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).
- Fever, 44-94%
- 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.
- Children are less likely to have fever or cough (Bialek et al).
- Cough, 68-83%
- Anosmia and/or ageusia (loss of sense of taste and/or smell) ~70%
- Upper respiratory symptoms (sore throat, dripping nose, nasal or sinus congestion), 5-61%
- Shortness of breath, 11- 40%
- Fatigue, 23-38%
- Muscle aches 11-63%
- Headache 8-14%
- Confusion 9%
- Gastrointestinal symptoms (nausea, vomiting, diarrhea), 3-17%
Literature Review: University of Washington Literature Report (Clinical Characteristics)
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.
- 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).
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.
- Fever: 12 days
- Shortness of breath: 13 days
- Cough: 19 days
- Multi-System Inflammatory Syndrome in Children (MIS-C): 6 days (range 4-8 days).
- Sepsis: median onset 9 days (range 7-13 days)
- Acute Respiratory Distress Syndrome (ARDS): median onset 12 days (range 7-15 days)
- Need for mechanical ventilation: median onset 10 days (range 3-12.5 days)
- Acute cardiac injury: median onset 15 days (range 10-17 days)
- Acute kidney injury: median onset 15 days (range 13-19.5 days)
- Secondary infection: median onset 17 days (range 13-19 days)
- Death: Median 18.5 days, interquartile range 15-22 days (Zhou et al)
- Illness severity has been noted to have two peaks at ~14 days and ~22 days (Ruan et al)
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.
- Asymptomatic infection is present in at least 20% of cases, maybe more (Bi et al; Mizumuto et al; Pollan et al).
- Mild symptoms to mild pneumonia: 81-91% of symptomatic patients
- Severe symptoms (need for supplemental oxygen, or >50% lung involvement): 9-14% of patients
- Critical symptoms (respiratory failure, shock, multiorgan dysfunction): approximately 5% of patients (Wu et al).
- Among critically-ill patients, many receive mechanical ventilation. Median time on 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).
Updated Date: May, 2020
Multiple factors have been associated with worse prognosis in people infected with SARS COV-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).
- Children are less likely to have severe disease, but pediatric deaths have been reported (Bialek et al).
- Children appear to be as likely to contract the infection as adults, although symptomatic cases of children are more rare (Bi et al).
- Comorbidities: The following conditions are associated with more severe COVID-19 disease and are often associated with worse outcomes (Fang et al; Guan et al; Yang et al; Zhang et al; Chen et al; Tang et al; Zhou et al; WHO-China Joint Mission on COVID-19; Yu et al).
- Coronary Artery Disease
- Chronic Lung Disease (Though Asthma may be an exception)
- Malignancy (cancer)
- Race: Please see Health Equity for a discussion on racial differences in COVID infection and severity.
- 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).
- 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.
Normal ranges (For many US labs, units and values may vary)
White Blood Cell Count (WBC)
> 10 K/uL (K/uL=10^3/uL)
Male and Female- Adults: 3.4-9.6 x10^3/uL
< 1.00 K/uL (K/uL=10^3/uL)
Male and Female- Adults: 0.95-3.07 x10^3/uL
< 150 K/uL (K/uL=10^3/uL)
Male Adults: 135-317 x 10^3/uL
Female Adults: 157-371 x10^3/uL
> 1.5 mg/dL
Male Adults: 0.74-1.35 mg/dL
Female Adults: 0.59-1.04 mg/dL
< 3 g/dL
Alanine transaminase (ALT)
> 40 U/L
Males: 7-55 U/L
Females: 7-45 U/L
Creatinine kinase (CK)
> 185 U/L
Males: 39-308 U/L
Females: 26-192 U/L
Troponin T, high-sensitivity (hs-TnT)
> ~20 ng/L
Male <23 ng/L
Female <15 ng/L
C-reactive protein (CRP)
> 125 mg/L
< or =8.0 mg/L
Lactate dehydrogenase (LDH)
> 245 U/L
Adults: 122-222 U/L
> 300 ug/L (severe disease); Ferritin > 1000 ug/L (death)
Males: 24-336 ug/L
Females: 11-307 ug/L
Interleukin 6 (IL-6)
> 10 pg/mL
< or =1.8 pg/mL
> 1000 ng/mL
< 250 ng/mL
> 0.5 ng/mL
< or =0.15 ng/mL
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%
- 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.
