Mortality
The leading cause of death is respiratory failure from acute respiratory distress syndrome (ARDS).[894]Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080116/
http://www.ncbi.nlm.nih.gov/pubmed/32125452?tool=bestpractice.com
The overall pooled mortality rate from ARDS in COVID-19 patients is 39%; however, this varies significantly between countries (e.g., China 69%, Iran 28%, France 19%, Germany 13%).[895]Hasan SS, Capstick T, Ahmed R, et al. Mortality in COVID-19 patients with acute respiratory distress syndrome and corticosteroids use: a systematic review and meta-analysis. Expert Rev Respir Med. 2020 Jul 31 [Epub ahead of print].
https://www.tandfonline.com/doi/full/10.1080/17476348.2020.1804365
http://www.ncbi.nlm.nih.gov/pubmed/32734777?tool=bestpractice.com
Risk factors for respiratory failure include older age, male sex, cardiovascular disease, laboratory markers (such as lactate dehydrogenase, lymphocyte count, and C-reactive protein), and high viral load on admission.[896]de la Calle C, Lalueza A, Mancheño-Losa M, et al. Impact of viral load at admission on the development of respiratory failure in hospitalized patients with SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis. 2021 Jan 7 [Epub ahead of print].
https://link.springer.com/article/10.1007/s10096-020-04150-w
http://www.ncbi.nlm.nih.gov/pubmed/33409832?tool=bestpractice.com
People <65 years of age have a very small risk of death even in pandemic epicentres, and deaths in people <65 years of age without any underlying conditions is rare.[897]Ioannidis JPA, Axfors C, Contopoulos-Ioannidis DG. Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters. Environ Res. 2020 Sep;188:109890.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327471/
http://www.ncbi.nlm.nih.gov/pubmed/32846654?tool=bestpractice.com
Mortality rates have decreased over time despite stable patient characteristics. In one study among patients with critical illness admitted to an intensive care unit at an academic health system in the US, the mortality rate decreased from 43.5% to 19.2% over the study period.[898]Anesi GL, Jablonski J, Harhay MO, et al. Characteristics, outcomes, and trends of patients with COVID-19-related critical illness at a learning health system in the United States. Ann Intern Med. 2021 Jan 19 [Epub ahead of print].
https://www.acpjournals.org/doi/10.7326/M20-5327
http://www.ncbi.nlm.nih.gov/pubmed/33460330?tool=bestpractice.com
In another study in the UK, adjusted in-hospital mortality decreased from 52.2% in the first week of March 2020 to 16.8% in the last week of May 2020.[899]Navaratnam AV, Gray WK, Day J, et al. Patient factors and temporal trends associated with COVID-19 in-hospital mortality in England: an observational study using administrative data. Lancet Respir Med. 2021 Feb 15 [Epub ahead of print].
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30579-8/fulltext
This may reflect the impact of changes in hospital strategy and clinical processes, and better adherence to evidence-based standard of care therapies for critical illness over time, such as high-flow nasal oxygen to avert intubation, prone positioning, and decreased use of mechanical ventilation. Further studies are needed to confirm these results and investigate causal mechanisms.
Infection fatality rate (IFR)
Defined as the proportion of deaths among all infected individuals including confirmed cases, undiagnosed cases (e.g., asymptomatic or mildly symptomatic cases), and unreported cases. The IFR gives a more accurate picture of the lethality of a disease compared with the case fatality rate.
Approximately 10% of the global population may have been infected by October 2020, with an estimated overall IFR of 0.15% to 0.2% (0.03% to 0.04% in those <70 years of age).[900]Ioannidis JPA. Global perspective of COVID-19 epidemiology for a full-cycle pandemic. Eur J Clin Invest. 2020 Oct 7:e13421.
https://onlinelibrary.wiley.com/doi/abs/10.1111/eci.13423
http://www.ncbi.nlm.nih.gov/pubmed/33026101?tool=bestpractice.com
The US Centers for Disease Control and Prevention’s current best estimate of the IFR, according to age (as of 10 September 2020):[136]Centers for Disease Control and Prevention. COVID-19 pandemic planning scenarios. 2020 [internet publication].
https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html
0 to 19 years – 0.003%
20 to 49 years – 0.02%
50 to 69 years – 0.5%
≥70 years – 5.4%.
