Mortality
The leading cause of death is respiratory failure from acute respiratory distress syndrome (ARDS).[916]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%).[917]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 Nov;14(11):1149-63.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544968
http://www.ncbi.nlm.nih.gov/pubmed/32734777?tool=bestpractice.com
There is no evidence to suggest worse outcomes (i.e., mechanical ventilator-free days, length of stay in intensive care unit or hospital, or mortality) for patients with COVID-19-related ARDS compared with the general ARDS population.[918]Dmytriw AA, Chibbar R, Chen PPY, et al. Outcomes of acute respiratory distress syndrome in COVID-19 patients compared to the general population: a systematic review and meta-analysis. Expert Rev Respir Med. 2021 Oct;15(10):1347-54.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108193
http://www.ncbi.nlm.nih.gov/pubmed/33882768?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.[919]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 Jun;40(6):1209-16.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787698
http://www.ncbi.nlm.nih.gov/pubmed/33409832?tool=bestpractice.com
Other common causes of death include sepsis or septic shock, sepsis-related multiorgan failure, bacterial or viral coinfections, venous thromboembolism, and cardiac failure.[920]Elezkurtaj S, Greuel S, Ihlow J, et al. Causes of death and comorbidities in hospitalized patients with COVID-19. Sci Rep. 2021 Feb 19;11(1):4263.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895917
http://www.ncbi.nlm.nih.gov/pubmed/33608563?tool=bestpractice.com
Mortality rate depends on age and the presence of underlying medical conditions.
People <65 years of age have a very small risk of death even in pandemic epicenters, and deaths in people <65 years of age without any underlying conditions is rare.[921]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
Deaths in children and young people are rare. A systematic review and meta-analysis found that 3.3% of children were hospitalized, 0.3% were admitted to the intensive care unit, and 0.02% died in community-based studies (23.9%, 2.9%, and 0.2%, respectively, in hospital-based screening studies).[922]Sumner MW, Kanngiesser A, Lotfali-Khani K, et al. Severe outcomes associated with SARS-CoV-2 infection in children: a systematic review and meta-analysis. Front Pediatr. 2022 Jun 9;10:916655.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9218576
http://www.ncbi.nlm.nih.gov/pubmed/35757137?tool=bestpractice.com
Approximately 99% of patients who died of COVID-19 had at least one underlying health condition in a US cohort study. The strongest risk factors for death were obesity, anxiety and fear-related disorders, and diabetes, as well as the total number of underlying conditions.[156]Kompaniyets L, Pennington AF, Goodman AB, et al. Underlying medical conditions and severe illness among 540,667 adults hospitalized with COVID-19, March 2020 – March 2021. Prev Chronic Dis. 2021 Jul 1;18:E66.
https://www.cdc.gov/pcd/issues/2021/21_0123.htm
http://www.ncbi.nlm.nih.gov/pubmed/34197283?tool=bestpractice.com
The three most prevalent comorbidities in deceased patients were hypertension, diabetes mellitus, and respiratory disease.[923]Justino DCP, Silva DFO, Costa KTDS, et al. Prevalence of comorbidities in deceased patients with COVID-19: a systematic review. Medicine (Baltimore). 2022 Sep 23;101(38):e30246.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9508958
http://www.ncbi.nlm.nih.gov/pubmed/36197209?tool=bestpractice.com
Mortality rates are high in critically ill patients.
Global all-cause mortality was 35% in the intensive care unit and 32% in hospital for critically ill patients for the year 2020. However, mortality rates vary between regions. For example, the mortality was as high as 48% in Southeast Asia and as low as 15% in America.[924]Qian Z, Lu S, Luo X, et al. Mortality and clinical interventions in critically ill patient with coronavirus disease 2019: a systematic review and meta-analysis. Front Med (Lausanne). 2021 Jul 23;8:635560.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342953
http://www.ncbi.nlm.nih.gov/pubmed/34368175?tool=bestpractice.com
A systematic review and meta-analysis of data up to 31 December 2021 found that in critically ill patients who require intensive care, the in-hospital case fatality rate (CFR), intensive care unit CFR, mechanical ventilation CFR, renal replacement therapy CFR, and extracorporeal membrane oxygenation (ECMO) CFR was 25.9%, 37.3%, 51.6%, 66.1%, and 58%, respectively. Overall, mechanical ventilation mortality has significantly decreased since the start of the pandemic (52.7% to 31.3%).[925]Chandel A, Leazer S, Alcover KC, et al. Intensive care and organ support related mortality in patients with COVID-19: a systematic review and meta-analysis. Crit Care Explor. 2023 Mar;5(3):e0876.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988289
http://www.ncbi.nlm.nih.gov/pubmed/36890875?tool=bestpractice.com
Mortality rates have decreased over time despite stable patient characteristics.