Updated Date: December 16, 2020
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).
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).
Updated date: December 18, 2020
- Autopsy studies indicate universal damage to pulmonary tissue (Falasca et al; Elsoukkary et al). Pulmonary histology of COVID-19 shows bilateral diffuse alveolar damage, desquamation of pneumocytes, pulmonary edema, hyaline membrane formation, inflammatory cell infiltrates, and multinucleated giant cells, as well as some evidence of direct viral injury (Xu et al; Geng et al). Vascular involvement in the lung is also quite common, with microthrombi, endotheliitis, severe capillaritis, vascular complement deposition, and pulmonary thromboemboli, often in small and mid-sized vessels (Calabrese et al).
- Cardiac injury and thrombotic complications are widely prevalent, including cardiac inflammatory infiltrates, epicardial edema, and pericardial effusion in some autopsies (Falasca et al; Elsoukkary et al; Geng et al).
- Acute kidney injury, while common in hospitalized COVID patients, was found to be mild in post-mortem patients with theoretical potential for recovery (Santoriello et al).
- Neurologic lesions in autopsy series of 43 patients (not necessarily with neurologic manifestations) showed fresh ischemic lesions in 14%, and neuroinflammatory changes with infiltration of cytotoxic T lymphocytes most pronounced in the brainstem (also cerebellum and meninges) (Matschke et al). In patients with significant neurologic decline, more severe findings have been noted including hemorrhagic lesions through the cerebral hemispheres, marked axonal injury, areas of necrosis, and pathology similar to acute disseminated encephalomyelitis (ADEM). (See e.g. Reichard et al).
Literature Review: University of Washington Literature Report (Geographic Spread)
Literature Review: University of Washington Literature Report (Modeling and Prediction)
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).
COVID-19 transmission is primarily human-to-human following a suspected animal-to-human initiating event (Li et al). It is thought that it may have emerged from racoon dogs or civets, but this is still being investigated (Mallapaty). The virus was initially recognized in December 2019 by Chinese authorities in the setting of cases of pneumonia that seemed to be clustered around a seafood market in Wuhan, Hubei Province (Wuhan Municipal Health Commission, 2019).
This section is in process
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). Viral genomes have been published to GenBank from diverse geographies.
Updated Date: December 19, 2020
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 (Bullard et al). Patients who have higher levels of virus in their respiratory tracts and oropharynx are most infectious, irrespective of symptom status. Symptom status does not seem to correlate predictably with viral load (Walsh et al; Lee S. et al; Zou L et al).
Upper airway viral load peaks within ~5 days of symptom onset, followed by decline (Wölfel et al; Young et al). Consequently, patients appear to be most infectious in the 2-3 days before symptom onset and the 2-3 days after (Ferretti et al). PCR detection continues for a median of 20 days from time of symptom onset, with an interquartile range 17-24 days (Zhou et al). There are rare cases that remain positive up to ~60 days after infection (McKie et al). However, the virus is very rarely culturable (our closest proxy to infectivity) after 9 days (Cevik et al). The culture data underlies the newer guidance (after November 2020) about quarantine time. See testing for a diagram of test positivity compared with infectivity and symptoms.
Asymptomatic, 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. 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).
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 CDC has changed it’s recommendations on the duration of isolation and quarantine as well as releasing patients from isolation (Cevik et al).
We do not yet know how all available and pending vaccines will perform with respect to asymptomatic infection. This is an evolving area of research, but the data suggests that being vaccinated does NOT preclude asymptomatic infection or transmission from one person to another, and therefore most global agencies recommend that people who have been vaccinated continue transmission reduction measures like masks and distancing (CDC).
Updated Date: December 18, 2020
Literature Review: University of Washington Literature Report (Transmission)
Basic Reproduction Number (R0)
Tool: For global estimates of R0, see here. For the United States, state-by-state estimates of R0 are available here (data from The COVID Tracking Project). Please keep in mind these are merely estimates and all models are fallible.