Based on these figures, the overall IFR for people <70 years of age is approximately 0.18%.
The IFR can vary across locations. A meta-analysis reports the point estimate of the IFR to be 0.68% across populations, with high heterogeneity (as of July 2020). The rate varied across locations from 0.17% to 1.7%.[901]Meyerowitz-Katz G, Merone L. A systematic review and meta-analysis of published research data on COVID-19 infection-fatality rates. Int J Infect Dis. 2020 Sep 29 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524446/
http://www.ncbi.nlm.nih.gov/pubmed/33007452?tool=bestpractice.com
Among people on board the Diamond Princess cruise ship, a unique situation where an accurate assessment of the IFR in a quarantined population can be made, the IFR was 0.85%. However, all deaths occurred in patients >70 years of age, and the rate in a younger, healthier population would be much lower.[902]Rajgor DD, Lee MH, Archuleta S, et al. The many estimates of the COVID-19 case fatality rate. Lancet Infect Dis. 2020 Jul;20(7):776-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270047/
http://www.ncbi.nlm.nih.gov/pubmed/32224313?tool=bestpractice.com
These estimates have limitations and are likely to change as more data emerge over the course of the pandemic.
Seroprevalence studies
Estimates of the IFR can be inferred from seroprevalence studies.
Worldwide seroprevalence estimates range between 0.37% and 22.1%, with a pooled estimate of 3.38% (based on data from 23 countries as of August 2020).[903]Rostami A, Sepidarkish M, Leeflang MMG, et al. SARS-CoV-2 seroprevalence worldwide: a systematic review and meta-analysis. Clin Microbiol Infect. 2020 Oct 24 [Epub ahead of print].
https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(20)30651-0/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33228974?tool=bestpractice.com
UK: seroprevalence was 7.1% in the UK overall according to the first round of results of the UK Biobank COVID-19 antibody study. Previous infection was most common among people who lived in London (10.4%), and least common among those who lived in the south west of England and Scotland (4.4% in both).[904]Department of Health and Social Care. UK Biobank COVID-19 antibody study: round 1 results. 2020 [internet publication].
https://www.gov.uk/government/publications/uk-biobank-covid-19-seroprevalence-study-round-1-results/uk-biobank-covid-19-seroprevalence-study-round-1-results
US: less than 10% of people are thought to have detectable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies based on data from July to September 2020.[905]Bajema KL, Wiegand RE, Cuffe K, et al. Estimated SARS-CoV-2 seroprevalence in the US as of September 2020. JAMA Intern Med. 2020 Nov 24 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/10.1001/jamainternmed.2020.7976
http://www.ncbi.nlm.nih.gov/pubmed/33231628?tool=bestpractice.com
Current seroprevalence estimates for 10 sites in the US are available.
CDC: commercial laboratory seroprevalence survey data
external link opens in a new window
China: seroprevalence was 3.2% to 3.8% in Wuhan, and decreased in other Chinese cities as the distance to the epicenter increased.[906]Xu X, Sun J, Nie S, et al. Seroprevalence of immunoglobulin M and G antibodies against SARS-CoV-2 in China. Nat Med. 2020 Jun 5 [Epub ahead of print].
https://www.nature.com/articles/s41591-020-0949-6
http://www.ncbi.nlm.nih.gov/pubmed/32504052?tool=bestpractice.com
These studies suggest that the prevalence of infections is much higher than the official case counts suggest, and therefore the virus is much less lethal than initially thought.
Case fatality rate (CFR)
Defined as the total number of deaths reported divided by the total number of detected cases reported. CFR is subject to selection bias as more severe/hospitalised cases are likely to be tested.
The World Health Organization’s current estimate of the global CFR is 2.2% (as of 21 February 2021).[907]World Health Organization. Coronavirus disease (COVID-19) weekly epidemiological updates. 2021 [internet publication].
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/
This is much lower than the reported CFR of severe acute respiratory syndrome coronavirus (SARS), which was 10%, and Middle East respiratory syndrome (MERS), which was 37%.[46]Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30183-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31986264?tool=bestpractice.com
CFR varies considerably between countries.