In-hospital mortality decreased from 32.3% to 16.4% between March and August 2020 in a UK cohort study of over 80,000 patients. Mortality declined in all age groups, in all ethnic groups, in men and women, and in patients with and without comorbidities, over and above contributions from declining illness severity.[926]Docherty AB, Mulholland RH, Lone NI, et al. Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK. Lancet Respir Med. 2021 Jul;9(7):773-85.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121531
http://www.ncbi.nlm.nih.gov/pubmed/34000238?tool=bestpractice.com
Adjusted in-hospital mortality rates declined during the early part of the first wave in the UK and this was largely maintained during the second wave of the pandemic.[927]Gray WK, Navaratnam AV, Day J, et al. COVID-19 hospital activity and in-hospital mortality during the first and second waves of the pandemic in England: an observational study. Thorax. 2022 Nov;77(11):1113-20.
https://thorax.bmj.com/content/77/11/1113.long
http://www.ncbi.nlm.nih.gov/pubmed/34819384?tool=bestpractice.com
Mortality rates decreased sharply in the US over the first 6 months of the pandemic.[928]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. 2021 Apr 1;181(4):471-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756246
http://www.ncbi.nlm.nih.gov/pubmed/33351068?tool=bestpractice.com
[929]Nguyen NT, Chinn J, Nahmias J, et al. Outcomes and mortality among adults hospitalized with COVID-19 at US medical centers. JAMA Netw Open. 2021 Mar 1;4(3):e210417.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2777028
http://www.ncbi.nlm.nih.gov/pubmed/33666657?tool=bestpractice.com
In-hospital mortality decreased from 10.6% to 9.3% between March and November 2020 in one US cohort study of over 500,000 patients across 209 acute care hospitals.[930]Finelli L, Gupta V, Petigara T, et al. Mortality among US patients hospitalized with SARS-CoV-2 infection in 2020. JAMA Netw Open. 2021 Apr 1;4(4):e216556.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2778237
http://www.ncbi.nlm.nih.gov/pubmed/33830226?tool=bestpractice.com
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.[931]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 May;174(5):613-21.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901669
http://www.ncbi.nlm.nih.gov/pubmed/33460330?tool=bestpractice.com
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 use of corticosteroids, 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.
It has been estimated that approximately 1.5 to 2 billion infections have occurred globally as of February 2021, with an estimated overall IFR of 0.15%. There are substantial differences in IFR and infection spread across continents, countries, and locations.[932]Ioannidis JPA. Reconciling estimates of global spread and infection fatality rates of COVID-19: an overview of systematic evaluations. Eur J Clin Invest. 2021 Mar 26:e13554.
https://onlinelibrary.wiley.com/doi/10.1111/eci.13554
http://www.ncbi.nlm.nih.gov/pubmed/33768536?tool=bestpractice.com
Preprint (not peer reviewed) data suggests that the median IFR in community-dwelling people ages ≥70 years was 2.9% (4.9% in people ages ≥70 years overall), but was much lower at younger ages (median 0.0013%, 0.0088%, 0.021%, 0.042%, 0.14%, and 0.65%, at 0-19, 20-29, 30-39, 40-49, 50-59, and 60-69 years respectively).[933]Axfors C, Ioannidis JPA. Infection fatality rate of COVID-19 in community-dwelling elderly populations. Eur J Epidemiol. 2022 Mar;37(3):235-49.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934243
http://www.ncbi.nlm.nih.gov/pubmed/35306604?tool=bestpractice.com
The US Centers for Disease Control and Prevention’s current best estimate of the IFR, according to age:[934]Centers for Disease Control and Prevention. COVID-19 pandemic planning scenarios. 2021 [internet publication].
https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html
0 to 17 years – 0.002%
18 to 49 years – 0.05%
50 to 64 years – 0.6%
≥65 years – 9%.
Based on these figures, the overall IFR for people <65 years of age is approximately 0.2%.
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.[935]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, especially in the context of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.
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/hospitalized cases are likely to be tested. CFR is a dynamic estimate that changes with time, population, socioeconomic factors, and mitigation measures.[936]Ghayda RA, Lee KH, Han YJ, et al. The global case fatality rate of coronavirus disease 2019 by continents and national income: a meta-analysis. J Med Virol. 2022 Jun;94(6):2402-13.
https://onlinelibrary.wiley.com/doi/10.1002/jmv.27610
http://www.ncbi.nlm.nih.gov/pubmed/35099819?tool=bestpractice.com
The World Health Organization’s current estimate of the global CFR is 0.9% (as of 16 April 2023).[20]World Health Organization. Coronavirus disease (COVID-19) weekly epidemiological update and weekly operational update. 2023 [internet publication].
