The leading cause of death is respiratory failure from acute respiratory distress syndrome (ARDS). 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%). 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. 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.
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. Data from the US indicate that only 5.5% of death certificates in 2020 had COVID-19 without any other conditions listed.
Mortality rates have decreased over time despite stable patient characteristics. Mortality rates decreased sharply in the US over the first 6 months of the pandemic. 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. 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. 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. 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.
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.
The US Centers for Disease Control and Prevention’s current best estimate of the IFR, according to age (as of 19 March 2021):
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%.
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%.
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.
These estimates have limitations and are likely to change as more data emerge over the course of the pandemic.
Estimates of the IFR can be inferred from seroprevalence studies.
Worldwide seroprevalence estimates vary. Seroprevalence in the general population has been estimated to be approximately 8%, with higher rates reported in close contacts (18%) and high-risk healthcare workers (17.1%). Pooled estimates of seroprevalence in the general population were highest in the South-East Asian (19.6%), African (16.3%), and Eastern Mediterranean (13.4%) regions. Lower estimates were reported in the Americas (6.8%), European (4.7%), and Western Pacific (1.7%) regions.
Current seroprevalence estimates for 10 sites in the US are available. CDC: commercial laboratory seroprevalence survey data external link opens in a new window
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 2.1% (as of 9 May 2021). 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%.
CFR varies considerably between countries.
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%).
In China, the majority of deaths were in patients ages ≥60 years. 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%).
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%).
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).
CFR increases with disease severity.
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.
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.
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.
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.
Mortality rate by country
The number of deaths (per 100,000 population) for different countries varies:
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.
Blood type A
Presence of comorbidities
Chronic lung disease
Chronic kidney disease
Bacterial or fungal coinfection
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
Bilateral pneumonia on chest imaging
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.
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. 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%).
People discharged from hospital after acute infection had an increased risk of readmission, multi-organ dysfunction, and mortality compared with the general population. The relative increase in risk was not confined to older people and was not uniform across ethnic groups. Researchers matched approximately 50,000 patients in England who were hospitalized and discharged with COVID-19 to members of the general population; 29% of COVID-19 patients were readmitted during a mean 140 days of follow-up, while 12% died after discharge. Patients with COVID-19 were more frequently diagnosed with cardiovascular events, chronic kidney or liver disease, and diabetes compared with their matched controls.
Approximately 9% of over 106,000 patients were readmitted to the same hospital within 2 months of discharge from the initial hospitalization. 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:
Age ≥65 years
Presence of chronic conditions (COPD, heart failure, diabetes, chronic kidney disease, obesity)
Hospitalization within the 3 months preceding the first COVID-19 hospitalization
Discharge to a skilled nursing facility or with home health care.
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.
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.
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%. 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. 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.
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). 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.
A preprint study of residents and healthcare staff in care homes in the UK found that natural immunity substantially reduces the risk of reinfection for approximately 10 months following primary infection. The risk of reinfection was <1% per month in people who had been previously infected.
Cases of reinfection are rare.
Consider reinfection in the following circumstances:
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).
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.
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.
The immune response to SARS-CoV-2 is not yet fully understood, but involves both cell-mediated and antibody-mediated immunity. This is an area of rapidly emerging new evidence.
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.
Current evidence is uncertain to predict the presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection.
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.
Maternal IgG antibodies to SARS-CoV-2 have been found to transfer across the placenta after infection in pregnant women.
There were some early studies that suggested asymptomatic people may have a weaker antibody response to infection; however, this has not been confirmed.
Antibodies have been detected up to 8 months after infection.
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.
A Public Health England 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.
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.
A prospective study in 3000 mostly young male Marine recruits found that around 10% of seropositive participants tested positive for the virus at least once in the 6-week follow-up period compared with 48% of seronegative participants, an 82% reduced incidence rate of infection.
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.
A 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.
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. 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.
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.
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