R0 (R-naught) is a measure of transmissibility. It represents the theoretical number of secondary infections from an infectious individual. This is a property both of the infectiousness of the virus and the behaviors of humans to decrease spread.
- An R0 > 1 is consistent with sustained outbreak.
- An R0 < 1 means an epidemic is declining.
The R0 for COVID-19 is likely similar to, or slightly higher than, many other respiratory viruses, but because it is so highly influenced by human behavior, it can be changed. The initial R0 of COVID in Wuhan in the absence of containment measures was thought to be about 2.5 (Majumder et al). However, R0 declines with control measures (Zhao et al; Riou et al; Flaxman et al; Read et al; Shen et al).
The pre-control R0 of 2.5 is:
- 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)
It is believed that COVID-19 transmission primarily occurs through liquid respiratory particles that travel through the air between people who are within a distance of about 2 meters of one another. Growing evidence indicates that transmission beyond a distance of 2 meters is also possible, especially in poorly-ventilated spaces and with periods of exposure exceeding 30 minutes (Lancet Editorial).
Modes of transmission have been a contested topic. The discussion has been complicated by lack of standardized definitions and usage of terms such as large droplets, small droplets, and aerosols. It is believed that most transmission occurs with droplets produced when a person coughs or sneezes, though other modes also occur.
Droplet transmission: liquid respiratory particles vary in size and are produced during breathing, talking, singing, coughing, and sneezing (CDC). Larger particles of 60-100 micrometers typically do not travel through the air farther than 2 meters (Lancet Editorial).
Airborne/Aerosol transmission: very small respiratory droplets, often called aerosols, may remain suspended in the air and travel a distance exceeding 2 meters (Lancet Editorial). The risk of producing aerosols is heightened during coughing, sneezing, and certain medical procedures (WHO-China Joint Mission on COVID-19). Aerosolized particles appear to remain in the air for at least 3 hours (Van Dorelmalen et al).
Fomite (objects and surfaces) transmission: transmission may occur through touching contaminated objects before touching the mouth, nose, or eyes, but this is an inefficient mode of transmission (Kampf et al). While SARS-CoV-2 can persist for days on some surfaces, attempts to culture from surfaces have been unsuccessful. Viral particles have been shown to survive < 24h on cardboard and < 72h on plastic or steel (Van Dorelmalen et al). In cases of suspected transmission through fomites and direct contact, full exclusion of respiratory transmission as the actual mode has not been possible. Transmission through the handling of contaminated objects is presumed to be unusual (Meyerowitz et al). Adherence to standard precautions and disinfection of equipment and surfaces is still indicated (Mondelli et al).
Water and sewage: Persistence of SARS-CoV-2 virus in drinking-water is possible; indeed, some organizations and public health departments are tracking COVID infection rates by measuring waste-water RNA (see CDC wastewater testing, and Larsen et al). There is no evidence to date about survival of the virus in water or sewage, but it is likely to become inactivated significantly faster than non-enveloped human enteric viruses with known waterborne transmission (such as adenoviruses, norovirus, rotavirus and hepatitis A).
- 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.
- Urine does not appear to contain viral ribonucleic acid (Wölfel et al).
- 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).
- 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).
- 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 contacts of an index case appear more likely to contract the virus than other contacts (Bi et al). Most transmission events occur within households (Luo et al). The household secondary attack rate (e.g. number of people who get infected from an index case) is very variable, thought to be about 17.2% in one meta analysis (Fung et al), though very few studies tested more than once, so many cases may not have been missed The results ranged from 10.3-32.4% when contacts were tested at least twice. One recent study that did daily testing estimated SAR at 35% excluding those who had positive tests at enrollment, 53% including cases positive on enrolment. 75% of secondary cases occurred within 5 days of the index patient’s symptom onset (Grijalva et al). However, when prevalence increases, more community (meaning with no known exposure) transmissions tend to occur, highlighting the necessity of non-pharmaceutical interventions (e.g. masks) coupled with public health strategies such as sentinel and syndromic surveillance.