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
CFR varies considerably between countries. The pooled CFR in the general population in a systematic review and meta-analysis was 1%.[937]Alimohamadi Y, Tola HH, Abbasi-Ghahramanloo A, et al. Case fatality rate of COVID-19: a systematic review and meta-analysis. J Prev Med Hyg. 2021 Jun;62(2):E311-20.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451339
http://www.ncbi.nlm.nih.gov/pubmed/34604571?tool=bestpractice.com
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%.[33]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 increases with age.
In the US, the majority of deaths were in patients ages ≥65 years. The CFR was highest among patients ages ≥85 years (10% to 27%), followed by those ages 65 to 84 years (3% to 11%), then those ages 55 to 64 years (1% to 3%), and finally those ages 20 to 54 years (<1%).[133]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 ages ≥60 years.[938]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 ages ≥80 years (13.4%), followed by those ages 60 to 79 years (6.4%), and then those ages <60 years (0.32%).[939]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 ages ≥80 years (52.5%), followed by those ages 70 to 79 years (35.5%), and then those ages 60 to 69 years (8.5%).[940]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.[25]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
[133]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 one study, 70% of deaths occurred in those ages 10 to 20 years, 20% in those ages 1 to 9 years, and 10% in children under 1 year of age.[941]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 preexisting 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).[938]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 pooled CFR in hospitalized patients was 13%.[937]Alimohamadi Y, Tola HH, Abbasi-Ghahramanloo A, et al. Case fatality rate of COVID-19: a systematic review and meta-analysis. J Prev Med Hyg. 2021 Jun;62(2):E311-20.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451339
http://www.ncbi.nlm.nih.gov/pubmed/34604571?tool=bestpractice.com
The CFR is highest in patients with critical disease, ranging from 26% to 67% in studies.[938]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
[942]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
[943]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
CFR is lower with the Omicron variant.
The Omicron variant had a lower CFR compared with the Delta variant.[944]Kim K, Cho K, Song J, et al. The case fatality rate of COVID-19 during the Delta and the Omicron epidemic phase: a meta-analysis. J Med Virol. 2023 Feb;95(2):e28522.
http://www.ncbi.nlm.nih.gov/pubmed/36691933?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.[945]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 recognized; however, a positive PCR test does not necessarily equal a diagnosis of COVID-19, or mean that a person is infected or infectious.[946]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
[947]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.[948]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.[945]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
[949]Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020 May 12;323(18):1775-6.
https://jamanetwork.com/journals/jama/fullarticle/2763667
http://www.ncbi.nlm.nih.gov/pubmed/32203977?tool=bestpractice.com
Prognostic factors
Prognostic factors that have been associated with increased risk of severe disease, hospitalization or intensive care unit admission, poor outcomes, and mortality include:[950]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
[951]Booth A, Reed AB, Ponzo S, et al. Population risk factors for severe disease and mortality in COVID-19: a global systematic review and meta-analysis. PLoS One. 2021 Mar 4;16(3):e0247461.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247461
http://www.ncbi.nlm.nih.gov/pubmed/33661992?tool=bestpractice.com
[952]Zhang L, Hou J, Ma FZ, et al. The common risk factors for progression and mortality in COVID-19 patients: a meta-analysis. Arch Virol. 2021 Aug;166(8):2071-87.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017903
http://www.ncbi.nlm.nih.gov/pubmed/33797621?tool=bestpractice.com
[953]Dumitrascu F, Branje KE, Hladkowicz ES, et al. Association of frailty with outcomes in individuals with COVID-19: a living review and meta-analysis. J Am Geriatr Soc. 2021 Sep;69(9):2419-29.
https://agsjournals.onlinelibrary.wiley.com/doi/epdf/10.1111/jgs.17299
http://www.ncbi.nlm.nih.gov/pubmed/34048599?tool=bestpractice.com
[954]Bellou V, Tzoulaki I, van Smeden M, et al. Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis. Eur Respir J. 2022 Feb 3;59(2):2002964.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8576809
http://www.ncbi.nlm.nih.gov/pubmed/34172467?tool=bestpractice.com
[955]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
[956]Shi C, Wang L, Ye J, et al. Predictors of mortality in patients with coronavirus disease 2019: a systematic review and meta-analysis. BMC Infect Dis. 2021 Jul 8;21(1):663.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264491
http://www.ncbi.nlm.nih.gov/pubmed/34238232?tool=bestpractice.com
The most common underlying diseases in deceased patients were hypertension, diabetes, and cardiovascular diseases.[957]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
In children and adolescents, congenital heart disease, chronic pulmonary disease, neurologic diseases, obesity, multisystem inflammatory syndrome, shortness of breath, acute respiratory distress syndrome, acute kidney injury, gastrointestinal symptoms, and elevated C-reactive protein and D-dimer have been associated with unfavorable prognosis.[958]Shi Q, Wang Z, Liu J, et al. Risk factors for poor prognosis in children and adolescents with COVID-19: a systematic review and meta-analysis. EClinicalMedicine. 2021 Nov;41:101155.