In China, the overall CFR has been reported to be between 1.4% and 2.3% (0.9% in patients without comorbidities).[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
[908]Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-77.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158570/
http://www.ncbi.nlm.nih.gov/pubmed/32240634?tool=bestpractice.com
CFR increases with age.
In the US, the majority of deaths were in patients aged ≥65 years. The CFR was highest among patients aged ≥85 years (10% to 27%), followed by those aged 65 to 84 years (3% to 11%), then those aged 55 to 64 years (1% to 3%), and finally those aged 20 to 54 years (<1%).[7]CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19): United States, February 12 - March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-6.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w
http://www.ncbi.nlm.nih.gov/pubmed/32214079?tool=bestpractice.com
In China, the majority of deaths were in patients aged ≥60 years.[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
The CFR was highest among patients aged ≥80 years (13.4%), followed by those aged 60 to 79 years (6.4%), and then those aged <60 years (0.32%).[908]Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. Lancet Infect Dis. 2020 Jun;20(6):669-77.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158570/
http://www.ncbi.nlm.nih.gov/pubmed/32240634?tool=bestpractice.com
In Italy, the CFR was highest among patients aged ≥80 years (52.5%), followed by those aged 70 to 79 years (35.5%), and then those aged 60 to 69 years (8.5%).[909]Sorbello M, El-Boghdadly K, Di Giacinto I, et al. The Italian COVID-19 outbreak: experiences and recommendations from clinical practice. Anaesthesia. 2020 Jun;75(6):724-32.
https://onlinelibrary.wiley.com/doi/full/10.1111/anae.15049
http://www.ncbi.nlm.nih.gov/pubmed/32221973?tool=bestpractice.com
Deaths are rare in children.[7]CDC COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19): United States, February 12 - March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020 Mar 27;69(12):343-6.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm?s_cid=mm6912e2_w
http://www.ncbi.nlm.nih.gov/pubmed/32214079?tool=bestpractice.com
[21]Castagnoli R, Votto M, Licari A, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents: a systematic review. JAMA Pediatr. 2020 Sep 1;174(9):882-9.
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2765169
http://www.ncbi.nlm.nih.gov/pubmed/32320004?tool=bestpractice.com
In one study, 70% of deaths occurred in those aged 10 to 20 years, 20% in those aged 1 to 9 years, and 10% in children under 1 year of age.[910]Bixler D, Miller AD, Mattison CP, et al. SARS-CoV-2–associated deaths among persons aged <21 years: United States, February 12–July 31, 2020. MMWR Morb Mortal Wkly Rep. 2020 Sep 18;69(37):1324-9.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6937e4.htm
http://www.ncbi.nlm.nih.gov/pubmed/32941417?tool=bestpractice.com
CFR increases with the presence of comorbidities.
In China, the majority of deaths were in patients who had pre-existing underlying health conditions (10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6% for hypertension, and 5.6% for cancer).[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
CFR increases with disease severity.
The CFR is highest in patients with critical disease, ranging from 26% to 67% in studies.[4]Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51.
http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51
http://www.ncbi.nlm.nih.gov/pubmed/32064853?tool=bestpractice.com
[911]Grasselli G, Zangrillo A, Zanella A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6;323(16):1574-81.
https://jamanetwork.com/journals/jama/fullarticle/2764365
http://www.ncbi.nlm.nih.gov/pubmed/32250385?tool=bestpractice.com
[912]Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA. 2020 Mar 19;323(16):1612-4.
https://jamanetwork.com/journals/jama/fullarticle/2763485
http://www.ncbi.nlm.nih.gov/pubmed/32191259?tool=bestpractice.com
Limitations of IFR/CFR
Estimating the IFR and CFR in the early stages of a pandemic is subject to considerable uncertainties and estimates are likely to change as more data emerges. Rates tend to be high at the start of a pandemic and then trend downwards as more data becomes available.[913]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Global COVID-19 case fatality rates. 2020 [internet publication].
https://www.cebm.net/global-covid-19-case-fatality-rates/
There is currently no set case definition of a confirmed case, and case definitions vary. A positive polymerase chain reaction (PCR) result is sometimes the only criterion for a case to be recognised; however, a positive PCR test does not necessarily equal a diagnosis of COVID-19, or mean that a person is infected or infectious.[914]Mahase E. Covid-19: the problems with case counting. BMJ. 2020 Sep 3;370:m3374.
