poor sanitation, lack of medical care, violence, and increased rates of chronic medical conditions (U.S. Department of Justice Special Report). Early data from the COVID-19 pandemic demonstrated up to 5 times higher rates of death among incarcerated people, despite disproportionately younger age distributions relative to nearby communities (Saloner et al). Since the start of the pandemic across all states, incarcerated persons have >3 times the per-capita number of cases as the general population (The Marshall Project). Dormitory housing has been shown to be a strong risk factor for infection (Kennedy et al).

Decarceration (release from prison) remains the most evidence-based intervention to reduce infection among incarcerated people, and by extension, the local communities that prison workers belong to (Hawks et al; Barnert et al; Okano et al). In place of full decarceration, compassionate release of low-risk offenders and elimination of cash bails that contribute to growing prison populations can also prevent infections (Nowotny et al).

• Since COVID-19 was identified, over 25 states in the United States have engaged in early release efforts, 14 states have reduced jail and prison admissions, and 47 states have suspended medical co-pays for incarcerated individuals (Prison Policy Initiative: Responses to the COVID-19 Pandemic).

When isolation and containment strategies are used in prisons, additional interventions should be supported to address the mental health burden they create for incarcerated people, especially those living with chronic mental illness (Hewson et al).

• If available, some safe ways to support incarcerated people include waiving in-state licensure requirements for telemedicine and expanding access to virtual family visits through videoconferencing (Robinson et al).

Other solutions include mass testing of incarcerated people and prison workers, providing personal protective equipment (PPE), and improving sanitation (Akiyama et al). It is particularly critical to focus efforts on occupational health interventions that can prevent transmission of infection to nearby communities (Sears et al).

People with DisabilitiesCopy Link!

Updated Date: November, 2020
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People with disabilities may be disproportionately marginalized by COVID-19 response efforts due to inadequate recognition of their unique needs. People with disabilities may not have equitable access to safe living situations or healthcare resources. Some disabilities do not affect severity or prognosis with COVID infection, but some disabilities may (generally due to related comorbidities such as structural heart disease). For example, if infected, individuals with Down Syndrome are five times more likely to be hospitalized and 10 times more likely to die (Wadman M).

Policies and institutional guidance should consider the needs of disabled patients.

• Alternative support structures should be considered for patients with disabilities who are unable to participate in standard public health protocols, such as home-based COVID testing for people with autism spectrum disorder (Eshraghi et al).
• Health policy leaders must be attentive to inequities in access to care and resources, disproportionate hardships imposed by pandemic mitigation strategies, and increased risk of harm from COVID infection in the context of pre-existing health disparities (Armitage et al).
• Creation of equitable resource allocation protocols, especially when considering Crisis Standards of Care, should be guided by near-term survival calculations and objective measures to avoid bias against people with physical and intellectual disabilities in allocating resources (Solomon et al).

People with disabilities and their caregivers should be engaged in all stages of the outbreak response, from initial planning to implementation to assessment. During the pandemic, some strategies for providers to help patients with disabilities include:

• If caregivers need to be moved into quarantine, plans should be made to ensure continued support for people with disabilities who need care and support.
• Consider exceptions to Visitor Policies for patients who need support from caregivers in order to participate in care.
• Messages should be shared in understandable ways to people with intellectual, cognitive, and psychosocial disabilities.

• When available, masks with clear impermeable windows can improve communication for those who are deaf of hard of hearing.
• Non-written communication (audio recordings, imaging, verbal communication) and instruction may be particularly important for this group.
• Photographs of clinical care team members without their masks can relieve anxiety.

• Community-based organizations and leaders in the community can be useful partners in communicating and providing MHPSS support for people with disabilities who have been separated from their families and caregivers.
• Trauma-informed care can help build trust (CDC guide).
• People who cannot remove a mask independently, avoid touching masks frequently, avoid excessive licking or saliva on masks, or otherwise tolerate wearing a mask should be excused from wearing one under CDC recommendations.

Tool: COVID-19 response: Considerations for Children and Adults with Disabilities, UNICEF

Tool: COVID-19 and persons with psychosocial disabilities, Pan African Network of Persons with Psychosocial Disabilities, et al

People without Secure HousingCopy Link!

Updated Date: November, 2020
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Undomiciled (homeless) people under 65 years of age have all-cause mortality rates 5-10 higher than the general population at baseline (Baggett et al). Living conditions, higher rates of comorbidities (including substance abuse and mental illness), limited medical services, and the difficulty for public health agencies in tracing undomiciled individuals are all likely challenges during the pandemic (Tsai et al).

People Living in Congregate HousingCopy Link!

Updated Date: November, 2020
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Skilled nursing facilities, nursing homes, and other congregate living settings often struggle with social distancing and house populations with significant medical risk factors for poor outcomes (McMichael et al).

• In the United States, as of April 23, “there have been over 10,000 reported deaths due to COVID-19 in long-term care facilities (including residents and staff), representing 27% of deaths due to COVID-19 in those states (Kaiser Family Foundation).
• COVID has impacted long-term care facilities around the world, with data from many countries showing 40% of COVID deaths to be connected to long-term care facilities. Rates in some higher-income countries are 80% (WHO).

Tool: Rates in Long Term Care Facilities (USA only, third chart) (Kaiser Family Foundation )

People with Substance Use Disorders (SUDS)Copy Link!

Updated Date: November, 2020
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People with SUD are disproportionately likely to become sick with COVID and are more likely to experience severe illness and death. A team of researchers in the United States analyzing electronic health records found that 15.6% of the COVID cases were people with SUD, but people with SUD represented only 10.3% of the study population. Effects were strongest for those with opioid use disorder.

Possible explanations include higher rates of comorbid pulmonary and cardiac pathologies in people with SUD, as well as disparities in access to healthcare associated with stigma and marginalization. Black Americans with a recent diagnosis of opioid use disorder were four times more likely to become sick with COVID-19 than white peers (Wang et al).

Please see Alcohol Use Disorders and Opiate Use Disorders.

Tool: Harm Reduction Strategies For people who use substances during the COVID-19 pandemic (Harm Reduction Coalition, English/US Focus)

Intimate Partner Violence (IPV)Copy Link!

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The World Health Organization has long identified violence against women as a globally pervasive and urgent public health problem (WHO, 2013). Nearly one third of women around the world report having experienced physical and/or sexual violence perpetrated by an intimate partner (WHO). Patterns of comparable violence against men are not as well understood (Kolbe et al) but are also recognized as complex public health problem (CDC). Intimate partner violence can and does occur across all socioeconomic settings, but prevalence is affected by social determinants of health, such as economic stability, housing security, social support, and childcare access (Evans et al). It is also important to acknowledge that gender inequality is associated with IPV (McCloskey et al).

Economic dependence is a particularly salient risk factor for IPV. Job losses during the pandemic have exacerbated the economic vulnerability of women, immigrants, and workers with lower levels of education. The pandemic has also restricted the movements of people seeking alternate housing to escape IPV, and is likely affecting access to common reporting venues such as primary care delivery sites and police precincts (Evans et al). Additionally, job insecurity and economic stress are associated with a cycle of increased alcohol consumption, smoking and drug abuse (Compton et al); which in turn increases the risk of IPV (Lee et al).

Current impact data are limited, but one study comparing rates of physical IPV during the COVID-19 pandemic to rates of physical IPV during the preceding three years indicated a 1.8-fold increase in incidents, accompanied by a higher rate of severe injuries and a lower rate of reporting (Gosangi et al).

In the context of the COVID-19 pandemic, it is important to support programs that prevent IPV. Social support, cash transfer, food distribution, housing, availability and accessibility to health care, and health insurance coverage are critical to mitigating the impact of COVID-19 and preventing increasing IPV.

Tool: Identifying & Mitigating Gender-based Violence Risks within the COVID-19 Response, UNICEF, IASC

Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

Whom to TestCopy Link!

Tool: PRIoritize_Dx, intended to help policy-makers allocate tests.
Tool: PATH COVID-19 Diagnostics Dashboard to support product selection and procurement decisions.

Tool: The Foundation for Innovative New Diagnostics (FIND), a global non-profit, conducted Independent Evaluations of test kits between April and August of 2020.

Testing Symptomatic PatientsCopy Link!

Updated Date: January 7, 2022

Prioritize testing people with symptoms suggesting acute infection (see Screening Questions and Common Symptoms).

• The standard of care for diagnostic testing symptomatic patients is PCR-based testing, as it has the best sensitivity and specificity.
• If testing is very limited, prioritize testing patients when it will specifically change management or isolation status/location.
• When PCR-based testing capacity is restricted, use of the antigen test can increase testing capacity as well as offer advantages in terms of more low-cost testing with short turnaround time. The antigen test is discussed in more detail in Types of Test Section.
• Exact testing algorithms will depend on each institution and the availability and type of testing. One potential algorithm is presented below based on whether same day testing is available or not. Same day testing has advantages.

Algorithm for Symptomatic Patients Based on Whether Same Day Testing is AvailableCopy Link!

Details for each path are discussed below:

1. If same-day testing is available:

1. Fast turnaround (same-day) Nucleic Acid Amplification Test (PCR)

1. If positive, the patient is “confirmed COVID.”
2. If negative, categorize according to Case Definitions and clinical suspicion.

1. If discharging home, Isolate at home and initiate contact tracing.
2. If admitting, repeat testing in 12-24 hours.

1. If negative on the second test:

1. Consider alternative etiologies (influenza, malaria, other infections), and discontinue the “suspected” or “probable” Case Definition if one is found.
2. Consider alternative testing (e.g. serology) or repeat testing (typically 72 hours from first) if clinical suspicion remains high.
3. Consider downgrading the case to “suspected” from “probable” depending on clinical suspicion.

2. Rapid Antigen Testing (antigen rapid diagnostic test or Ag RDT for short).

1. If positive, admit as a “confirmed” case or isolate at home, initiate contact tracing. If in a high prevalence setting or in a symptomatic patient with likely COVID-19, confirmatory PCR testing is not needed.
2. If negative, treat as a “suspected” or “probable” case based on Case Definitions and clinical suspicion.

1. If discharging, isolate at home and follow-up with a call or visit, homevisit or clinic visit. Consider retesting 2 to 4 days later. Consider contact tracing if suspicion is high for COVID-19.
2. If admitting, request PCR testing and if not available, repeat rapid antigen testing in 2-4 days (see ECDC report).

2. If no same-day testing is available (testing is located offsite and/or turnaround times are long):

1. Send the specimen to the facility with the fastest reliable turnaround times.
2. Follow-up and retesting strategy:

1. If discharging to home, isolate at home and call or arrange a visit to share results. If the test returns negative, consider retesting, especially if symptoms persist or worsen.Also, consider retesting if it is deemed important to understand whether the case is COVID-19 and doing so would lead to important contact tracing activities.
2. If admitting, triage as “suspected” or “probable” case based on Case Definitions and clinical suspicion for disease. If the test returns negative, retest with PCR testing.

3. If no testing at all is available:

1. If no testing is available, use clinical judgement and risk factors to determine likelihood of COVID infection and treatment plan. Case Definitions can help. Consider other lab testing to help stratify if available, including lymphocyte count, LFTs, and C-reactive protein. Err on the side of isolation.

Testing Asymptomatic PatientsCopy Link!

Updated Date: January 18, 2022

Asymptomatic Patients with an ExposureCopy Link!

If test capacity permits, testing asymptomatic people with known exposure to COVID-19 may be helpful (ideally as a part of a contact tracing initiative).