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00435-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/34693233?tool=bestpractice.com
Hospital readmission
Approximately 10% of recovered patients require hospital readmission during the first year after discharge, based on very low-quality evidence. Most hospital readmissions occur within 30 days of discharge. Higher readmission rates have been reported in patients with underlying diseases, but the current evidence is contradictory and comes from studies with a low level of evidence. Higher readmission rates have also been reported in developed countries compared with developing countries, possibly due to the better access to medical services and the higher medical benefits provided in developed countries. The prevalence of post-discharge all-cause mortality of recovered patients was 7.87% within 1 year of discharge.[959]Ramzi ZS. Hospital readmissions and post-discharge all-cause mortality in COVID-19 recovered patients: a systematic review and meta-analysis. Am J Emerg Med. 2022 Jan;51:267-79.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570797
http://www.ncbi.nlm.nih.gov/pubmed/34781153?tool=bestpractice.com
Persistent infections have been reported in immunocompromised people.[960]Choi B, Choudhary MC, Regan J, et al. Persistence and evolution of SARS-CoV-2 in an immunocompromised host. N Engl J Med. 2020 Dec 3;383(23):2291-3.
https://www.nejm.org/doi/full/10.1056/NEJMc2031364
http://www.ncbi.nlm.nih.gov/pubmed/33176080?tool=bestpractice.com
The risk of severe post-acute complications in patients who were not admitted to hospital for the primary infection appears to be low. However, they may be at slightly increased risk of venous thromboembolism, dyspnea, and initiating bronchodilator or triptan therapy compared with people who tested negative for SARS-CoV-2. These patients visited their general practitioner and outpatient hospital clinics more often after the primary infection than those who tested negative, which may indicate persistent symptoms that do not lead to specific drug treatment or hospital admission.[961]Lund LC, Hallas J, Nielsen H, et al. Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study. Lancet Infect Dis. 2021 Oct;21(10):1373-82.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110209
http://www.ncbi.nlm.nih.gov/pubmed/33984263?tool=bestpractice.com
Reinfection
Reinfection refers to a new infection following previous confirmed infection (i.e., severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] real-time reverse transcription polymerase chain reaction [RT-PCR] positive), and is distinct from persistent infection and relapse. There is currently no standard case definition for SARS-CoV-2 reinfection.[962]UK Health Security Agency. COVID-19: investigation and management of suspected SARS-CoV-2 reinfections. 2021 [internet publication].
https://www.gov.uk/government/publications/covid-19-investigation-and-management-of-suspected-sars-cov-2-reinfections
Cases of infection are rare.
A systematic review and meta-analysis reported the pooled reinfection rate to be 0.65% in the pre-Omicron period. The rate was higher in high-risk populations (1.6%), and the rate of symptomatic reinfection was lower (0.4%).[963]Mao YJ, Wang WW, Ma J, et al. Reinfection rates among patients previously infected by SARS-CoV-2: systematic review and meta-analysis. Chin Med J (Engl). 2021 Dec 13;135(2):145-52.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8769121
http://www.ncbi.nlm.nih.gov/pubmed/34908003?tool=bestpractice.com
Across 18 studies, the reinfection risk ranged from 0% to 2.2%, and previous infection reduced the risk for reinfection by 87%. Protection remained above 80% for at least 7 months.[964]Helfand M, Fiordalisi C, Wiedrick J, et al. Risk for reinfection after SARS-CoV-2: a living, rapid review for American College of Physicians practice points on the role of the antibody response in conferring immunity following SARS-CoV-2 infection. Ann Intern Med. 2022 Apr;175(4):547-55.
https://www.acpjournals.org/doi/10.7326/M21-4245
http://www.ncbi.nlm.nih.gov/pubmed/35073157?tool=bestpractice.com
The risk of reinfection increased during the Omicron period.[373]World Health Organization. Enhancing readiness for Omicron (B.1.1.529): technical brief and priority actions for member states. January 21 2022 [internet publication].
https://www.who.int/publications/m/item/enhancing-readiness-for-omicron-(b.1.1.529)-technical-brief-and-priority-actions-for-member-states
[965]Roskosky M, Borah BF, DeJonge PM, et al. Notes from the field: SARS-CoV-2 omicron variant infection in 10 persons within 90 days of previous SARS-CoV-2 Delta variant infection - four states, October 2021 – January 2022. MMWR Morb Mortal Wkly Rep. 2022 Apr 8;71(14):524-6.