https://www.bmj.com/content/370/bmj.m3374
http://www.ncbi.nlm.nih.gov/pubmed/32883657?tool=bestpractice.com
[915]Centre for Evidence-Based Medicine; Spencer E, Jefferson T, Brassey J, et al. When is Covid, Covid? 2020 [internet publication].
https://www.cebm.net/covid-19/when-is-covid-covid/
The number of deaths reported on a particular day may not accurately reflect the number of deaths from the previous day due to delays associated with reporting deaths. This makes it difficult to know whether deaths are falling over time in the short term.[916]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Reconciling COVID-19 death data in the UK. 2020 [internet publication].
https://www.cebm.net/covid-19/reconciling-covid-19-death-data-in-the-uk/
Patients who die 'with' COVID-19 and patients who die 'from' COVID-19 may be counted towards the death toll in some countries. For example, in Italy only 12% of death certificates reported direct causality from COVID-19, while 88% of patients who died had at least one comorbidity.[913]Centre for Evidence-Based Medicine; Oke J, Heneghan C. Global COVID-19 case fatality rates. 2020 [internet publication].
https://www.cebm.net/global-covid-19-case-fatality-rates/
[917]Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020 Mar 23 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2763667
http://www.ncbi.nlm.nih.gov/pubmed/32203977?tool=bestpractice.com
Mortality rate by country
Mortality rates decreased sharply in the US over the first 6 months of the pandemic.[918]Asch DA, Sheils NE, Islam MN, et al. Variation in US hospital mortality rates for patients admitted with COVID-19 during the first 6 months of the pandemic. JAMA Intern Med. 2020 Dec 22 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2774572
http://www.ncbi.nlm.nih.gov/pubmed/33351068?tool=bestpractice.com
The number of deaths (per 100,000 population) for different countries varies:[919]Bilinski A, Emanuel EJ. COVID-19 and excess all-cause mortality in the US and 18 comparison countries. JAMA. 2020 Oct 12 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2771841
http://www.ncbi.nlm.nih.gov/pubmed/33044514?tool=bestpractice.com
South Korea – 0.7
Japan – 1.2
Australia – 3.3
Germany – 11.3
Canada – 24.6
France – 46.6
Sweden – 57.4
Italy – 59.1
US – 60.3
UK – 62.6
Spain – 65.0
Belgium – 86.8.
Prognostic factors
Prognostic factors that have been associated with increased risk of severe disease and mortality include:[920]Izcovich A, Ragusa MA, Tortosa F, et al. Prognostic factors for severity and mortality in patients infected with COVID-19: a systematic review. PLoS One. 2020;15(11):e0241955.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671522/
http://www.ncbi.nlm.nih.gov/pubmed/33201896?tool=bestpractice.com
Increasing age
Male sex
Smoking
Presence of comorbidities (e.g., hypertension, diabetes, cardiovascular or cerebrovascular disease, arrhythmias, COPD, dementia, malignancy)
Dyspnoea
Tachypnoea
Hypoxaemia
Respiratory failure
Hypotension
Tachycardia
Lymphopenia
Leukocytosis
Neutrophilia
Thrombocytopenia
Hypoalbuminaemia
Liver, kidney impairment, or cardiac injury
Elevated inflammatory markers (C-reactive protein, procalcitonin, erythrocyte sedimentation rate)
Elevated lactate dehydrogenase
Elevated creatine kinase
Elevated cardiac markers
Elevated D-dimer
Elevated interleukin-6
Consolidative infiltrate or pleural effusion on chest imaging
High sequential organ failure assessment (SOFA) score.
The most common underlying diseases in deceased patients were hypertension, diabetes, and cardiovascular diseases.[921]Javanmardi F, Keshavarzi A, Akbari A, et al. Prevalence of underlying diseases in died cases of COVID-19: a systematic review and meta-analysis. PLoS One. 2020 Oct 23;15(10):e0241265.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584167/
http://www.ncbi.nlm.nih.gov/pubmed/33095835?tool=bestpractice.com
A ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) ≤200 mmHg and respiratory failure at admission are also independently associated with an increased risk of in-hospital mortality.[922]Santus P, Radovanovic D, Saderi L, et al. Severity of respiratory failure at admission and in-hospital mortality in patients with COVID-19: a prospective observational multicentre study. BMJ Open. 2020 Oct 10;10(10):e043651.