Super-Spreading Events 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).
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). However, large-scale studies of over 500,000 contacts of 85,000 infected cases in India have noted that children are a significant source of spread, even despite school closures (Laxminarayan et al). This thorough review of the literature on school transmission and safety summarizes some of the unique challenges and recommendations (Massachusetts General Hospital COVID-19 Resource Library). Decisions on whether or not to open schools depends significantly on local policy and local epidemiology.
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.
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).
This section is in process.
Updated Date: December 18, 2020
The majority of patients with RT-PCR-confirmed COVID-19 develop antibodies against the virus (Zhao et al; Wang et al). These two large series of serial samples found antibodies in 161/173 and 308/310 patients respectively. Time to seroconversion, correlation with protection, and durability of immunity, continue to be studied.
When assessing research studies, details may depend on exactly which antibodies are being assessed(e.g,. IgA/IgM/IgG or total antibody, antibodies to the nucleocapsid vs those to the spike protein, or whether the antibodies are “neutralizing” -- for example, antibodies directed against the receptor-binding domain (a component of the spike protein) may appear earlier than antibodies to other antigens (To et al; Okba et al).
Seroconversion (detection of circulating antibodies) typically occurs 7-14 days after symptom onset (Deeks et al; Huang et al). In one study of 173 patients, 100% were seropositive (total antibody) at 15 days (Zhao et al).
- Although IgM seroconversion is often thought of as occurring before seroconversion for IgG, this has not been consistently observed for SARS-CoV-2 (e.g., Qu et al; Xiang et al; Wang et al; Zhao et al).
- IgA antibodies are important in mucosal immunity and may play an important role in the response to SARS-CoV-2 (Sterlin et al; Wang et al), but data are currently limited (Deeks et al).
- The sensitivity of serology (IgM or IgG) may be higher than that of PCR by the second week of illness (day 8 in Zhao et al, day 6 in Guo et al), based on studies with serial samples from individual patients.
- Antibody detection may identify cases with negative upper airway PCR but high clinical suspicion when timed appropriately; Guo et al found positive IgM in 54 of 58 probable cases without detectable nucleic acid.
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.
- 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.
- 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.
- Fortunately, over 90% of people seropositive for SARS-CoV-2 appear to have detectable neutralizing antibody responses (Wajnberg et al).
Cross-reactivity occurs when a pre-existing immune response to seasonal human coronaviruses recognizes SARS-CoV-2. It has been seen in both T-cell (e.g., Mateus et al) and humoral (e.g., Ng et al) arms of the immune system. This presence or absence of this response has been hypothesized to contribute to variable outcomes in COVID-19 (Beretta et al). A possible altered immune response due to pre-existing antibodies has also raised the possibility of antibody-dependent enhancement after SARS-CoV-2 vaccination or convalescent plasma therapy. Fortunately, such enhancement has not been reported to date (Wen et al).
Reinfection refers to individuals who have been infected and cleared the original virus, but again show viral replication after exposure to a new SARS-CoV-2 virus. This has been documented in a handful of cases, most often in patients with weakened immune systems.
- RT-qPCR alone does not distinguish reinfection with a new SARS-CoV-2 virus from prolonged or recrudescent infection with the same virus (Falahi et al). Conclusive demonstration of reinfection requires genomic sequencing of the virus during initial and subsequent infections and analysis to show the two viruses are too different to have incubated in a single host.
Tool: Track Cases of Reinfection.
The duration of immunity after infection is not yet conclusively known (Iwasaki), since COVID-19 is a new infectious disease. Host factors likely play a significant role, including immune status, age, and severity of initial infection. Studies documenting decay of IgG antibodies may underestimate immunity, since T-cell responses likely also play a significant role (Karlsson et al).
- Patients with mild infection lose detectable antibodies more quickly but appear to have an immune memory that may allow them to rapidly produce antibodies again on re-exposure (Stephens et al).