Generally we recommend testing patients who meet criteria for an exposure as soon as possible when they become aware of the exposure and again 5-7 days after the first test. This is because initial tests are often negative early in disease. Please note that even if an initial test is negative, the patient must still quarantine until they meet criteria for release from quarantine (in selected cases, testing may be used to reduce quarantine duration). Some healthcare systems recommend against testing in these instances either because of limited testing resources, or because the concerns about false reassurance from early false negatives.

Asymptomatic Screening and Public Health SurveillanceCopy Link!

Literature Review (Not Comprehensive): Gallery View, Grid View

To understand population-level prevalence and incidence, local institutions or departments of health may perform testing (PCR or Antibody) on entire cohorts regardless of exposure or symptoms. Details on design of epidemiologic, surveillance, or infection control studies are beyond the scope of this site.

Asymptomatic people who have a high likelihood of transmission to others should they become infected may be regularly tested for COVID-19, even without a confirmed contact. This is especially important if they spend time with persons that are at risk of complications from COVID-19, the classic example is periodically testing both residents and staff of nursing homes. This is sometimes called “asymptomatic screening” or “expanded screening”.

• Common high-risk groups that may be considered for screening:

• Health care workers, particularly those caring for patients with COVID-19 or in high patient-flow areas
• People living or working in congregate living settings (nursing homes, dormitories)
• Travelers coming from high prevalence areas
• Teachers and students
• Other essential employees (grocery workers, sanitation workers etc).

• More options for the use of rapid antigen tests for COVID-19 for asymptomatic screening and in public health surveillance have been published by the European Center for Disease Prevention and Control and by the Africa CDC.
• For asymptomatic screening, testing is typically done frequently to minimize the window of time in which a person might be infectious but not yet have symptoms or a positive test. Below is a summary of recommended frequencies for asymptomatic screening testing adapted from CDC guidance. This is not a replacement for masks, distancing, and other standard infection prevention measures.

Asymptomatic Screening Frequencies by Prevalence Indicators:

Impact of Vaccination on TestingCopy Link!

Neither RNA- nor protein-based vaccines should have any impact on nucleic-acid based tests (NAAT) or rapid antigen tests used to diagnose COVID-19. Some antibody tests could conceivably turn positive after vaccination in rare combinations where a vaccine and test use the same viral antigens, but this is not yet verified for this purpose. Most serologic tests look for antibodies to the nucleocapsid and not spike protein, and thus do not detect vaccine-induced antibodies. As of February 2021, vaccination status should not be routinely considered in interpreting any COVID-19 test results. (CDC)

Newly symptomatic patients who have been vaccinated should still be tested, as breakthrough cases still do occur. Exposed vaccinated people are covered here (generally not needed).

Testing Previously Infected PatientsCopy Link!

Updated Date: April 23, 2021

Patients >90 days from initial illness with new symptoms of COVID-19 can be retested on a case-by-case basis. Reinfection is rare, but not impossible. Generally, patients who are <90 days from initial illness are not tested, however with the emergence of new variants this may be changing: a patient who had fully recovered and then develops new symptoms should be considered potentially re-infected with a new variant and should be re-tested.

• If the patient tests positive, keep in mind the possibility of residual viral RNA even 90 days after initial infection, and consider alternate causes of illness (pulmonary embolism, bacterial superinfection) and (where possible) viral sequencing.
• Recurrence of symptoms along with reemergence of positive PCR testing (particularly in patients with weakened immune systems) can occur in the absence of true reinfection.

Types of TestsCopy Link!

Updated Date: January 18, 2022

In a pandemic, clinically suspected cases should initially be isolated regardless of test status. See Screening, Case Definitions, and Isolation. All tests have both false positives and false negatives. A high index of suspicion should be used to protect staff and other patients.

Remember:

• No currently available test fully rules out the diagnosis, especially if clinical suspicion is high. When possible, negative or positive results that are inconsistent with the clinical pictures should be discussed with someone who has expertise in diagnostic testing of COVID-19
• None of the commercially available tests measures active, infectious virus. Whether a person who tests positive is infectious requires clinical judgment and knowledge of their disease course.
• In all cases, please follow local public health authority guidelines in reporting all suspected, presumed, and confirmed cases of COVID-19.

Overview of COVID-19 TestsCopy Link!

Updated Date: January 18, 2022

The three most clinically relevant categories of testing for COVID-19 are:

1. Nucleic Acid Amplification Test (NAAT): While not a perfect test, NAAT is considered the gold standard. The test uses enzymes to amplify and detect the genetic material of the virus. The most familiar is RT-qPCR (reverse transcriptase - quantitative polymerase chain reaction; related versions are often referred to as PCR or RT-PCR), but there are others. These are often collectively called “molecular tests.”
2. Antigen Rapid Diagnostic Test (RDT): Requires less time and infrastructure to perform than NAAT tests. Uses manufactured antibodies to detect SARS-CoV-2 proteins.
3. Antibody (IgM/IgG) RDT: Has different uses and interpretation than the nucleic acid and antigen tests. Uses manufactured antigens to detect a patient’s antibodies to SARS-CoV-2. Since this depends on the body’s immune response, it takes longer to turn positive than tests that directly detect the virus, and a negative antibody test DOES NOT rule out acute infection. The antibody test is NOT used as the sole test to diagnose active or contagious disease; it is more common in epidemiology and research. The test can be used to support the diagnosis in COVID-19 in patients that present late with symptoms (at least 8 days after the onset of symptoms) or to help assess whether a symptom or sequelae is due to a post-COVID-19 infection.

In these lists and elsewhere, tests that measure nucleic acids are often referred to as molecular assays, while antigen and antibody tests are considered immunoassays or serological assays.

General test characteristics are summarized in the table below:

Specific data on the availability and performance of commercial COVID-19 diagnostic testing options continues to change rapidly.

Tool: PATH COVID-19 Diagnostics Dashboard to support product selection and procurement decisions. Collects data from U.S. FDA, WHO, FIND, and other lists curated by private entities. Includes information on regional or national regulatory approval.
Tool: The Foundation for Innovative New Diagnostics (FIND), a global non-profit, conducted Independent Evaluations of test kits between April and August of 2020.
Tool: The Cochrane Library, a resource by the international charitable organization Cochrane, has published independent reviews of Molecular/Antigen tests (updated 2020-08-26) and Antibody Tests (Updated 2020-06-25).

Timeframe of Test PositivityCopy Link!

Updated Date: December 19, 2020

The relative time frames of exposure, symptoms, viral markers, and antibodies are illustrated in the subsequent figure. This is an illustration of average time frames and it should be noted that information is still emerging on the timeframes of Incubation and Window Period, Infectivity, and Durable Immunity.

• Infectious Period: On average, the person is most infectious 2 days prior to the onset of symptoms to about 5 days after the onset. This is referred to as the pre-symptomatic and early symptomatic time frame. In general, people are no longer infectious 10 days after symptom onset (20 days in severely ill persons, see Infectivity).
• The Antigen Test is likely to be positive at the same period that a person is most infectious from about 2 days prior to the onset of symptoms to about 2-3 days after the onset. This is because the viral load is highest in this time period.
• The RT-PCR test (and other NAATs) is more sensitive than antigen testing. On average, it can (but does not always) pick up cases earlier than even 3 or 4 days before the onset of symptoms or 10+ days after symptom onset.
• The antibody test in some cases turns positive after the patient may no longer be infectious. For this reason, the antibody test is not typically used to diagnose active disease.

Nucleic Acid Amplification TestsCopy Link!

Updated Date: January 18, 2022

Literature Review (not comprehensive): Gallery View, Grid View

These tests work by amplifying minute amounts of viral RNA. PCR (technically, RT-qPCR) of a nasopharyngeal swab specimen is most widely used and should be considered the standard of care when available.

How it WorksCopy Link!

Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) works by reverse transcribing the viral RNA genome to DNA, and then amplifying the DNA exponentially by repeatedly cycling the reaction. Samples with a small amount of virus require more cycles to reach a detection threshold than samples with a large amount of virus, allowing some RT-qPCR tests to quantify how much virus was present and approximate viral load.

Newer amplification technologies are being developed to make this process cheaper, faster, and less dependent on complex laboratory infrastructure. The term nucleic acid amplification test (NAAT) includes PCR, isothermal amplification, and CRISPR-based tests (Behera et al., Kilic et al). Xpert® Xpress SARS-CoV-2 is an example of an automated cartridge-based system on the same Xpert® machines used for diagnosis of tuberculosis that does not need a sophisticated laboratory setting. All have the common feature of detecting minute quantities of SARS-CoV-2 nucleic acids.

The main advantages to nucleic acid testing are:

• The amplification steps allow detection of very small amounts of viral RNA, with higher specificity than serological assays.
• Live virus is not required. Samples can be inactivated and made safe to handle.
• Nucleic acid amplification is common in biology research. Government labs, universities, and highly-resourced clinical labs may be able to rapidly deploy new or modified tests before commercial kits are available. This may become relevant if a new strain or resistant mutation emerges.

The main disadvantages to nucleic acid testing are:

• Most methods require significant infrastructure, usually including custom machines, reliable electricity, cold storage, a supply chain for reagents, and skilled personnel.
• Test performance can depend heavily on how and when a sample is taken. For example, lower respiratory samples can be positive when upper respiratory samples are not.
• Fragments of viral nucleic acids can persist in the body long after the virus has been killed. Persistently positive tests may not mean that a person is still infectious.
• Variant strains of SARS-CoV-2 may affect the sensitivity of some nucleic acid-based tests, resulting in false negatives. Tests that use multiple genetic targets are less likely to be affected by the increasing diversity of SARS-CoV-2. As of February 2021, U.S. FDA advice is to consider negative results in clinical context and to consider repeating testing with a different test if clinical suspicion remains after an initial negative test.
• These tests tend to take longer than antigen tests to get results, resulting in longer isolation periods for patients waiting for results. In situations where it may be difficult to reach a patient after they leave the testing site, this should be taken into consideration.

Test PerformanceCopy Link!

Sensitivity and Specificity:

On artificial samples, NAAT sensitivity and specificity approaches 100% (Giri). NAAT tests have analytical sensitivity (the lowest viral concentration where >95% tests are positive; also called limit of detection) down to 100-5000 copies of viral RNA/ml. But published real-world estimates of sensitivities for different NAATs to diagnose COVID-19 range from ~60-95%, depending in part on what reference method is used as a comparator or “gold standard.” Specificity is excellent, and false positives are rare in the absence of contamination, though there is increasing recognition that false positives due to contamination or cross-reaction with other genetic material do occur and may have significant consequences (Surkova et al)

Interpreting reported clinical sensitivities involves a range of factors:

1. There is significant variability in how studies define a "true positive" or "gold standard":

1. The reference standard can be "composite," including laboratory, radiographic, and clinical data. A single center study at University of Kong Kong-Shenzhen, China, compared initial RT-qPCR in 82 patients to a a retrospective diagnosis made by combining serial RT-qPCR and chest CT findings, with a resulting sensitivity of 79% and a specificity of 100% (He et al).
2. The reference standard is often serial NAAT. since this is often the only data available for large numbers of patients. A retrospective analysis of over 20000 patients used repeat PCR within seven days (felt too short for interim infection to play a large role) and found that only 3.5% of patients initially negative by PCR subsequently tested positive. This suggested a low false negative rate, but they pointed out that this was not a true clinical sensitivity since they lacked a final confirmatory diagnosis (Long et al).
3. The reference standard can be other previously validated NAAT’s. FindDx reports that the tests they validated agreed 92-100% when comparing to their a reference PCR assay, demonstrating small but real variability between tests.