https://bmjopen.bmj.com/content/10/10/e043651
http://www.ncbi.nlm.nih.gov/pubmed/33040020?tool=bestpractice.com
Almost half of patients who received invasive mechanical ventilation died. The mortality rate was higher in older patients >80 years (84%) compared with younger patients ≤40 years (48%).[923]Lim ZJ, Subramaniam A, Reddy MP, et al. Case fatality rates for COVID-19 patients requiring invasive mechanical ventilation: a meta-analysis. Am J Respir Crit Care Med. 2020 Oct 29 [Epub ahead of print].
https://www.atsjournals.org/doi/pdf/10.1164/rccm.202006-2405OC
http://www.ncbi.nlm.nih.gov/pubmed/33119402?tool=bestpractice.com
Hospital readmission
Approximately 9% of over 106,000 patients were readmitted to the same hospital within 2 months of discharge from the initial hospitalisation. Multiple readmissions occurred in 1.6% of patients. The median time from discharge to the first readmission was 8 days. Less than 0.1% of patients died during readmission. Risk factors for readmission include:[924]Lavery AM, Preston LE, Ko JY, et al. Characteristics of hospitalized COVID-19 patients discharged and experiencing same-hospital readmission: United States, March–August 2020. MMWR Morb Mortal Wkly Rep. 2020 Nov 13;69(45):1695-9.
https://www.cdc.gov/mmwr/volumes/69/wr/mm6945e2.htm
http://www.ncbi.nlm.nih.gov/pubmed/33180754?tool=bestpractice.com
Age ≥65 years
Presence of chronic conditions (COPD, heart failure, diabetes, chronic kidney disease, obesity)
Hospitalisation within the 3 months preceding the first COVID-19 hospitalisation
Discharge to a skilled nursing facility or with home health care.
Reinfection
There is limited information about reinfection. Recurrent RT-PCR positivity in patients 1 to 60 days after recovery ranges between 7% to 23% in studies, with an estimated pooled rate of 12%.[925]Mattiuzzi C, Henry BM, Sanchis-Gomar F, et al. SARS-CoV-2 recurrent RNA positivity after recovering from coronavirus disease 2019 (COVID-19): a meta-analysis. Acta Biomed. 2020 Sep 7;91(3):e2020014.
https://www.mattioli1885journals.com/index.php/actabiomedica/article/view/10303
http://www.ncbi.nlm.nih.gov/pubmed/32921710?tool=bestpractice.com
Patients with longer initial illness and younger age were more likely to experience recurrent RT-PCR positivity, while those with severe disease, diabetes, and a low lymphocyte count were less likely.[926]Azam M, Sulistiana R, Ratnawati M, et al. Recurrent SARS-CoV-2 RNA positivity after COVID-19: a systematic review and meta-analysis. Sci Rep. 2020 Nov 26;10(1):20692.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691365/
http://www.ncbi.nlm.nih.gov/pubmed/33244060?tool=bestpractice.com
It is currently unclear whether this is due to reinfection; whether it is due to factors such as the type of specimen collection and technical errors associated with swab testing, infection by mutated SARS-CoV-2, or persistent viral shedding; or whether the test result was a false-negative at the time of discharge.[927]SeyedAlinaghi S, Oliaei S, Kianzad S, et al. Reinfection risk of novel coronavirus (COVID-19): a systematic review of current evidence. World J Virol. 2020 Dec 15;9(5):79-90.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747024/
http://www.ncbi.nlm.nih.gov/pubmed/33363000?tool=bestpractice.com
Studies have repeatedly reported positive RT-PCR tests for up to 90 days after initial infection; therefore, it is most likely that these cases are actually protracted initial infections. It is important to note that although persistent viral shedding has been reported for up to 90 days after the onset of infection, replication-competent virus has not been identified 10 to 20 days after the onset of symptoms (depending on disease severity).[928]Arafkas M, Khosrawipour T, Kocbach P, et al. Current meta-analysis does not support the possibility of COVID-19 reinfections. J Med Virol. 2020 Sep 8 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/pubmed/32897549?tool=bestpractice.com
A cohort study of 200 patients with past infection found that despite persistent pharyngeal RT-PCR positivity for up to 90 days after recovery, transmission to close contacts was not observed, indicating that these patients are not contagious at the post-symptomatic stage of infection.[929]Vibholm LK, Nielsen SS, Pahus MH, et al. SARS-CoV-2 persistence is associated with antigen-specific CD8 T-cell responses. EBioMedicine. 2021 Jan 30;64:103230.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00023-2/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33530000?tool=bestpractice.com
True cases of reinfection (defined as two episodes of infection at least 3 months apart by virus strains with different genomic sequences) have been reported in Hong Kong, India, Ecuador, and Belgium.[930]Parry J. Covid-19: Hong Kong scientists report first confirmed case of reinfection. BMJ. 2020 Aug 26;370:m3340.