https://www.cdc.gov/mmwr/volumes/71/wr/mm7114a2.htm
http://www.ncbi.nlm.nih.gov/pubmed/35389976?tool=bestpractice.com
Although the reinfection rates increased, the risk of severe disease was very low.[966]Flacco ME, Acuti Martellucci C, Baccolini V, et al. Risk of reinfection and disease after SARS-CoV-2 primary infection: meta-analysis. Eur J Clin Invest. 2022 Oct;52(10):e13845.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353414
http://www.ncbi.nlm.nih.gov/pubmed/35904405?tool=bestpractice.com
Consider reinfection in the following circumstances:[962]UK Health Security Agency. COVID-19: investigation and management of suspected SARS-CoV-2 reinfections. 2021 [internet publication].
https://www.gov.uk/government/publications/covid-19-investigation-and-management-of-suspected-sars-cov-2-reinfections
A repeat positive RT-PCR test 90 days or more after a previous positive RT-PCR test
New symptoms in a patient with previous RT-PCR-positive infection after apparent full recovery (i.e., resolution of previous symptoms) and a repeat positive RT-PCR test (including within 90 days after a previous positive RT-PCR test).
Diagnosis
A compatible clinical presentation together with diagnostic evidence (such as a low RT-PCR cycle threshold value) may be sufficient to diagnose reinfection. However, the diagnosis should be made in conjunction with an infectious disease specialist following a risk assessment that involves reviewing available clinical, diagnostic, and epidemiologic information to inform whether reinfection is likely. Confirmation of reinfection should be obtained through whole genome sequencing of paired specimens, if available.[962]UK Health Security Agency. COVID-19: investigation and management of suspected SARS-CoV-2 reinfections. 2021 [internet publication].
https://www.gov.uk/government/publications/covid-19-investigation-and-management-of-suspected-sars-cov-2-reinfections
Management
Manage patients with suspected reinfection as if they are infectious, as for a new or first infection. Advise the patient to self-isolate pending further investigation and clinical risk assessment. It is important to note that illness due to reinfection may not necessarily follow the same clinical course as the previous episode.[962]UK Health Security Agency. COVID-19: investigation and management of suspected SARS-CoV-2 reinfections. 2021 [internet publication].
https://www.gov.uk/government/publications/covid-19-investigation-and-management-of-suspected-sars-cov-2-reinfections
Immunity
The global population has varied immune histories to SARS-CoV-2 derived from various exposures to infection, virus variants, and vaccination.
The immune response to SARS-CoV-2 involves both cell-mediated and antibody-mediated immunity. Adaptive immunity 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 immunoglobulin A (IgA) and IgM antibodies by day 5 to 7, and IgG by day 7 to 10 from the onset of symptoms. 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. Antibody and T-cell response differ among individuals, and depend on age and disease severity.[967]Stephens DS, McElrath MJ. COVID-19 and the path to immunity. JAMA. 2020 Oct 6;324(13):1279-81.
https://jamanetwork.com/journals/jama/fullarticle/2770758
http://www.ncbi.nlm.nih.gov/pubmed/32915201?tool=bestpractice.com
Observational evidence suggests that prior infection with SARS-CoV-1 was associated with detectable levels of antibodies that cross-react and neutralize SARS-CoV-2.[968]Ng RWY, Boon SS, Chen Z, et al. Cross-clade memory immunity in adults following SARS-CoV-1 infection in 2003. JAMA Netw Open. 2022 Dec 1;5(12):e2247723.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2799725
http://www.ncbi.nlm.nih.gov/pubmed/36538327?tool=bestpractice.com
Antibody-mediated immunity
Approximately 85% to 99% of infected people develop detectable neutralizing antibodies within 4 weeks following natural infection. However, this varies depending on disease severity, study setting, time since infection, and method used to measure antibodies.[969]World Health Organization. COVID-19 natural immunity: scientific brief. 2021 [internet publication].
https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci_Brief-Natural_immunity-2021.1
[970]Savage HR, Santos VS, Edwards T, et al. Prevalence of neutralising antibodies against SARS-CoV-2 in acute infection and convalescence: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2021 Jul 8;15(7):e0009551.