2. The site of sampling might not contain virus at the time of sampling. See Sample Collection.
3. Laboratory factors (sample storage, frequency of contamination).

These same factors should be systematically considered when a clinician suspects a false negative:

1. Exactly what other data makes me feel like the patient has COVID-19?,
2. Do we need to repeat the sample or collect another sample type?, and
3. Could there have been a lab error?

Typical clinical use:

If you do not know your test’s characteristics, sensitivity of ~80% may be a reasonable approximation for nasopharyngeal swabs collected at the time of patient presentation, assuming no laboratory errors.

• If the RT-PCR is negative but suspicion for COVID-19 remains, then ongoing isolation and re-sampling several days later should be considered.
• In practice, test results should be interpreted based on negative and positive predictive values (NPV, PPV) rather than sensitivity and specificity, since these incorporate pretest probability.

Sample CollectionCopy Link!

Literature Review (not comprehensive): Gallery View, Grid View

Upper Respiratory Tract Specimens. Most commercial kits have been evaluated on specific upper respiratory sample types. Of these, the nasopharyngeal swab is the most common and best validated; in most situations this is the best option unless a specific manufacturer recommends otherwise or there is a clinical reason to choose an alternative site.

Sites include:

• Nasopharyngeal Swab
• Nasopharyngeal Wash/Aspirate
• Oropharyngeal Swabs
• Mid-turbinate and Anterior Nasal Swabs

• A few manufacturers allow these to be collected by the patient at-home (unsupervised) or supervised by a provider at a safe distance resulting in less risk to the HCW.

• Saliva

• Potential to significantly simplify sample collection cost and complexity
• Many new platforms being developed, but still limited comparative performance data (Wyllie et al)

Tool: U.S. CDC Collection Protocol

Tool: Video Demonstration

Lower Respiratory Tract Specimens are also sometimes used, though they often require different processing and validation due to the presence of mucus. When obtaining lower respiratory tract specimens, many sampling techniques require airborne precautions for providers (see Aerosol Generating Procedures).

Sites Include:

• Expectorated Deep Sputum (similar to sputum collected for TB testing in patients with productive cough).
• Bronchoalveolar Lavage
• Endotracheal Aspirates

• Preferred in intubated patients due to higher sensitivity, though this depends on sample quality Like any respiratory sample, high quality samples are characterized by Gram stains with many polymorphonuclear cells and few epithelial cells.

The relative performance of testing different sample types, optimal timing for sample collection relative to exposure or symptoms, and the interpretation of discordant results (for example, if the nasopharynx is negative but sputum is positive), all continue to be studied.

U.S. CDC guidelines for processing of sputum specimens for SARS-CoV-2 RT-PCR recommend the use of dithiothreitol (DTT) for liquefaction of viscous mucoid/mucopurulent material prior to nucleic acid extraction

Tool: CDC Specimen Processing

Other Specimens: Viral RNA has been documented in other body sites including stool and rarely blood, but it is not known whether this represents transmissible virus (Wang et al). Testing samples from these sites requires extra laboratory expertise for sample handling and clinical expertise for interpretation. These sites should not be tested routinely.

Antigen Rapid Diagnostic TestsCopy Link!

Updated Date: January 18, 2022

Literature Review (not comprehensive): Gallery View, Grid View

How it WorksCopy Link!

Rapid Diagnostic Tests (RDT’s) for viral antigens use premade, labeled antibodies to the virus to capture viral particles. The most common approach is the lateral flow test, where sample diffuses along a manufactured strip in a way that can be visually detected at the “test line” only if viral antigens are present. Note that a few manufacturers do make “rapid” NAAT assays. This discussion does not address those tests.

The main advantages to antigen RDT’s are:

• Running a test involves adding the sample (and sometimes a single liquid reagent) and waiting for diffusion.
• They generally do not require special trainings or machinery to run, and many are licensed to be run outside of a laboratory setting (e.g. CLIA waiver)
• They are typically fast, cheap, and have a simple visual yes/no readout that does not require interpretation.
• Patients can often be notified of their results while still at the testing site.
• With more outpatient treatments becoming readily available, antigen RDT’s will be useful to implement a test and treat program (widespread screening, early detection of disease, and prompt initiation of appropriate treatment).

The main disadvantages to antigen testing are:

• They are less sensitive than NAATs, since there is no amplification step. Negative tests may need confirmation with NAAT if clinical suspicion is high.
• As with NAATs, performance can depend heavily on how and when a sample is taken.
• Fragments of viral proteins can persist after the virus has been killed, though likely not as long as nucleic acids.
• If future viral mutations change the antigen region targeted by a particular test, it will take longer to create new antigen RDT’s (which involves new manufacturing) than it would to modify most NAAT’s (which involves new reagents only).
• Consult the manufacturer’s insert for specimen collection requirements; many are designed for nasopharyngeal swab only.

Test PerformanceCopy Link!

Clinical sensitivity for antigen RDT’s is highly variable. The average of sensitivity was 56% for four antigen RDT’s reviewed in an August 2020 Cochrane review, with 95% confidence interval of ~30-80%. The same review found much higher average specificities of 99.5% (95% confidence interval 98.1-99.9%) (Dinnes et al). The sensitivity may vary based on symptomatology, with some performing as poorly as 32% sensitive (Quidel EUA), and others as high as 79% (Alemany et al) in asymptomatic people. However, many of the cases that these tests miss may not be infectious, but this is still an area of active research.

Finding the real-world sensitivity of antigen RDT’s suffers from many of the same difficulties discussed in the NAAT section above, though these are usually compared with NAAT as a gold-standard. The minimum performance requirements for Ag-RDT set by the WHO are >80% sensitivity and >97% specificity compared to a NAAT reference assay (WHO)

Use of RDTs for Screening Symptomatic PatientsCopy Link!

Rapid Antigen RDTs are an alternative to NAAT as screening tests where testing capacity is limited and the proportion of test positivity is high (≥10%) (ECDC Recommendation). Positive and negative predictive values (PPV and NPV) of all in vitro diagnostic tests depend on disease prevalence in the target population and the test performance.

In a high prevalence setting CDC considers high prevalence to be when NAAT positivity over the last 14 days is greater than 5% or when there are greater than 20 new cases of COVID-19 per 100,000 persons within the last 14 days., rapid antigen tests will have a high PPV, meaning a positive result from a rapid antigen test is likely to indicate a true infection and may not require confirmation by RT-PCR. In contrast, any negative test result should be confirmed by RT-PCR immediately or with another rapid antigen test a few days later (where RT-PCR is very limited).

In a low prevalence setting CDC considers low prevalence to be when NAAT positivity over the last 14 days is less than 5% or when there are fewer than 20 new cases of COVID-19 per 100,000 persons within the last 14 days., rapid antigen tests will have a high NPV but a low PPV. Therefore, a negative antigen test most likely represents a true negative and may not require confirmation by NAAT, however false negatives are still possible and people being tested should be reminded that they should still take all precautions to prevent spread (e.g. masking, distancing, etc). In this situation, a negative test result may not require confirmation by NAAT, whereas a positive test will need confirmation by NAAT.

Scenarios Antigen RDT Can be Used for Screening of Asymptomatic Individuals:Copy Link!

(modified from WHO and ECDC). (For use of Antigen RDT for symptomatic individuals, including contacts, see testing symptomatic patients).

Antibody TestingCopy Link!

Updated Date: December 19, 2021

Literature Review (not comprehensive): Gallery View, Grid View

How it WorksCopy Link!

Antibody tests measure the host adaptive immune response, rather than the presence of the virus. This test is most often performed on circulating blood (from fingerstick or blood draw).

Adaptive immune response requires several days to make antibodies that bind to the pathogen. See Antibody Response and Durable Immunity for a more in-depth discussion of antibody patterns over time. It is not yet known what impact antibodies have on the risk of transmission to others or risk of re-infection.

The main advantages to antibody testing are:

• Respiratory samples are not required. Antibody testing can be done on blood drawn for other reasons in clinical care. There are versions to test dried blood spots.
• IgG may last for months to years, so it is useful in epidemiology to know who has been previously infected (even if they were asymptomatic).
• A strategy that uses both NAAT and serology may improve sensitivity for COVID-19 over using NAAT alone. 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).

The main disadvantages (and why antibody testing alone is not recommended to guide clinical decision making) are:

• Antibodies take several days for the human body to develop, so antibody testing is often negative in early infection; this is known as the “Window Period.” In fact, a positive IgG argues against acute early infection.
• False positives can occur due in patients who have been exposed to coronaviruses other than SARS-CoV-2, including some types of the common cold.
• IgM is often less specific than IgG, so false positives may be more common for IgM results, making the test less accurate for acute infection.
• Although antibody RDT’s using principles of lateral flow are available, the most sensitive versions require laboratory infrastructure for techniques such as ELISA.
• The immune system simultaneously makes many different antibodies, but test manufacturers choose a single antibody to detect. This can result in increased variability between test performance from different manufacturers.
• For these reasons, antibody testing alone is not recommended to guide clinical decision making.
• Prior vaccination for COVID-19 is unlikely to affect the interpretation of antibody testing in most circumstances, though this is still being studied (CDC).
• Most diagnostic tests detect antibodies without specifying whether they are neutralizing. The first test to receive a U.S. FDA EUA for specifically detecting neutralizing antibodies is the cPass SARS-CoV-2 Neutralization Antibody Detection Kit, by GenScript, USA.

Test PerformanceCopy Link!

Combined IgM/IgG testing has low sensitivity early in infection (30%) but reaches 91% by 15-21 days after onset of symptoms, in a June 2020 Cochrane Review summarizing 54 cohorts with a total of nearly 16000 patients. The same review found a high average specificity of ~98% (Deeks et al).

InterpretationCopy Link!

Viral CultureCopy Link!

Updated Date: December 19, 2020

Viral culture is not generally used in clinical settings. Availability is very limited, since safe viral culture requires laboratories with advanced biosafety capabilities (typically BSL 3 in the USA). It is the most definitive test for the presence of viable virus, since both antigens and RNA can persist even after the virus is “killed.”

• It is often used in research settings to tell which types of samples are potentially infectious.
• It can be used to confirm that patient or pharmaceutical antibodies neutralize viral replication, since some antibodies might bind to the virus without inhibiting replication.

Viral SequencingCopy Link!

Updated Date: December 19, 2020
Literature Review (Novel Diagnostics): Gallery View, Grid View

Full-genome viral sequencing is not generally useful in the acute clinical setting. When available, viral genomic sequencing from patient samples can be used for local outbreak tracing, assessing re-infection, and large-scale epidemiology. Sequencing may also be used in the future to look for mutations and decreased responsiveness to vaccines or therapeutics, though this will require significantly improved understanding of SARS-CoV-2 biology.

Several groups are developing technologies to reduce the hardware and infrastructure investment needed and finding innovative applications that may eventually impact front-line workers (Khatib et al).

Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

Transmission PreventionCopy Link!

This section addresses transmission prevention. Please see COVID overview for the causes of Infectivity and Transmission.

Literature Review (Infection Control): Gallery View, Grid View

Wearing Face Masks and ShieldsCopy Link!

Updated Date: December 19, 2020
Literature Review: Gallery View, Grid View

This section covers general public use of face masks and shields, for health care usage, see Personal Protective Equipment

Universal masking has been shown to reduce transmission. More data exist for medical settings, but the United States CDC and the WHO both recommend mask use in non-medical settings as well (CDC, WHO).

How do Face Masks Work?Copy Link!

1. Face Masks provide a barrier against a high percentage of the viral particles released from a wearer’s mouth and nose (Ma et al).