https://www.doi.org/10.1136/bmj.m3340
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[931]Gupta V, Bhoyar RC, Jain A, et al. Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2. Clin Infect Dis. 2020 Sep 23 [Epub ahead of print].
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1451/5910388
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[932]Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic SARS-CoV-2 reinfection by a phylogenetically distinct strain. Clin Infect Dis. 2020 Sep 5 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499557/
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[933]Prado-Vivar B, Becerra-Wong M, Guadalupe JJ, et al. A case of SARS-CoV-2 reinfection in Ecuador. Lancet Infect Dis. 2020 Nov 23 [Epub ahead of print].
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30910-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33242475?tool=bestpractice.com
Two possible cases of reinfection have also been reported in the US; however, while different genomic variants were responsible for the two episodes in both men, the infections occurred less than 2 months apart.[934]Larson D, Brodniak SL, Voegtly LJ, et al. A case of early re-infection with SARS-CoV-2. Clin Infect Dis. 2020 Sep 19 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543357/
http://www.ncbi.nlm.nih.gov/pubmed/32949240?tool=bestpractice.com
[935]Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis. 2020 Oct 12 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550103/
http://www.ncbi.nlm.nih.gov/pubmed/33058797?tool=bestpractice.com
Cases of reinfection with SARS-CoV-2 variants have been reported in Brazil, the UK, and South Africa.[936]Zucman N, Uhel F, Descamps D, et al. Severe reinfection with South African SARS-CoV-2 variant 501Y.V2: a case report. Clin Infect Dis. 2021 Feb 10 [Epub ahead of print].
https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab129/6132402
http://www.ncbi.nlm.nih.gov/pubmed/33566076?tool=bestpractice.com
[937]Resende PC, Bezerra JF, de Vasconcelos RHT, et al. Spike E484K mutation in the first SARS-CoV-2 reinfection case confirmed in Brazil, 2020. 2021 [internet publication].
https://virological.org/t/spike-e484k-mutation-in-the-first-sars-cov-2-reinfection-case-confirmed-in-brazil-2020/584
[938]Naveca F, da Costa C, Nascimento V, et al. SARS-CoV-2 reinfection by the new variant of concern (VOC) P.1 in Amazonas, Brazil. 2021 [internet publication].
https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596
[939]Nonaka, CKV, Franco MM, Gräf, T, et al. Genomic evidence of a Sars-Cov-2 reinfection case with E484K spike mutation in Brazil. Preprints. 2021 Jan 27 [Epub ahead of print].
https://www.preprints.org/manuscript/202101.0132/v1
Immunity
The immune response, including duration of immunity, is not yet fully understood. There is evidence that suggests that infection with SARS-CoV-2 is likely to confer protective immunity against reinfection.[480]Watson J, Richter A, Deeks J. Testing for SARS-CoV-2 antibodies. BMJ. 2020 Sep 8;370:m3325.
https://www.bmj.com/content/370/bmj.m3325
http://www.ncbi.nlm.nih.gov/pubmed/32900692?tool=bestpractice.com
[940]Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral immune response to SARS-CoV-2 in Iceland. N Engl J Med. 2020 Sep 1 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2026116
http://www.ncbi.nlm.nih.gov/pubmed/32871063?tool=bestpractice.com
[941]Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020 May 20 [Epub ahead of print].