https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009551
http://www.ncbi.nlm.nih.gov/pubmed/34237072?tool=bestpractice.com
Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection. IgM levels peak early in the disease course at approximately 20 days and then decline. IgG levels peak later at approximately 25 days after symptom onset and may remain detectable for at least 120 days. Most adults generate neutralizing antibodies, which may persist for several months. Some adults do not develop antibodies after infection; the reasons for this are unclear.[971]Arkhipova-Jenkins I, Helfand M, Armstrong C, et al. Antibody response after SARS-CoV-2 infection and implications for immunity: a rapid living review. Ann Intern Med. 2021 Jun;174(6):811-21.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025942
http://www.ncbi.nlm.nih.gov/pubmed/33721517?tool=bestpractice.com
Maternal IgG antibodies to SARS-CoV-2 have been found to transfer across the placenta after infection in pregnant women.[972]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 Jun 1;175(6):594-600.
https://jamanetwork.com/journals/jamapediatrics/fullarticle/2775945
http://www.ncbi.nlm.nih.gov/pubmed/33512440?tool=bestpractice.com
Extreme-aged (some over 100 years), frail residents of a long-term care facility have been found to elicit a robust immune response that was capable of neutralizing the SARS-CoV-2 virus.[973]Foley MK, Searle SD, Toloue A, et al. Centenarians and extremely old people living with frailty can elicit durable SARS-CoV-2 spike specific IgG antibodies with virus neutralization functions following virus infection as determined by serological study. EClinicalMedicine. 2021 Jun 27:100975.
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00255-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/34222846?tool=bestpractice.com
There were some early studies that suggested asymptomatic people may have a weaker antibody response to infection; however, this has not been confirmed.[974]Long QX, Tang XJ, Shi QL, et al. Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections. Nat Med. 2020 Aug;26(8):1200-4.
https://www.nature.com/articles/s41591-020-0965-6
http://www.ncbi.nlm.nih.gov/pubmed/32555424?tool=bestpractice.com
Current evidence suggests that the immune responses remain robust and protective against reinfection in most people for at least 10 months after infection.[975]Alfego D, Sullivan A, Poirier B, et al. A population-based analysis of the longevity of SARS-CoV-2 antibody seropositivity in the United States. EClinicalMedicine. 2021 May 24:100902.
https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00182-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/34056568?tool=bestpractice.com
[976]Egbert ER, Xiao S, Colantuoni E, et al. Durability of spike immunoglobin G antibodies to SARS-CoV-2 among health care workers with prior infection. JAMA Netw Open. 2021 Aug 2;4(8):e2123256.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2783618
http://www.ncbi.nlm.nih.gov/pubmed/34459910?tool=bestpractice.com
A cross-sectional study of unvaccinated adults found evidence of natural immunity up to 20 months after infection, although it is unclear how antibody levels correlate with future protection, particularly with emerging variants.[977]Alejo JL, Mitchell J, Chang A, et al. Prevalence and durability of SARS-CoV-2 antibodies among unvaccinated US adults by history of COVID-19. JAMA. 2022 Mar 15;327(11):1085-7.
https://jamanetwork.com/journals/jama/fullarticle/2788894
http://www.ncbi.nlm.nih.gov/pubmed/35113143?tool=bestpractice.com
Some SARS-CoV-2 variants with key changes in the spike protein have a reduced susceptibility to neutralization by antibodies. However, cellular immunity elicited by natural infection also targets other viral proteins, which tend to be more conserved across variants than the spike protein.[969]World Health Organization. COVID-19 natural immunity: scientific brief. 2021 [internet publication].
https://www.who.int/publications/i/item/WHO-2019-nCoV-Sci_Brief-Natural_immunity-2021.1
Cell-mediated immunity
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.[978]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
CD4+ and CD8+ T cells declined with a half-life of 3 to 5 months in adults who recovered, and are likely to be present in most adults at least 6 to 8 months after primary infection.[979]Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science. 2021 Feb 5;371(6529):eabf4063.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919858
http://www.ncbi.nlm.nih.gov/pubmed/33408181?tool=bestpractice.com
[980]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
Emerging data suggest that T-cell responses are largely unaffected by SARS-CoV-2 variants.[981]Tarke A, Sidney J, Methot N, et al. Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals. Cell Rep Med. 2021 Jul 20;2(7):100355.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249675
http://www.ncbi.nlm.nih.gov/pubmed/34230917?tool=bestpractice.com
[982]Redd AD, Nardin A, Kared H, et al. CD8+ T-cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants. Open Forum Infect Dis. 2021 Jul;8(7):ofab143.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083629
http://www.ncbi.nlm.nih.gov/pubmed/34322559?tool=bestpractice.com
Evidence suggests that natural infection with SARS-CoV-2 is likely to confer high protective immunity against reinfection.