1. Wearing a medical mask has been demonstrated to result in a six-fold decrease in particle emission during breathing (Asadi et al). Systematic review of research literature on face masks shows that they reduce risk of infection by 85%, with greater effect noted in healthcare settings (MacIntyre et al). Even loose-fitting masks appear to block 51% of particles. (Brooks et al)

2. Available evidence also indicates that face masks can protect the wearer from inhaling viral particles. Face masks with multiple layers of cloth containing higher thread counts are more effective (CDC).
3. The effectiveness of masks may be different as new more transmissible viral variants with higher viral loads, such as Delta variant, emerge (Hetemäki et al). However, they are likely to retain some efficacy.
4. Populations can more easily adhere to universal masking advice than stay-at-home orders in some settings. Face masks allow people to leave their homes for essential reasons with less risk to others.

Can Face Masks Harm People?Copy Link!

Face masks do not interfere with the exchange of oxygen or carbon dioxide, even in patients with severe lung impairment (Samannan et al). Depending on the face mask, it may change the rate of flow of air, which can make people feel uncomfortable, especially if they have obstructive lung disease that also impedes air flow, such as COPD or asthma. Wearing a medical mask can be uncomfortable, but will not cause oxygen deficiency or carbon dioxide intoxication. Make sure that face masks remain dry (WHO). CDC recommends face masks above age 2; WHO recommends against requiring face masks for children under the age of 5 (WHO).

Types of Face MaskCopy Link!

There are several major categories of face masks. In many places manufactured medical-grade face masks (surgical, KN95, and 95) are in short supply. If there is a shortage of medical-grade face masks, they should be reserved for healthcare workers, confirmed COVID-19 patients, patients with symptoms of COVID-19, or patients at high risk of complications (WHO). More details on different types of medical-grade masks are available in PPE Types and Uses.

Tool: Instructions on How to Make Your Own Face Mask.

Face Shields and GogglesCopy Link!

Face shields and goggles are meant to prevent droplets and sprays from entering the eyes (for example, when caring for a hospital patient or a sick family member at home).Regulatory guidance and standards on forms of eye protection are highly variable. For best protection, wear a face shield that fits snugly against the forehead and extends the full length of the face and to the point of each ear (Roberge).. There is lack of evidence to demonstrate that face shields alone are sufficient as a form of source control for protecting others (CDC). They are also not sufficient to protect the wearer when worn alone, and should generally be worn with a face mask (Roberge). When a face mask cannot be worn, a face shield can be worn instead but does not offer the same level of infection control (CDC).

When to Wear a Face MaskCopy Link!

1. When leaving the house
2. In quarantine/self-quarantine/isolation when contact with others is necessary
3. In workplaces and on public transportation
4. When entering someone else’s home to provide an essential service
5. When indoors with people who do not belong to your household, including relatives
6. When cleaning streets or disposing of domestic rubbish
7. A face mask is suggested, but not absolutely necessary in some outdoor areas if a 2-meter distance can be kept from other people at all times. Consult local rules and regulations.

How to Use a Face MaskCopy Link!

1. Wash your hands with soap and water or an alcohol-based hand sanitizer before putting on, touching, or removing a face mask (WHO). This prevents you from accidentally contaminating your face if you have coronavirus on your hands. Avoid touching the front of a face mask by touching the strings or ties instead.
2. The face mask must be worn over both the mouth and the nose, it is not effective if used over the mouth alone. Tie securely to minimize gaps between face and mask.
3. Avoid touching the face mask while wearing it. If you do, perform hand hygiene.
4. When removing a face mask, undo the ties and carefully fold the face mask inside-out. Place directly in a designated area for disposal or washing, or in a plastic bag.
5. Wash cloth face mask in soap or detergent, preferably with hot water. If hot water cannot be used, boil the mask for 1 minute after washing with detergent (WHO). Only use a cloth face mask that has been properly cleaned.
6. If a face mask becomes damp or noticeably soiled, replace it immediately with a clean one.

Tool: WHO Infographics on How to Wear a Face Mask

Policy Interventions Around Face Mask UseCopy Link!

Adapted in large part from the South African Recommendations:

1. Public health leaders should create media campaigns to educate the public on the use of face masks, including how to safely use them.
2. In COVID-19 hotspots it is reasonable for policy makers to make face masks mandatory, especially in spaces where physical distancing is challenging. Educational campaigns should be prioritized over punitive measures to promote adherence.
3. Face masks are not a substitute for other preventive measures like regular handwashing, cleaning surfaces, physical distancing and contact tracing. All must be done together whenever possible.

Physical DistancingCopy Link!

Updated Date: December 19, 2020
Literature Review: Gallery View, Grid View

Physical DistancingCopy Link!

The World Health Organization recommends people maintain a physical distance of 1 meter between them. This is based on research on bacterial meningitis and rhinovirus spread (WHO)

In contrast the United States Centers for Disease Control (CDC) recommend a distance of 2 meters. This recommendation is based on measurements of influenza transmission, sometimes from studies in the 1930-40s (Wells).

There is no known distance cutoff that absolutely protects a person from being exposed to any droplets or aerosolized particles (see Aerosols, Droplets, and Fomites). Sneezing and coughing can create turbulent gas clouds that can spread droplets well past a distance of 2 meters (Bourouiba). However, the density of droplets seems to decline the farther away from another person you stand.

Outdoor TransmissionCopy Link!

Transmission is less likely outdoors and in other well-ventilated spaces. Systematic review of evidence indicates that COVID transmission is significantly reduced outdoors: outdoor transmission is responsible for <10 % of reported transmissions globally (Bulfone et al). In indoor spaces, low ventilation and lack of ventilation are both associated with higher transmission rates of airborne diseases (WHO). In one study of transmission in China, only one case among 7300 was associated with outdoor transmission (Qian). However, with more infectious variants such as the Delta variant there are reports of outdoor transmissions at music festivals in the USA and playgrounds in Australia, especially with shoulder-to-shoulder events. However, it is still far less likely than indoors.

Surface DecontaminationCopy Link!

Updated Date: December 19, 2020
Literature Review (Fomites):Gallery View, Grid View

Surface decontamination can help prevent the spread of COVID-19, though transmission through transmission from surfaces and fomites is not common (see Aerosols, Droplets, and Fomites). Particular attention should be paid to cleaning high touch surfaces frequently. Instructions for making cleaning products and example cleaning schedules are found in Disinfection and Cleaning.

Hand HygieneCopy Link!

Updated Date: December 19, 2020

Effective hand washing is a proven way to remove bacteria and viruses from hands and prevent illness. The exact contribution hand washing has made to population health during the COVID pandemic is currently unknown (CDC), but it is presumed to reduce COVID transmission. Hand washing should be performed with soap and water for at least 20 seconds. Alcohol solutions with at least 70% alcohol can also be used.

When around someone with known COVID-19 infection, hand washing is always a critical protection for staff, patients, and families. Gloves should be used for all blood and body fluids.

The WHO recommends handwashing at five times:

1. Before touching a patient
2. Before clean/aseptic procedures
3. After touching a patient
4. After body fluid exposure
5. After touching a patient’s surroundings

Exposures, Isolation and QuarantineCopy Link!

Exposure to COVIDCopy Link!

Updated Date: December 19, 2020
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If a patient believes they have been exposed to COVID-19 it is important to assess risk in order minimize anxiety of lower-risk exposures and identify higher-risk exposures and prevent further transmission.

Definition of COVID ExposureCopy Link!

An exposure is defined differently by different groups. Some general guidance is being within 1 meter (WHO) or 2 meters (CDC) feet of an infectious COVID positive person for greater than 15 minutes or direct physical contact without PPE. It should be noted that there is no evidence for a minimum amount of time that it takes when exposed to become infected.

• A person is considered infectious:

• If Symptomatic: from 2 days before symptom onset until 14 days after (WHO) or until meeting criteria for discontinuing isolation (CDC) (see Releasing Patients from Isolation).
• If Asymptomatic: from 2 days before the date of positive test until meeting criteria for discontinuing isolation.

Risk of Developing Disease After ExposedCopy Link!

Risk depends considerably on the duration and proximity of the exposure and how symptomatic the original patient was. Using a similar exposure definition to the CDC definition, investigators found 13% of exposed individuals subsequently developed COVID-19 (Boulware et al). This is higher amongst household contacts (see Household Transmission).

Prophylaxis: Casirivimab-imdevimab can be given subcutaneously for post exposure prophylaxis in select patients (those who are at high risk for progression to severe COVID-19 disease AND immunocompromised or unvaccinated) but is rarely available due to supply issues. A large trial of hydroxychloroquine as post-exposure prophylaxis demonstrated no benefit and increased risk of self-reported adverse events in the treatment arm (Boulware et al).

Testing after ExposureCopy Link!

Please see Testing Asymptomatic Patients

Quarantine and IsolationCopy Link!

Updated Date: April 23, 2021

IsolationCopy Link!

Isolation is the separation of a sick person with a contagious disease from people who are not sick. We recommend isolation for all suspected, presumptive and confirmed cases of COVID-19. Duration of isolation depends on many different factors, and this is covered in Releasing Patients from Isolation. (CDC guidelines). Facility based isolation of COVID-19 cases is discussed in Transmission Prevention in Facilities.

QuarantineCopy Link!

Quarantine is the separation of people who were exposed to a contagious disease to see if they become sick. We recommend quarantine of all persons that have been exposed to COVID-19 cases.

• Duration of quarantine is typically 14 days from last exposure.
• December 2, 2020 CDC guidance states quarantine can be reduced in certain circumstances. Keep in mind this may not apply everywhere, and local authorities may have longer or shorter guidelines as they consider changing evidence and resources. As the CDC states:

• 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%.
• Quarantine can end after Day 7 if a diagnostic specimen (collected within 48h of Day 7) 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%.
• Please note: for COVID vaccinated patients defined as individuals two week out from final dose of COVID vaccine, the CDC states individuals may refrain from a full quarantine if they do not have symptoms of COVID-19 after contact with someone who has COVID-19. They do recommend fully vaccinated people should get tested 3-5 days after their exposure, even if they don’t have symptoms and wear a mask indoors in public for 14 days following exposure or until their test result is negative. We expect that this may change given the emergence of variants. This is liable to be different in different epidemiologic contexts, and consulting your local public health regulations is advised.

IPC for Home Quarantine or IsolationCopy Link!

Releasing Patients from IsolationCopy Link!

Updated Date: December 19, 2020
Literature Review (Clearance and Return to Work): Gallery View, Grid View

Knowing when a patient has recovered from COVID infection and is no longer infectious is important to allowing them to return to contact with other individuals, including work, school, and living environments.

Time based vs testing based criteria: Most situations call for time-based criteria, because the interpretation of positive tests after infection is complicated (PCR often remains positive even in people who are no longer infectious, see Infectivity). A test-based strategy can be used for selected recovered persons for whom there is low tolerance for virus shedding and infectious risk (for example, working in healthcare facilities, residing in congregate living facilities, immunocompromised, etc). Some institutions require more stringent clearance criteria than those outlined here.

Tool: CDC When Can You Be Around Others When You’ve Had COVID-19

Tool: WHO Criteria for Releasing from Isolation
Tool: Massachusetts General Brigham Case Clearance

1. Symptomatic patients (CDC, WHO):

1. Time-based criteria: 10 days have passed since symptom onset
2. 24 hours have passed since last fever without use of fever reducing medications (whichever is longer)
3. Other COVID symptoms are improving (Note: Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation​)

2. Asymptomatic patients

1. Time-based criteria: 10 days after positive test (CDC, WHO)

3. Patients with severe illness or patients with prolonged symptoms:

1. Time-based criteria: The CDC recommends up to 20 days from symptom onset. WHO makes no distinction based on severity when determining duration of isolation for symptomatic patients.