https://science.sciencemag.org/content/early/2020/05/19/science.abc4776
http://www.ncbi.nlm.nih.gov/pubmed/32434946?tool=bestpractice.com
[942]Kirkcaldy RD, King BA, Brooks JT. COVID-19 and postinfection immunity: limited evidence, many remaining questions. JAMA. 2020 May 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2766097
http://www.ncbi.nlm.nih.gov/pubmed/32391855?tool=bestpractice.com
[943]Ni L, Ye F, Cheng ML, et al. Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals. Immunity. 2020 Jun 16;52(6):971-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196424/
http://www.ncbi.nlm.nih.gov/pubmed/32413330?tool=bestpractice.com
However, studies are of variable quality and comparison of findings is difficult.[944]Post N, Eddy D, Huntley C, et al. Antibody response to SARS-CoV-2 infection in humans: a systematic review. PLoS One. 2020;15(12):e0244126.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244126
http://www.ncbi.nlm.nih.gov/pubmed/33382764?tool=bestpractice.com
A Public Health England study found that naturally acquired immunity, as a result of past infection, provides 83% protection against reinfection compared with people who have not had the disease previously. Protection appears to last for at least 5 months.[945]Public Health England. Past COVID-19 infection provides some immunity but people may still carry and transmit virus. 2021 [internet publication].
https://www.gov.uk/government/news/past-covid-19-infection-provides-some-immunity-but-people-may-still-carry-and-transmit-virus
According to a large, retrospective study, people who were seropositive for SARS-CoV-2 appeared to be at lower risk for future infection, for at least several months.[946]Harvey RA, Rassen JA, Kabelac CA, et al. Association of SARS-CoV-2 seropositive antibody test with risk of future infection. JAMA Intern Med. 2021 Feb 24 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2776810
http://www.ncbi.nlm.nih.gov/pubmed/33625463?tool=bestpractice.com
Emerging studies suggest that the majority of people develop a strong and broad T-cell response with both CD4+ and CD8+ T cells, and some have a memory phenotype.[947]Centre for Evidence-Based Medicine; Plüddemann A, Aronson JK. What is the role of T cells in COVID-19 infection? Why immunity is about more than antibodies. 2020 [internet publication].
https://www.cebm.net/covid-19/what-is-the-role-of-t-cells-in-covid-19-infection-why-immunity-is-about-more-than-antibodies
A preprint study found that spike immunoglobulin G (IgG) was relatively stable over 6 months, spike-specific memory B cells were more abundant at 6 months than at 1 month, and CD4+ and CD8+ T cells declined with a half-life of 3 to 5 months in adults (mostly with mild disease) who recovered from COVID-19.[948]Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021 Jan 6 [Epub ahead of print].
https://science.sciencemag.org/content/early/2021/01/06/science.abf4063.long
http://www.ncbi.nlm.nih.gov/pubmed/33408181?tool=bestpractice.com
Another study in over 12,000 healthcare workers found that prior SARS-CoV-2 infection that generated antibody responses offered protection from reinfection for most people in the 6 months following infection.[949]Lumley SF, O'Donnell D, Stoesser NE, et al. Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med. 2020 Dec 23 [Epub ahead of print].
https://www.nejm.org/doi/full/10.1056/NEJMoa2034545
http://www.ncbi.nlm.nih.gov/pubmed/33369366?tool=bestpractice.com
This bodes well for potential longer-term immunity.
The immune response to SARS-CoV-2 involves both cell-mediated immunity and antibody production. Adaptive immunity to SARS-CoV-2 is thought to occur within the first 7 to 10 days of infection. A robust memory B-cell and plasmablast response is detected early in infection, with secretion of IgA and IgM antibodies by day 5 to 7, and IgG by day 7 to 10 from the onset of symptoms. IgA and IgM titres decline after approximately 28 days, and IgG titres peak at approximately 49 days. T cells are simultaneously activated in the first week of infection and SARS-CoV-2-specific memory CD4+ and CD8+ T cells peak within 2 weeks, but remain detectable for ≥100 days. Antibody and T-cell responses differ among individuals, and depend on age and disease severity. Preprint studies have found that T-cell response is likely to be present in most adults at least 6 to 8 months after primary infection.[950]Stephens DS, McElrath MJ. COVID-19 and the path to immunity. JAMA. 2020 Sep 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2770758
http://www.ncbi.nlm.nih.gov/pubmed/32915201?tool=bestpractice.com
[951]Shrotri M, van Schalkwyk MCI, Post N, et al. T cell response to SARS-CoV-2 infection in humans: a systematic review. PLoS One. 2021;16(1):e0245532.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833159/
http://www.ncbi.nlm.nih.gov/pubmed/33493185?tool=bestpractice.com
While there have been concerns about early declining IgG neutralising antibodies during convalescence, this is not thought to be an issue, because antibody levels always decline after the acute phase of an infection, and it is the levels of antibody titres after an infection that is important as this represents the generation of long-lived plasma cells to protect against subsequent infection.[950]Stephens DS, McElrath MJ. COVID-19 and the path to immunity. JAMA. 2020 Sep 11 [Epub ahead of print].