- Longer term analysis of 2003 SARS-CoV-1 infection showed IgG and neutralizing antibody titers peaked at 4 months and diminished over a 3-year follow up period (Cao et al). In a cohort of 23 patients with a history of SARS-CoV-1 infection, specific IgG Ab to SARS-CoV-1 was undetectable in 91.3% of former patients after 6 years (Tang et al).
At the end of 2020, there were approximately 75 vaccines worldwide in phases I through III of clinical research, 5 in limited use, and ~2 holding approvals (depending on country) for full use after completion of phase III (not counting trials underway for repurposing of pre-existing vaccines). Most of these vaccines fall into one of 4 categories:
- Genetic vaccines (typically lipid envelopes carrying SARS-CoV-2 genetic material into cells)
- Viral vector vaccines (repurposed viruses such as adenovirus carrying SARS-CoV-2 genetic material into cells)
- Protein-based vaccines (delivering coronavirus proteins only)
- Traditional “inactivated/attenuated” coronavirus vaccines.
The best-studied vaccines are the mRNA vaccines produced by Pfizer/BioNTech and Moderna, and key “viral vector” vaccines include adenovirus-vector examples produced by Oxford/AstraZeneca, CanSino Biologics (China), the Russian Ministry of Health, and Johnson & Johnson/Beth Israel Deaconess Medical Center.
- The mRNA vaccines: code for the coronavirus “spike” protein to induce an immune response mediated by antibodies and T cells. Both Moderna and Pfizer versions have a greater than 90% efficacy after 2 doses (94.1 and 95%, respectively), although longer-term study is needed to determine how immunity and infectivity change over time. Due to the temperature-sensitivity of genetic material (Simmons-Duffin), these vaccines require somewhat different but very cold storage and transportation environments as well as restrictions on how long they can be kept at room temperature.
- 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.
Efficacy of vaccines. Efficacy data is currently available for three vaccines. The Pfizer/BioNTech vaccine in its EUA cited efficacy of 95% at preventing symptomatic infection. Asymptomatic infection was not studied in this trial (Pfizer EUA). The Moderna vaccine showed 94% efficacy, and asymptomatic infection rates are not yet known after two doses, but after a single dose it reduces asymptomatic infection by 63% (data after the second shot is forthcoming, Moderna EUA). The Oxford/AstraZeneca vaccine had an efficacy of 90% at one dosing schedule (the now intended schedule) though they had two different dosing schedules and the other one did not perform as well. In the intended dosing schedule, it demonstrates 59% efficacy in preventing asymptomatic infection (Ledford; Knoll et al).
Adverse events/Reactogenicity: Most observed adverse events in trials of these vaccines are injection-related or reflect the body’s expected immune response. Many people feel ill following vaccine administration for about 1-3 days, especially after the second dose of the vaccine, and this is expected and does not mean that you have been infected with coronavirus.
Ability to transmit to others: We do not yet have information about viral transmission, but based on asymptomatic infection rates it is likely still possible to transmit the virus to others even if vaccinated and asymptomatic. Please see Transmission.
This section is forthcoming
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
- 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).
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).
This section is in process
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 e 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:
- 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).
- Exposure risk on public transit: more likely to rely on public transport to attend work (Pew Research).
- Exposure risk in shared living spaces: more likely to cohabitate with others (Census).
- 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).
- 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.
- Racism in healthcare delivery: many minority patients experience consciously- and subconsciously-biased health systems and providers when they seek care.
- Chronic stress: stress and allostatic load can affect immune function.
- Environmental factors: risk for severe COVID has been associated with poorer air quality (Wu et al; Pozzer et al).
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).
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).
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 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).
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 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.
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).
During the pandemic, some strategies for providers to help patients with disabilities include:
- When available, masks with clear impermeable windows can improve communication for those who are deaf of hard of hearing.
- Seeing photographs of clinical care team members without their masks can relieve anxiety.
- Trauma-informed care can help build trust (CDC guide).
- Consider exceptions to Visitor Policies for patients who need support from caregivers in order to participate in care.
- 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.
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).
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 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).
Tool: Harm Reduction Strategies
For people who use substances during the COVID-19 pandemic (Harm Reduction Coalition, English/US focus)