4. Currently hospitalized patients:

1. Time based criteria: This is not universally defined. BWH uses 20 days since first positive test + 1 day after fever and symptom resolution
2. Test based criteria: This is not universally defined. BWH uses 1 day after symptom resolution + at least 2 negative PCR swabs at least 24 hours apart

5. Severely immunocompromised patients: Defined by the CDC as patients on chemotherapy for cancer, untreated HIV infection with CD4 T lymphocyte count < 200, combined primary immunodeficiency disorder, and receipt of prednisone >20mg/day for more than 14 days

1. Time based criteria: 20 days after symptom onset (+ 1 days after symptom resolution). Exact determination of isolation duration in immunocompromised patients should be made in consultation with an Infectious Disease specialist (CDC)

Transmission Prevention in FacilitiesCopy Link!

Updated Date: December 20, 2020

In health care facilities, IPC is critical to reducing the spread of COVID-19.

Screening and movement: Screen all people (staff, patients, and visitors) entering clinical spaces using Screening Questions. Make modifications to patient flow to ensure patients with symptoms of or at risk for COVID-19 are appropriately classified by likelihood of disease, transported safely, and isolated in designated locations.

Physical distancing: Modify waiting and treatment areas to allow physical distancing.

• Distances between people should be at least 1 meter (WHO recommendation), and ideally 2 meters (CDC recommendation) in all contexts.
• Avoid gatherings of staff in confined spaces. For example, consider outdoor staff meetings or use technology to hold remote meetings. Rotate meal times to avoid crowds in dining areas and rearrange break areas to allow physical distancing so staff can eat and drink safely. Add additional work spaces to avoid congregating at nursing stations.
• In spaces where COVID-related care is provided, the number of people (staff, patients, and visitors) should be kept to the minimum needed. Whenever possible, avoid large groupings of people.

PPE: Use appropriate Personal Protective Equipment and train staff on its use

• Universal Masking in healthcare spaces is always necessary. Medical-grade masks should be used whenever available.
• Wards and rooms should be clearly marked with appropriate and standardized signage indicating the category of precaution and PPE that is required to enter.

Isolation: Use appropriate facilities and protocols to isolate patients (see isolation). Positive COVID patients, PUIs, and patients without COVID symptoms should not be cohorted together. Ideally, patients should be separated as quickly as possible into separate spaces based on at least three categories (screening negative for possible COVID infection, screening low-likelihood for COVID infection, and screening high-likelihood for COVID infection). Some settings may use as many as five cohorting categories. See Likelihood Categories (Case Definitions), and Isolation.

Ventilation: Using outdoor spaces and spaces with good filtration or air turnover can decrease risk. All indoor spaces should be sufficiently ventilated and COVID care areas should be negative pressure whenever possible (see Ventilation and Filtration).

Decontamination: Clean all contact surfaces between patients for areas with frequent patient turnover (e.g. clinic rooms and triage areas) and equipment that is rotated between patients (e.g. vital sign monitors). Facilities should develop cleaning protocols for all patient and non-patient care areas.

IsolationCopy Link!

Updated Date: December 19, 2020

Isolation in Hospital Rooms and WardsCopy Link!

Never co-house a patient who screens negative in the same room or ward as confirmed positive COVID patients or PUIs. Confirmed positive patients should only ever be housed with other confirmed positives.

There is no universal set of strategic recommendations for inpatient housing arrangements. Healthcare settings vary greatly in terms of floor plan, layout, equipment, and other resources.These are some principles that can be adapted to local context.

Isolation in RoomsCopy Link!

Which patients need single rooms? In settings where most patients are kept in single or double rooms, confirmed positive COVID cases can be cohorted together in shared rooms. However, PUIs should never be roomed together, as this may result in COVID transmission from one roommate to another if one PUI is actually COVID-negative.

Requirements for rooms: The ideal room is a single private negative pressure room with transparent windows, doors that close, and continuous wireless pulse oximetry monitoring. This arrangement is often unavailable outside of critical care settings, even in the world’s best-resourced practice settings. If a room does not have adequate space and monitoring (direct patient visualization, pulse oximetry, and/or telemetry), rooming and location must balance patient safety risks and infection control needs.

Isolation in Wards and Common AreasCopy Link!

COVID-care wards should be as separated as possible (ideally in a different building) from care areas for patients who screen negative for possible COVID infection.

Separating wards by likelihood level: If single isolated rooms are not available or feasible we recommend using multiple wards or areas to separate patients by Likelihood of Disease. Wards for suspected or confirmed COVID patients should always be separate from wards for patients who screen negative for COVID symptoms. Providers should always move from low-risk patients to high-risk patients.

Whenever possible, at least three separate COVID-care wards should be established to safely cohort the following categories. For additional details, see Likelihood Categories (Case Definitions).

1. Lower-risk PUIs, including minimally symptomatic and asymptomatic patients with known exposure.*
2. Higher-risk PUIs, including symptomatic suspected cases and probable cases). Ideally these groups would be further subdivided into separate wards or areas based on their likelihood of having COVID (for example, separating suspected lower-likelihood cases from suspected and probable cases with a higher likelihood of disease).*
3. Confirmed positive COVID cases.

*These first two categories require the highest level of IPC to reduce transmission, as patients in these spaces are a mix of positive and negative.

When it is not possible to separate wards by likelihood level: If separate wards for each level are impossible, PUIs patients may be cohorted within the same ward and grouped according to risk level with physical distance or Barriers between each group of patients. Since not all PUIs will have COVID, it is important to adequately distance (1-2m) PUIs from each other, arrange the ward from the least likely to the most likely patients. Strict IPC and PPE practices are imperative, and providers should try to move from low to high risk patients if possible.

PrecautionsCopy Link!

Updated Date: December 19, 2020
Literature Review (Airborne v Droplet): Gallery View, Grid View
Literature Review (Aerosolization): Gallery View, Grid View

Precaution Type for COVID-19Copy Link!

WHO guidance recommends standard, contact and droplet precautions when caring for suspected or confirmed COVID-19 patients. If an Aerosol Generating Procedure is being performed airborne precautions are needed (WHO).

• Some hospitals may create their own definitions and specific policies with slightly more stringent requirements, such as Enhanced Droplet Precautions. Given concerns that coughing and sneezing may themselves cause aerosols, some hospitals may choose to put all patients on airborne precautions

Tool: CDC Guidance on Contact, Droplet and Airborne Precautions (including sample signs)

Tool: Detailed CDC Guidance Defining Different Levels of Precaution

Standard, Contact and Droplet PrecautionsCopy Link!

Standard, Contact, and Droplet precautions (drawing from CDC guidance) in the setting of COVID include the following (adapted from CDC and WHO) guidance:

1. Use high-quality hand washing
2. Use adequate PPE to protect against contact with the patient’s environment and droplets suspended in air (PPE is covered extensively here)
3. Use Respiratory hygiene/ cough etiquette (cover mouths when coughing and sneezing, tissues, no-touch receptacles)

1. Patients should wear medical masks whenever possible

4. Use appropriate patient rooming and distancing (see “isolation” above)
5. Use safe injection practices
6. Use safe waste management and linen management
7. Use designated equipment for COVID patients (or wards) and adequately sterilize equipment (stethoscope, blood pressure cuff, pulse oximeter) between each patient (e.g. with ethyl alcohol 70%).
8. Minimize patient movement and transportation and use appropriate precautions when transport is needed (see transport below) (see “transport”)
9. Maintain good ventilation

1. Open doors and windows when possible, though be careful not to ventilate from COVID areas to non-COVID areas.

10. Whenever possible, healthcare workers should move lower-risk to higher risk patients (from asymptomatic to symptomatic and then to confirmed positive patients).
11. Some additional guidance on specific procedures, lab transport, etc is available in BWH’s ICU Strict Isolation Manual

Airborne PrecautionsCopy Link!

Use airborne precautions when there is a risk of aerosolized particles. In the hospital setting, this generally means during Aerosol Generating Procedures (AGPs). (The role of aerosols in COVID-19 transmission is discussed in Aerosols, Droplets, and Fomites). Airborne precautions should be used for all patients (not only confirmed CoVID-19 patients and PUI) for AGPs in places with high prevalence, or where testing to rule out infection prior to the procedure is not possible. In addition to gown, gloves, and eye protection, aerosol-resistant respirators (N95 masks) are needed during aerosol-generating procedures and until adequate air turnover has occurred afterward (air turnover depends on your facility, in most BWH rooms this is 47 minutes). Please see Personal Protective Equipment for guidance.

1. Use negative pressure rooms wherever possible, or in a well - ventilated space if not (see Ventilation and Filtration).
2. Limit the number of people in the room to the fewest necessary.
3. There should be no other patients and no visitors present.

Aerosol Generating ProceduresCopy Link!

Updated Date: December 19, 2020
Literature Review (Airborne v Droplet): Gallery View, Grid View
Literature Review (Aerosolization): Gallery View, Grid View

Aerosol Generating Procedures (AGPs) must be performed with Airborne Precautions for COVID patients, and most non-COVID patients (see airborne precautions). Not all institutions use the same definition of an aerosol generating procedure. Some potential examples include:

1. Intubation
2. Extubation
3. Bronchoscopy
4. Sputum induction
5. Cardiopulmonary resuscitation (CPR) with chest compressions
6. Open suctioning of tracheostomy or endotracheal tube
7. Manual ventilation (e.g. manual bag- mask ventilation before intubation)
8. Nebulization
9. High flow oxygen therapy and non-invasive positive pressure ventilation (e.g., CPAP, BIPAP) (though this is not universal in different institutions, and it is not clear if this increases aerosols beyond coughing, see HFNC)
10. Oscillatory ventilation
11. Disconnecting patient from ventilator
12. Upper airway procedures / surgeries
13. Upper endoscopy (including transesophageal echocardiogram) and lower endoscopy
14. Chest physical therapy
15. Autopsy
16. Thoracentesis/small-bore (pigtail) chest tube placement (due to the increased risk of cough)
17. Airway surgeries
18. Tracheostomy changes
19. Disconnecting patients from ventilators and ventilator circuit manipulation
20. Upper endoscopy (including TEE)
21. Lower endoscopy
22. Mechanical In-Exsufflator
23. Dental procedures
24. Venturi mask with cool aerosol humidification (this is highly institution-dependent)

The following are NOT usually considered aerosol generating procedures:

1. Venturi mask without humidification
2. Nonrebreather, face mask, or face tent to 15 liters
3. Humidified trach mask to 20L (with inline suctioning)
4. Routine trach care
5. In-line suctioning of endotracheal tube when ventilator circuit has a viral filter in place
6. Labor and Cesarean section
7. Nasopharyngeal swab
8. Proning (unless ET tube becomes dislodged)

Patient TransportCopy Link!

Literature Review: Gallery View, Grid View

Within FacilitiesCopy Link!

Updated Date: December 19, 2020

Limit transport and movement of patients. When transport is necessary, follow guidelines outlined below.

1. If a patient must be moved, all staff who come into contact with the patient should don clean PPE.
2. Patients must wear face masks during transport. Generally this is a medical mask. If this is not possible, a cloth mask should be used. Surgical masks should be used over oxygen delivery devices if possible and if not, well-sealing oxygen delivery devices should be used. Some hospitals permit transport on CPAP/BIPAP or High Flow Nasal Cannula, others do not.
3. Once a patient is in an isolation area they should not leave it unless to go to a dedicated bathroom, a specific testing or healthcare delivery location (accompanied by a healthcare worker), or upon discharge.