Robust antibody and T-cell immunity against SARS-CoV-2 is present in the majority of recovered patients 12 months after moderate to critical infection. Neutralizing antibodies diminished between 6 and 12 months after infection, mostly in older people and critical patients. However, memory T-cells retained the ability to mediate cellular immunity in patients who had lost their neutralizing antibody responses. Memory T-cell responses to the original SARS-CoV-2 strain were not disrupted by new variants.[983]Guo L, Wang G, Wang Y, et al. SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study. Lancet Microbe. 2022 May;3(5):e348-56.
https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(22)00036-2/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/35345417?tool=bestpractice.com
Convalescent critically ill patients consistently generated substantial adaptive and humoral immune responses against SARS-CoV-2 for more than 1 year after hospital discharge.[984]Venet F, Gossez M, Bidar F, et al. T cell response against SARS-CoV-2 persists after one year in patients surviving severe COVID-19. EBioMedicine. 2022 Mar 26;78:103967.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00151-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/35349827?tool=bestpractice.com
Meta-analyses have found a high (84% to 87%) level of protection after infection that persisted for at least 1 year.[985]Petráš M. Highly effective naturally acquired protection against COVID-19 persists for at least 1 year: a meta-analysis. J Am Med Dir Assoc. 2021 Nov;22(11):2263-5.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443339
http://www.ncbi.nlm.nih.gov/pubmed/34582779?tool=bestpractice.com
[986]Chen Q, Zhu K, Liu X, et al. The protection provided by naturally acquired antibodies against subsequent SARS-CoV-2 infection: a systematic review and meta-analysis. Emerg Microbes Infect. 2022 Feb 23:1-44.
https://www.tandfonline.com/doi/full/10.1080/22221751.2022.2046446
http://www.ncbi.nlm.nih.gov/pubmed/35195494?tool=bestpractice.com
Protection against all outcomes (infection, symptomatic disease, severe disease) from pre-Omicron variants was very high (>85% on average) and remained high after 40 weeks. Protection against severe disease caused by the Omicron variant was also high (88.9%), but protection against reinfection or symptomatic disease caused by the Omicron variant was much lower (<55%) compared with pre-Omicron variants.[987]COVID-19 Forecasting Team. Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis. Lancet. 2023 Mar 11;401(10379):833-42.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9998097
http://www.ncbi.nlm.nih.gov/pubmed/36930674?tool=bestpractice.com
A UK Health Security Agency study found that naturally acquired immunity, as a result of past infection, provides 84% protection against reinfection compared with people who have not had the disease previously, and protection appeared to last for at least 7 months.[988]Hall VJ, Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet. 2021 Apr 17;397(10283):1459-69.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040523
http://www.ncbi.nlm.nih.gov/pubmed/33844963?tool=bestpractice.com
Similarly, a population-level observational study among 4 million PCR-tested people in Denmark found protection against repeat infection in the population to be 80% or higher in those younger than 65 years of age, and 47% in those older than 65 years of age. There was no evidence of waning protection over time.[989]Hansen CH, Michlmayr D, Gubbels SM, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet. 2021 Mar 27;397(10280):1204-12.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00575-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/33743221?tool=bestpractice.com
A registry-based study from Sweden found that natural immunity was associated with a 95% lower risk of reinfection and an 87% lower risk of hospitalization compared with no immunity, for up to 20 months. Vaccination appeared to further decrease the risk of both outcomes for up to 9 months, although the differences in absolute numbers were small.[990]Nordström P, Ballin M, Nordström A. Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden. Lancet Infect Dis. 2022 Mar 31;22(6):781-90.
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00143-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/35366962?tool=bestpractice.com
A cohort study across six US states found that unvaccinated people with prior symptomatic COVID-19 had an 85% lower risk of acquiring COVID-19 than unvaccinated individuals without prior COVID-19, and suggests that natural immunity was associated with similar protection against both mild and severe disease.[991]Ridgway JP, Tideman S, Wright B, et al. Rates of COVID-19 among unvaccinated adults with prior COVID-19. JAMA Netw Open. 2022 Apr 1;5(4):e227650.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2791312
http://www.ncbi.nlm.nih.gov/pubmed/35442459?tool=bestpractice.com
An observational study from Lombardy, Italy, found that natural immunity appears to confer a protective effect for at least 1 year; however, the study ended before SARS-CoV-2 variants began to spread, and it is unknown how well natural immunity to the wild-type virus will protect against these variants.[992]Vitale J, Mumoli N, Clerici P, et al. Assessment of SARS-CoV-2 reinfection 1 year after primary infection in a population in Lombardy, Italy. JAMA Intern Med. 2021 Oct 1;181(10):1407-8.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780557
http://www.ncbi.nlm.nih.gov/pubmed/34048531?tool=bestpractice.com
Preexisting immunity to SARS-CoV-2
Testing of blood samples taken before the COVID-19 pandemic has shown that some people already have immune cells that recognize 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.[993]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 recognize SARS-CoV-2 in one study.[994]Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science. 2020 Dec 11;370(6522):1339-43.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857411
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 preexisting immunity to SARS-CoV-2 in the human population is required.