https://jamanetwork.com/journals/jama/fullarticle/2770758
http://www.ncbi.nlm.nih.gov/pubmed/32915201?tool=bestpractice.com
Antibodies have been detected up to 8 months after infection.[952]Choe PG, Kim KH, Kang CK, et al. Antibody responses 8 months after asymptomatic or mild SARS-CoV-2 infection. Emerg Infect Dis. 2020 Dec 22;27(3).
https://wwwnc.cdc.gov/eid/article/27/3/20-4543_article
http://www.ncbi.nlm.nih.gov/pubmed/33350923?tool=bestpractice.com
Analysis of a large cohort of convalescent serum donors in New York City suggests that 99.5% of patients with confirmed mild disease seroconvert 4 weeks after illness. IgG antibodies developed over a period of 7 to 50 days from symptom onset, and 5 to 49 days from symptom resolution. This suggests that people with mild disease may have the ability to develop immunity.[953]Wajnberg A, Mansour M, Leven E, et al. Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study. Lancet Microbe. 2020 Sep 25 [Epub ahead of print].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518831/
http://www.ncbi.nlm.nih.gov/pubmed/33015652?tool=bestpractice.com
However, among patients who recovered from mild disease in China, neutralising antibody titres varied substantially.[954]Wu F, Liu M, Wang A, et al. Evaluating the association of clinical characteristics with neutralizing antibody levels in patients who have recovered from mild COVID-19 in Shanghai, China. JAMA Intern Med. 2020 Aug 18 [Epub ahead of print].
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2769741
http://www.ncbi.nlm.nih.gov/pubmed/32808970?tool=bestpractice.com
There are data to suggest that asymptomatic people may have a weaker immune response to infection; however, this is yet to be confirmed.[955]Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020 Jun 18 [Epub ahead of print].
https://www.nature.com/articles/s41591-020-0965-6
http://www.ncbi.nlm.nih.gov/pubmed/32555424?tool=bestpractice.com
Testing of blood samples taken before the COVID-19 pandemic have shown that some people already have immune cells that recognise SARS-CoV-2. Studies have reported T-cell reactivity against SARS-CoV-2 in 20% to 50% of people with no known exposure to the virus.[956]Doshi P. Covid-19: do many people have pre-existing immunity? BMJ. 2020 Sep 17;370:m3563.
https://www.bmj.com/content/370/bmj.m3563
http://www.ncbi.nlm.nih.gov/pubmed/32943427?tool=bestpractice.com
Approximately 5% of uninfected adults and 62% of uninfected children aged 6 to 16 years had antibodies that recognise SARS-CoV-2 in one study.[957]Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science. 2020 Nov 6 [Epub ahead of print].
https://science.sciencemag.org/content/early/2020/11/05/science.abe1107
http://www.ncbi.nlm.nih.gov/pubmed/33159009?tool=bestpractice.com
This may be a consequence of true immune memory derived in part from previous infection with common cold coronaviruses, or from other unknown animal coronaviruses. However, further research into whether there is pre-existing immunity to SARS-CoV-2 in the human population is required.
Maternal IgG antibodies to SARS-CoV-2 have been found to transfer across the placenta after asymptomatic or symptomatic infection in pregnancy.[958]Flannery DD, Gouma S, Dhudasia MB, et al. Assessment of maternal and neonatal cord blood SARS-CoV-2 antibodies and placental transfer ratios. JAMA Pediatr. 2021 Jan 29 [Epub ahead of print].
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2775945
http://www.ncbi.nlm.nih.gov/pubmed/33512440?tool=bestpractice.com