Interfacility TransferCopy Link!

Clinical considerations for transfer are covered in Patient Assessment under Interfacility Transfer.

IPC should be carefully considered for all pre-hospital and interfacility transport. During transport, providers and patients are frequently in close physical contact, and a patient’s COVID status may not be known. All transport systems should develop IPC guidelines adapted for their situation, including on what PPE should be used when. In addition, environmental steps to reduce transmission, such as physical barriers to separate the driver from the patient compartment and ensuring that air is not recirculated in the vehicle can be used.

Tool: CDC Recommendations for IPC for Emergency Medical Systems (EMS)

Tool: IPC Guidelines for Interfacility Transport Without Ambulance Systems (PIH)

Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

PPE Types and UsesCopy Link!

Updated Date: April 7, 2022
Literature Review: Gallery View, Grid View
Tool: PPE Training Online Module

This section covers professional PPE for healthcare workers. Wearing Face Masks and Shields covers public use.

Standard recommended PPE for care of suspected, probable, and confirmed COVID-19 patients or infectious material includes gown, gloves, eye protection, and N95 respirator or medical mask. Adapted from WHO.

Other Particulate Respirators

KF94 masks are similar in appearance to N95s and are able to filter 94% of particles according to standards of the South Korean government. A limited 2020 study demonstrated that KF94s provide protection from particles produced by coughing patients similar to the protection provided by N95s (Kim et al). KF94s have not been approved for healthcare worker use in the United States.

Powered Air Purifying Respirators (PAPRs)

PAPR are battery-powered respiratory protection devices that provide a higher filtration factor than N95s and other non-powered respirators. Air is blown through filter cartridges and into a breathing zone created by a tight or loose-fitting facepiece, hood, or helmet. User-friendly guidance on PAPR is available at this CDC site. International certification and regulatory standards for PAPR in healthcare settings are in slow development because PAPR are primarily certified for industrial applications (Licina et al). To be used in United States healthcare settings, PAPR must meet National Institute for Occupational Safety and Health (NIOSH) requirements. Lists of NIOSH approved PAPR are available here.

PAPR are among the most expensive forms of respiratory protection because of their battery components.There are no clinical trials available to evaluate the protective efficacy of PAPR in comparison to other forms of respiratory protection in healthcare settings, but reasonable application of the precautionary principle in consideration of their superior filtration capacities makes them attractive devices for protection against aerosols (Licina et al).

In some settings, available PAPR are reserved for healthcare workers who have failed fit seal tests or are otherwise unable to wear fitted respirators. Use of PAPR in operating rooms and other areas with sterile fields is controversial because air is not filtered upon exiting PAPR breathing zones. However, statistical differences between surgical masks and PAPR in protecting sterile fields has not been noted (Howard et al).

Seal (Fit) TestingCopy Link!

All N95 masks rely on a close seal to the face to ensure that all air is filtered through the mask. Ideally, qualitative fit testing should be performed to ensure a correct fit for each individual; this should be done annually for each type of N95. In addition, each time an N95 is used, the provider should perform a seal check, then adjust the position of the mask on their face if there is not a good seal.

Tool: Video Describing How to Perform a Seal Check

PPE During Clinical CareCopy Link!

Updated Date: April 7, 2022

Staff Supporting Care Delivery

PPE During TestingCopy Link!

Updated Date: September 24, 2020

Recommended Personal Protective Equipment (PPE) Euring COVID-19 Testing

Donning and DoffingCopy Link!

Updated Date: December 19, 2020

Putting on (donning) and taking off (doffing) PPE correctly is very important. Contamination of mucous membranes while removing PPE can expose the wearer to the virus.

*When using alcohol-based hand sanitizer, allow to dry before continuing.

Tool: WHO Infographic for Donning/Doffing PPE
Tool: Donning Technique Video
Tool: Doffing Technique Video
Tool: PPE Training Online Module by Lifebox

DecontaminationCopy Link!

Updated Date: December 19, 2020

1. Disinfecting Reusable PPE and Equipment:

1. For most reusable items (for example, thermometers): 70% ethyl alcohol
2. Reusable face shields can be soaked in sodium hypochlorite 0.5% for 1 hour and left in a clean, open space to dry for at least 1 hour.

2. Decontaminating N95 Masks: Facilities may consider decontaminating N95 masks when they are in short supply. Different techniques have different levels of efficacy, and some techniques are not effective. Vaporized hydrogen peroxide, UV-C chambers and humid heat are methods that have been implemented by health care facilities. N95decon.org has an Overview of decontamination methods and In-depth Guidance on multiple methods of decontamination. Note that Alcohol and sodium hypochlorite should not be used on N95 masks as they degrade filtration efficacy.
3. Disinfecting Surfaces: See Disinfection and Cleaning.
4. Washing Fabric: if reusable gowns are used, they should be machine washed with warm water at 60-90° C and laundry detergent. Laundry can then be dried according to routine procedures.

1. If machine washing is not possible:

1. Soak linens in hot water and detergent or soap in a large drum. Use a stick to stir and avoid splashing.
2. Empty dum and soak linens in 0.05% chlorine for approximately 30 minutes.
3. Rinse with clean water and allow linens to dry fully in sunlight.

Conservation of PPECopy Link!

Updated Date: December 20, 2020

It is critical to conserve PPE where possible as stock remains limited globally. Local stocks and availability may vary greatly, and individual institutions or local governments may have detailed guidance for the use of PPE that differs from what is presented here. These are some general strategies that can be used to try to conserve PPE while still maximizing patient and healthcare worker safety (adapted from WHO, United States Centers for Disease Control (CDC). To ensure that global PPE shortages do not negatively impact care of any kind of patient (including TB patients and surgical patients), it is important to conserve the use of PPE in all clinical areas.

Tool: PPE Consumption Tool

Institutional PoliciesCopy Link!

1. Decrease length of hospital stay for patients, if safe to do so
2. Limit total personnel and visitors in treatment areas
3. Temporarily suspend routine fit testing for N95s for employees with no COVID contact
4. Use N95 respirators beyond the manufacturer’s shelf life for training/testing
5. During known shortages:

1. Develop policies for extended use of N95 respirators:

1. Extended use refers to wearing the same respirator for repeated close contact encounters with different patients without removing the respirator between patients. CDC guidelines for extended use can be found here.

2. Limited Reuse of N95s:

1. Reuse refers to use of the same respirator by the same health care worker for multiple encounters and doffing it between encounters. Contact transmission may be possible with reuse. Reuse of N95s for care of tuberculosis patients is preferred over reuse of N95s for care of COVID patients because tuberculosis is not transmissible through contact.

3. When N95 supply is limited, prioritize the use of N95s for high-risk activities, such as aerosol generating procedures.

6. Do not stop striving to optimize PPE. Institutions remain responsible for safety even while engaging in pragmatic strategies to adapt to crises.

Care Provider ChoicesCopy Link!

1. Minimize the number of unnecessary aerosol generating procedures. Examples:

1. Use metered-dose inhalers (MDIs) instead of nebulizers
2. Do not use humidification with venturi masks

2. Plan patient care to minimize PPE use. Examples:

1. Cluster interventions: e.g. take vital signs and give medications at the same time
2. Time medication administrations so that interventions can be clustered (medications due at the same time)
3. Choose medications with daily dosing or oral dosing instead of frequent IV dosing
4. Where possible, use long-acting or scheduled protocols in lieu of protocols requiring frequent assessments and administrations for things like alcohol withdrawal and diabetic ketoacidosis

3. Arrange patient care areas, equipment, and daily staffing assignments so that caregivers do not need to don and doff PPE as frequently. Examples:

1. Monitors, IV pumps outside of doors
2. Where appropriate and possible, use technology (such as phones) to communicate with patients and consultants and minimize caregiver exposure

Equivalents and AlternativesCopy Link!

1. Due to global PPE shortages, using substitutes for N95 masks may be necessary.
2. The CDC and the National Institute for Occupational Safety and Health provide extensive guidance on selection and use of N95 equivalents, including an updated list of approved respirators as well as counterfeit respirators.

When Recommended PPE is Not AvailableCopy Link!

Updated Date: December 19, 2020

In addition to taking all possible steps to expand PPE supply and return to normal operations, crisis strategies when recommended PPE is not available are listed below. It should be noted that none of these strategies are sufficient to protect health care workers, and these should be strategies of last resort. In addition, consider excluding healthcare workers at increased risk for SARS-COV complications from patient contact.

1. Maintain a minimum 1 meter distance whenever possible to avoid inhalation of droplets
2. If gloves are not available, continue vigorous hand hygiene. Wash hands frequently for more than 20 seconds each time. Avoid touching face, mucus membranes, and surfaces.
3. When face shields or goggles are not available, use alternate eye coverings, such as glasses, to cover the eyes. If performing an aerosolizing procedure that would normally require an N95, consider:

1. A double medical mask
2. Remaining out of direct alignment with the patient’s nose and mouth
3. Use ventilation and portable HEPA filtration where possible to reduce ambient virus
4. Consider ventilated headboards for some AGPs if available

InnovationCopy Link!

While official PPE products are preferable, in instances of shortages some people may be able to create PPE alternatives by repurposing existing medical or household supplies, using 3D printers, or using innovative methods for extending the use of existing supplies. Though some have emergency use authorizations or preliminary testing data, very few of these have been officially tested and the level of protection they afford is unknown.

Tool: Frames to Enable Reuse and Improved fit of Respirators

Tool: Snorkel/Scuba Mask Face Shields with Anesthesia Filters

Tool: Elastomeric Mask Adaptations (Source 1 and Source 2)

Please note that as of April 2023, this website is no longer actively being updated.Copy Link!

Screening and TriagingCopy Link!

The screening and triaging process involves three parts:

1. A Quick Symptom and Exposure Screen to determine which patients are at risk for COVID
2. An Acuity Triage to determine how quickly and where patients need to be seen
3. Categorization by Likelihood (Case Definitions) to help sort patients who might have COVID by their likelihood of having it, and to help reduce transmission from likely cases to unlikely cases.

Screening QuestionsCopy Link!

Updated Date: December 20, 2020

Goal of screening: To quickly identify patients with possible COVID infections and prevent transmission of infection to other patients and healthcare workers.

Where to screen: At the point of entry. Most healthcare facilities reduce the number of available entrances and set up screening stations with trained staff at every entrance.

Whom to screen: All people entering a healthcare facility should be screened (patients, visitors, staff). Patients who are coming in for routine care should be screened prior to patient arrival if possible (typically via telephone 24 hours before the appointment) and again at the designated point of entry (whether or not the patient was already screened).

Sample Screening Questions:

1. Do you have any of the following new symptoms?

• Fever
• Cough
• Shortness of Breath
• Muscle Aches
• Sore Throat
• Runny Nose
• Loss of Smell or Taste

2. Have you been tested for or had COVID-19 in the last 14 days?
3. In the last 14 days have you spent at least 10 minutes within 6 feet of anyone with COVID-19 or symptoms of COVID?
4. Are you, or a household member, currently on home isolation or quarantine, or have you traveled to a place that requires quarantine?

If the patient answers “No” to all of the above, continue routine check in. People who screen negative should be separated from those who screen positive.

If the patient answers “Yes” to any of the above, give the patient additional PPE (a surgical mask) if screening in person and go to Acuity Triage below.

Acuity TriageCopy Link!

Updated Date: December 20, 2020

Literature Review (Virtual Care): Gallery View, Grid View

Facility Acuity TriageCopy Link!