Natural versus vaccine-induced immunity
Protection after natural infection appears to be comparable to that estimated for vaccine efficacy.[963]Mao YJ, Wang WW, Ma J, et al. Reinfection rates among patients previously infected by SARS-CoV-2: systematic review and meta-analysis. Chin Med J (Engl). 2021 Dec 13;135(2):145-52.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC8769121
http://www.ncbi.nlm.nih.gov/pubmed/34908003?tool=bestpractice.com
Evidence suggested that natural immunity may confer at least equal or longer-lasting and stronger protection against infection, symptomatic disease, and hospitalization caused by the Delta variant compared with vaccine-induced immunity.[995]Shenai MB, Rahme R, Noorchashm H. Equivalency of protection from natural immunity in COVID-19 recovered versus fully vaccinated persons: a systematic review and pooled analysis. Cureus. 2021 Oct 28;13(10):e19102.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627252
http://www.ncbi.nlm.nih.gov/pubmed/34868754?tool=bestpractice.com
Protection of natural infection waned with time after primary infection and reached approximately 70% by the 16th month (pre-Omicron period). This is similar to vaccine immunity, but occurs at a slower rate. Immune evasion of Omicron subvariants reduced the overall protection of pre-Omicron natural immunity and accelerated its waning, again, similar to vaccine immunity but at a slower rate. Protection of natural infection against severe reinfection remains strong with no evidence for waning (regardless of variant) for over 14 months after primary infection.[996]Chemaitelly H, Nagelkerke N, Ayoub HH, et al. Duration of immune protection of SARS-CoV-2 natural infection against reinfection. J Travel Med. 2022 Dec 27;29(8):taac109.
https://academic.oup.com/jtm/advance-article/doi/10.1093/jtm/taac109/6731972
http://www.ncbi.nlm.nih.gov/pubmed/36179099?tool=bestpractice.com
Previous natural infection has been associated with a lower incidence of infection, regardless of the variant, compared with the primary series of mRNA vaccination.[997]Chemaitelly H, Ayoub HH, AlMukdad S, et al. Protection from previous natural infection compared with mRNA vaccination against SARS-CoV-2 infection and severe COVID-19 in Qatar: a retrospective cohort study. Lancet Microbe. 2022 Dec;3(12):e944-55.
https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(22)00287-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/36375482?tool=bestpractice.com
Hybrid immunity
Hybrid immunity (immunity developed through a combination of infection and vaccination) provides higher and more sustained protection (including against severe disease and hospital admission) against reinfection with the Omicron variant than either vaccination or infection alone.[998]Bobrovitz N, Ware H, Ma X, et al. Protective effectiveness of previous SARS-CoV-2 infection and hybrid immunity against the omicron variant and severe disease: a systematic review and meta-regression. Lancet Infect Dis. 2023 May;23(5):556-67.
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00801-5/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/36681084?tool=bestpractice.com
Immunity and the Omicron variant
Infection with the Omicron variant has been found to induce strong immune protection against a subsequent Omicron infection, regardless of the subvariant.[999]Hansen CH, Friis NU, Bager P, et al. Risk of reinfection, vaccine protection, and severity of infection with the BA.5 omicron subvariant: a nation-wide population-based study in Denmark. Lancet Infect Dis. 2023 Feb;23(2):167-76.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9578720
http://www.ncbi.nlm.nih.gov/pubmed/36270311?tool=bestpractice.com
[1000]Altarawneh HN, Chemaitelly H, Ayoub HH, et al. Protective effect of previous SARS-CoV-2 infection against Omicron BA.4 and BA.5 subvariants. N Engl J Med. 2022 Oct 27;387(17):1620-2.
https://www.nejm.org/doi/full/10.1056/NEJMc2209306
http://www.ncbi.nlm.nih.gov/pubmed/36198139?tool=bestpractice.com
[1001]Chemaitelly H, Ayoub HH, Coyle P, et al. Protection of Omicron sub-lineage infection against reinfection with another Omicron sub-lineage. Nat Commun. 2022 Aug 9;13(1):4675.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9362989
http://www.ncbi.nlm.nih.gov/pubmed/35945213?tool=bestpractice.com
An additional earlier infection with a non-Omicron variant has been found to strengthen this protection against a subsequent Omicron infection in one study.[1002]Chemaitelly H, Ayoub HH, Tang P, et al. Immune imprinting and protection against repeat reinfection with SARS-CoV-2. N Engl J Med. 2022 Nov 3;387(18):1716-8.
https://www.nejm.org/doi/full/10.1056/NEJMc2211055
http://www.ncbi.nlm.nih.gov/pubmed/36223534?tool=bestpractice.com