Isolation: If the patient is positive during screening, they should be treated as a possible COVID-19 case, also called a “Person Under Investigation' (PUI) and be separated from patients who screen negative.

Acuity triage: After screening positive, patients should next undergo an acuity assessment to determine how urgently they need to be seen by a medical provider. For urgent care or emergency visits, this should be done with a standardized triage system. One triage system designed for LMICs is the WHO/ICRC/MSF Interagency Triage tool (see below). Patients who are designated as higher acuity by a triage system should be seen first.. Triage should be conducted in a dedicated space with equipment to measure vital signs, and there should be clear pathways from triage to a resuscitation area for patients who are identified as critical.

Tool: WHO/ICRC/MSF Interagency Triage Tool (Pages 11-15)

Home and Virtual Acuity TriageCopy Link!

When patients screen positive over the phone prior to a visit, a provider can assess symptoms over the phone or at a home visit to determine the urgency and best location of evaluation: at home via virtual visit (telephone or video), in person (outpatient), or in an emergency unit.

Below is suggested guidance, but individualized provider assessments should always take precedent. If a provider feels that evaluation in an outpatient clinic or emergency unit is necessary,, they should ensure that the specific location recommended has appropriate IPC and PPE to safely care for PUIs as not all facilities are equipped for this purpose.

Tool: PIH Intake and Symptom Screening Tool
Tool: BWH Telephone and Video Visit Tips

*If patient has home pulse oximeter, here are Instructions. Caution on the reliability of at home pulse oximeters: Trend may be more reliable than the value itself. Dyspnea does not always correlate with oxygen saturation (Shah et al).

Likelihood Categories (Case Definitions)Copy Link!

Updated Date: December 20, 2020

During or after the acuity assessment, a clinical staff member should verify the initial screening assessment and classify patients by their risk (likelihood) of having COVID. Patients who are acutely ill or unstable should not have care delayed for this step.

Why Categorize?Copy Link!

Not all patients who screen positive on questionnaires will have COVID and it is important to try to separate patients by how likely they are to have COVID in order to avoid exposing patients who do not have COVID. Patients who have tested negative or who are not suspected to have COVID-19 should never be co-housed with COVID positive or PUI patients. Keep risk categories as separate as possible. See Levels of Isolation.

How to Categorize?Copy Link!

Someone with clinical training should categorize patients by their likelihood of having disease using standard case definitions. This process can be combined with Clinical Evaluation and can be done in multiple locations (telephone, near facility points of entry, dedicated/ prepared clinics, or COVID-ready acute patient care settings). It is important to note that:

• Case categorization varies significantly in different hospitals and in different countries. Please follow your local guidance.
• Clinician judgment is an important part of the decision. If the patient has an obvious alternative explanation for why they have a symptom, their risk could be downgraded. If a patient has significant exposure or classic symptoms, their risk could be upgraded even if they do not meet all criteria.
• Testing: Test patients in these groups when possible, either before or during this evaluation.

Tool: WHO Case Definitions Handout

Adaptation of the WHO Guidelines for Case Definitions

*These case definitions are based on the World Health Organization classification system

Algorithm for Case Definitions

Clinical EvaluationCopy Link!

Updated Date: December 20, 2020

HistoryCopy Link!

When assessing a patient with possible COVID-19, ask the following:

1. Date of Symptom Onset

1. Patients typically worsen on Day 5-10 after symptom onset and develop acute respiratory distress syndrome (ARDS) at days 7-15 (see Time Course). Patients with severe symptoms before Day 5, or with any progressive dyspnea, require close monitoring as they are more likely to decompensate.

1. Ask about any known exposure to SARS-CoV-2 or sick contacts in the past 14 days.
2. Ask about household members:

1. Does anyone have increased exposure to SARS-CoV-2 (e.g. working in healthcare, schools, stores, transportation, etc.)?
2. Is there anyone at home to help monitor the patient?

1. Dyspnea (Difficulty Breathing)

1. Mild: Dyspnea that does not interfere with daily activities (e.g. just mild dyspnea with activities such as climbing 1-2 flights of stairs or walking briskly)
2. Moderate: Dyspnea that limits daily activities (e.g. dyspnea that limits the ability to walk up 1 flight of stairs without needing to rest or that interferes with meal preparation or light housekeeping)
3. Severe: Dyspnea so severe that it renders the patient unable to speak in complete sentences and interferes with basic activities such as toileting and dressing

2. Mental Status and Function

1. Has there been a decline or change in alertness, memory, behavior and attention? If so, this should prompt in person evaluation
2. Patients with recent falls or near falls should be evaluated in person and receive an assessment for traumatic injuries

3. Chest Pain/Tightness

1. Evaluate patients with chest pain or tightness in person. While chest pain is a feature of COVID-19 pneumonia, the high rates of cardiac and thromboembolic complications may necessitate ruling out acute coronary syndrome (ACS) or pulmonary embolism (PE).

4. Dizziness and Hypotension

1. Assess for orthostatic symptoms, dizziness, mental status changes, or reduced urine output as signs of possible hypotension.

5. Age and Comorbidities

1. See Patients with Comorbid Diseases below
2. Geriatric patients: Older adults are at increased risk of adverse outcomes and are more likely to present with atypical symptoms such as altered mental status, decreased appetite, non-focal pain

ExamCopy Link!

In addition to standard physical exam, pay particular attention to:

1. Vital Signs. Patients with COVID manifest significant hypoxemia without any subjective difficulty breathing (Tobin et al). See also Pulse Oximetry.
2. Pulmonary Exam:

1. Assess for tachypnea, cyanosis and use of accessory muscles. If present, these suggest a patient is having difficulty breathing and needs close monitoring even if oxygen saturation is normal. Dyspnea does not always correlate with oxygen saturation (Shah et al). Tachypnea can also suggest acidosis and shock.
2. Assess lung exam: although lung exam is often NORMAL even in patients with COVID-19 pneumonia, always listen to the lungs to evaluate for wheezing or crackles that would indicate other possible or additional cause of illness (e.g. asthma/chronic obstructive pulmonary disease (COPD)/congestive heart failure exacerbation).

3. Leg and calf swelling:

1. COVID-19 induces a hypercoagulable state, so always assess for deep venous thrombosis (DVT). Ultrasound with Doppler is the standard modality for diagnosing DVT. D-Dimer is not validated as a tool for stratification of DVT probability in COVID-19, given elevated D-dimers in patients in the absence of thrombosis.
2. Increased swelling in one leg should prompt consideration of deep venous thrombosis, while increased swelling in both legs more often reflects fluid overload or congestive heart failure

Differential DiagnosisCopy Link!

Keep a broad differential diagnosis, both in patients suspected of having COVID-19 and in patients with confirmed COVID-19, given the many diseases that can mimic features of COVID-19 and the risk of secondary infections or sequelae.

Mimics: Other diseases that can cause symptoms mimicking COVID-19 include tuberculosis, malaria, bacterial pneumonia, congestive heart failure, chronic obstructive pulmonary disease, urinary tract infections, and gastrointestinal illnesses. Any of these diseases can also coexist with COVID-19.

Patients should be evaluated for alternative or coexisting diagnoses based on the local burden of disease, patient risk factors, and clinical presentation. Over the course of their treatment, if a patient’s condition or symptoms change, providers should consider whether the cause is due to COVID-19 or if another process is contributing.

Coinfection: Patients with confirmed COVID-19 commonly have concurrent secondary infections. Most studies on co-infection and secondary infection are done in high-income or upper-middle income countries; it is unknown if and how co-infection patterns vary in low-income countries

• Viral coinfection depends on local epidemiology and season
• Bacterial coinfection is not very common (~3%), secondary bacterial infection is somewhat more common (~7%). See Bacterial Infection)
• Malaria, dengue and other tropical diseases can co-exist with COVID

Complications:

Patients with confirmed COVID-19 can also present with or develop a number of complications:

• Thromboembolism/Pulmonary Embolism
• Acute Coronary Syndromes and Myocarditis/Pericarditis
• Acute Hyperglycemia
• Cytokine Storm Syndrome
• Many other issues discussed in Specialty Care

Disease Severity and DispositionCopy Link!

Updated Date: December 20, 2020
Literature Review (Emergency Department): Gallery View, Grid View

The decision about severity of illness and where to admit varies considerably depending on the availability of beds, the location, and the patient’s resources to monitor and care at home. This is a general set of suggestions based on BWH, PIH, and WHO criteria, and should be adapted to local needs. In some settings, patients with severe or critical COVID may need to be transferred to facilities with higher-levels of care.

Tool: WHO Classification of Disease Severity (page 13)
Tool: PIH Algorithm for Initial Patient Assessment
Tool: MEWS (The Modified Early Warning Score for Clinical Deterioration) can offer estimates based on vital signs of the probability of ICU admission or death, and has been validated in low-income settings as well (Kruisselbrink et al).

Vitals and MonitoringCopy Link!

Updated Date: December 20, 2020
Tool: Normal vital signs by age
Tool: Vitals signs monitoring framework

Pulse Oximetry: Please note that pulse oximeters are less reliable in patients with darker skin tones, and accuracy is improved by trending over time or using both resting and exertional measures. See Home Pulse Oximetry for more details.

We base these recommendations on the assumption of staff and equipment availability. These frequencies may need to be adjusted based on resource availability in different settings.

Lab MonitoringCopy Link!

Laboratory FrequenciesCopy Link!

Updated Date: August 19, 2021

The table below provides a summary of the laboratory monitoring at a well-resourced academic tertiary institution. Monitoring labs such as IL-6 levels will not be possible in most institutions, and excellent care can still be provided without these specialized labs.

*Note: Consider discontinuation on day 8 if patient status and lab values are stable or improving

If the patient is acutely worsening

1. Redraw all admission labs above to assess the cause of the acute change, and include any other workup that may be needed (e.g. blood cultures, urine strep pneumo and legionella, chest x-ray, EKG)
2. Resume the regular trending lab frequency with the exception of troponin and Nt-Pro BNP which can be discontinued as soon as downtrending

When lab availability is limited, this is an alternate lab schedule:

Common Laboratory FindingsCopy Link!

Updated Date: May, 2020

Laboratory abnormalities are more frequent and significant in patients presenting with severe disease. Many of these are associated with more severe disease or death. (Arentz; Chen; Du et al; Guan et al; Young et al; Zhang et al; Zhou et al). Some common abnormalities in COVID patients include:

• Lymphopenia
• Mild Hepatocellular Injury (AST / ALT ~200s, GGT often elevated, AlkPhos rarely elevated) (Zhang et al)
• Anemia
• Elevated D-Dimer (see Thrombosis)
• Elevated Creatine Kinase (see Muscle Injury and Rhabdomyolysis)
• Elevated LDH
• Low/Normal Procalcitonin, elevated in severe disease and/or Superimposed Bacterial Infection
• Elevated Inflammatory Markers: LDH, CRP, ESR, ferritin, IL-6 (see Cytokine Storm)
• Elevated PTT or INR in COVID-19-related Coagulopathy

Interpretation:

• Coagulopathy:

• Elevations in PTT and/or INR can be a sign of coagulopathy (i.e. dysfunction in the body’s clotting system which leads to an increased risk of bleeding and increased risk of clotting). Suspect disseminated intravascular coagulation when platelets drop and D-dimer, PTT, and INR increase.

• D-Dimer:

• An elevated D-dimer in patients with COVID-19 is not always a sign of thrombosis, though it can be. Consider other signs and symptoms and use available diagnostic methods such as ultrasound and/or CT scan to further evaluate these cases.

• Inflammation and Cytokine Storm:

• Inflammatory labs such as D-dimer, LDH, CRP, and ESR are often elevated in patients with severe COVID-19, so if a previously stable patient deteriorates, check these. Cytokine Storm Syndrome, an inflammatory response that can lead to shock and multi-organ failure, should be considered if the following lab parameters are met (though some patients may not meet these cut-offs):

• CRP >50mg/L
• And at least two of the following:

• Ferritin >500 ng/mL
• LDH >300 U/L
• D-dimer >1000 ng/mL

ImagingCopy Link!

Updated Date: December 20, 2020
Literature Review (CT and Chest X-Ray): Gallery View, Grid View
Literature Review (Ultrasound): Gallery View, Grid View

Chest X-rayCopy Link!

Chest x-ray can help identify alternate causes of shortness of breath. Some chest x-ray findings can suggest a diagnosis of COVID-19. Normal chest x-rays do not rule out COVID: Chest X-rays may be normal in up to ~30% of COVID patients requiring hospitalization, particularly in early disease (Wong). Sensitivity 59% in one study, as compared to 86% for CT scan (Guan).

Low-risk patients with mild symptoms and confirmed PCR testing do not routinely need chest imaging. Most patients with Findings of COVID-19 Pneumonia can safely be managed at home unless clinically unstable, at high-risk of decompensation, or with pneumonia involving >50% of lung parenchyma. Where possible, portable chest X-rays are usually sufficient and require less personnel.

Consider chest x-ray in these circumstances:

1. High clinical concern for concomitant lobar pneumonia, CHF, TB, or other etiology that could be discovered on plain film.
2. Patients with oxygen saturation < 92% on supplemental oxygen, increased work of breathing, or new decompensation to rule out new or secondary causes
3. High clinical suspicion but negative PCR testing (patient could have a false negative test or have been tested too early in the course).
4. Sudden clinical change in a known COVID patient
5. To check critical care interventions (line and endotracheal tube placement)

Tool: BWH Guide on Radiology in COVID and Guidance for Radiologists

CT ScanCopy Link!

CT scan plays no role as a screening test for patients for COVID-19, for either diagnosis or exclusion (Simpson).

CT can be used if there is a concern for other pathology. Consider CT in these circumstances:

1. High clinical suspicion for pulmonary embolism (angiogram contrast scan)
2. High clinical concern for concurrent abscess, empyema, loculated effusion, significant hemoptysis, pneumomediastinum, etc or if clinician feels it would substantively change management

Tool: BWH Guide on Radiology in COVID and Guidance for Radiologists

Tool: Radiopedia on COVID

UltrasoundCopy Link!

Serial ultrasound is showing promise as a low-cost method to assess disease progression. Although ultrasound findings in COVID-19 have been shown to correlate with CT scan results, the false negative rate of ultrasound is not currently known (Zani et al). A standardized approach using 12 designated zones has been proposed and is strongly recommended to allow for serial comparison (Kruisselbrink et al; Convissar et al).

Tool: POCUS 101 Complete Guide to Lung Ultrasound

Patients with Comorbid DiseasesCopy Link!

Updated Date: December 20, 2020

Patients with chronic conditions have specific risks and needs related to COVID-19 diagnosis, treatment, and social support (e.g. to allow safe isolation/quarantine if needed.) Patients with diabetes, hypertension, heart disease, and obesity have been shown to have higher rates of hospitalization and severe illness due to COVID-19. (See Prognostic Indicators)

Relevant comorbidities are covered in greater detail in different chapters, and include the following:

• Diabetes
• Underlying heart disease, particularly Heart Failure
• Hypertension
• Obesity
• Underlying Lung Disease: Chronic Obstructive Pulmonary Disease, prior TB, etc.
• Chronic Kidney Disease
• Chronic Liver Disease
• Hematologic conditions: Oncologic Disease, Sickle Cell Disease, etc
• Immune deficiency including Immunosuppressive Medications and HIV.

• Immunosuppressed patients may have atypical presentations of COVID-19 (e.g no fever). Patients with HIV who present with respiratory symptoms should be evaluated for TB in addition to COVID-19 as clinically indicated.

Management of existing medications is an important consideration in these patients. These medications are discussed in Treatments for Comorbid Diseases and may include the following.

• ACE inhibitors
• Immunosuppressants
• Nonsteroidal anti-inflammatory drugs
• Steroids
• Inhalers

Interfacility TransferCopy Link!

Updated Date: January 11, 2021

Reasons to transferCopy Link!

There are many potential reasons to transfer a COVID19 patient to another facility including:

• Need for higher levels of oxygen delivery
• Higher Monitoring Capacity
• Intubation and Mechanical Ventilation
• Renal Failure Requiring Renal Replacement Therapy
• Hemodynamic Support
• Specialty care
• Proning or other ICU level nursing care
• ECMO

When deciding whether or not to transfer, consider:

1. Resources and specialty service availability: What resources are currently needed or will soon be needed for patient care? Are those resources available at the current facility? Are they available at the receiving facility? Consider specialized and subspecialized services such as critical care, OB/GYN, pediatrics/neonatology, and surgical specialty teams.
2. Receiving facility capacity: Does the receiving facility have sufficient capacity to accept the patient? Receiving facilities that may normally be able to accept transfers may be overburdened as a result of the COVID-19 pandemic. Prior to transfer, the receiving facility should be contacted to discuss the transfer and verify that they have adequate resources and space to accept the transfer.
3. Patient goals of care: What are the goals of care for the patient and family, and how does transfer fit within those goals? For example, unless there is another reason for transfer, a patient who does not want intubation and mechanical ventilation may not benefit from transfer to a facility where these services are available
4. PPE availability: Is adequate PPE available for transfer, and at the receiving facility?
5. Stabilization: Has the patient been stabilized as much as is reasonably possible at the current facility, or do the benefits of transfer outweigh the risks? For example, if a patient is currently at a facility without surgery capacity or the ability to perform blood transfusions, it may not be possible to fully stabilize a patient with an intra-abdominal hemorrhage and the patient may need to be transferred while still unstable. Patients should always be transferred with medications and supplies needed for ongoing treatment en route.

Stabilization Prior to TransferCopy Link!

A full discussion on stabilization for transfer is beyond the scope of this site. For the transfer of COVID19 pneumonia patients the top concern is generally the amount of oxygen required by the patient safe for transport and whether to intubate prior to transfer. This is especially true as patients considered for transfer often have a rapidly worsening trajectory and are at high risk for deterioration.

Whether to Intubate Prior to TransferCopy Link!

Intubation should not be done if it is not indicated (see Candidacy for Intubation). Intubation carries risks, especially in certain patients (e.g. patients with right heart failure or a difficult airway). The decision about whether to intubate prior to transfer should balance risks and benefits and take into consideration the following questions:

1. Is the patient likely to require intubation en route?

1. Consider the current clinical status of the patient (including work of breathing, vital signs, and mental status).
2. Consider what the projected clinical course for the patient is over the time it will take for them to arrive at the receiving facility.

1. If a patient is rapidly worsening (including a rapidly escalating oxygen requirement), intubation may be appropriate before departure regardless of transport time.

3. If a patient is slowly worsening, but does not currently warrant intubation, transport without intubation may be appropriate if transport time is brief, while intubation prior to transfer may be needed if transport times are prolonged

2. Is safe intubation feasible at the transferring facility? Is the transporting team able to perform a safe intubation? If neither is possible, maximize oxygen and other respiratory support (such as non-invasive ventilation, if available) for transport.
3. Is emergent intubation possible during the transfer? Intubation during transfer may not be possible or may be higher-risk depending on provider training, vehicle space and layout, equipment available, and road conditions during transport. If emergent intubation during transfer would be difficult or impossible, intubation prior to transfer may be indicated.
4. Are there conditions that would make emergent intubation challenging? If so and there is possibility the patient may need intubation en route, early intubation in a controlled setting prior to transfer may be preferred. This is particularly relevant if there is:

1. Known or suspected difficult airway. Challenging airways are always difficult to manage in emergent situations, and even more so during transport when equipment is limited.
2. Hemodynamic instability. Unstable patients are difficult to intubate under controlled circumstances and even more challenging to manage during an emergent intubation during transport.

5. What is the capacity for monitoring, sedation and ventilation available during transport?

1. Consider the level of training of personnel accompanying the patient, and the availability of battery-powered transport ventilators versus need for bag-valve mask ventilation during transport.
2. In settings where transport of ventilated patients is uncommon, ensure that transport ventilators can connect to the available oxygen canisters. Ensure all ventilators have sufficient back up electrical supplies, and that providers are trained to bag patients as a back up.
3. When transport resources are limited, it may be necessary to send trained medical staff with the patient to manage advanced equipment.
4. In settings where monitored transport is not possible and where medical staff cannot accompany the patient, risks and benefits of intubation prior to transfer should be carefully weighted, as a dislodged endotracheal tube or an accidental disconnect of a ventilator can be fatal.

6. Can the receiving facility manage an intubated patient? It is important that the receiving facility has the capacity and resources to manage an intubated patient. Capacity may fluctuate depending on patient volume at the receiving facility.
7. Is the patient nearing the limits of oxygen delivery capability of the transport system? See below for specifics on air transport. Generally, mechanical ventilation for intubated patients consumes less oxygen supply than non-intubated patients on oxygen delivery devices with high oxygen flows (e.g. high flow nasal cannula or CPAP/BIPAP with a significant leak).

Calculating Transport Oxygen NeedsCopy Link!

Non-intubated patients on oxygen delivery devices with high oxygen flows (e.g. high flow nasal cannula, non-rebreather facemask, CPAP/BIPAP/NIPPV) may rapidly exhaust or exceed the available oxygen supply during transport. This can be life threatening.

1. Calculate total oxygen demand in advance. For example, for an 8-hour transport time, a patient on a non-rebreather facemask at 15 liters per minute will require either 2 portable oxygen concentrators (may vary depending on device output) and a reliable portable power generator, or two full J cylinders (See Oxygen Cylinder Duration Calculator).
2. Factor in a buffer in case oxygen demand increases, or the trip is longer than expected.
3. Make sure there is at least one power backup for electrically-powered delivery devices.

Additional air transport needs: During air transport barometric pressure drops, while FiO2 stays constant. The result is less partial pressure of oxygen delivered to the alveoli and the volume expansion of any trapped gas. This can precipitate the deterioration of a patient in two ways:

1. Worsening hypoxia at altitude. Pressurized aircraft are generally maintained at the equivalent of 5000ft (~1500m) to 8000ft (~2500m) above sea level. This is roughly the equivalent of three quarters of the oxygen delivered at sea level that is delivered in each breath. The effective altitude during transport should be accounted for when estimating oxygen needs during transport. At higher effective altitudes more oxygen will be required and less potential oxygen can be delivered than at sea level (i.e. a patient on requiring 100% FiO2 with an SpO2<100% at sea level, will desaturate when brought to altitude).
2. Air transport can lead to expansion of gas in body cavities and can lead to pneumothorax or tension pneumothorax. Providers should be trained to recognize tension pneumothorax and perform a needle decompression if needed.

Other Factors that May Affect Transfer DecisionsCopy Link!

Tool: Tools for Interfacility Transfer and Documentation (OCC)

Tool: Interfacility Transfer Checklist

Tool: IPC Guidelines for Interfacility Transport Without Ambulance Systems (PIH)

Tool: Algorithm for COVID-19 Triage and Referral by WHO

Tool: Medical Transport Accreditation Standards, 11th Edition by Commision on Accreditation of Medical Transport Systems