Prognosis

Case fatality rate

The overall global case fatality rate (CFR), defined as the total number of deaths reported divided by the total number of detected cases reported, is currently estimated to be 3.1% based on World Health Organization data as of 21 September 2020. The CFR varies considerably between countries.[773]

The overall CFR in China has been estimated to be 2.3% (0.9% in patients without comorbidities) based on a large case series of 72,314 reported cases from 31 December 2019 to 11 February 2020 (mainly among hospitalised patients).[4] However, another study estimates the CFR in China to be lower at 1.38% (after adjusting the crude estimate for censoring, demography, and under-ascertainment).[774]

The overall cumulative incidence of death 90 days after the start of a study in over 10,000 COVID-19 patients in England was <0.01% in those aged 18 to 39 years, and 0.67% and 0.44% in men and women, respectively, in patients aged 80 years and older. Increased risk of death was associated with factors including increasing age, being male, Black and South Asian ethnicity, and comorbidities such as diabetes, severe asthma, and various other medical conditions.[775]

Reported CFRs need to be interpreted with extreme caution. In pandemics, CFRs tend to start high and then trend downwards as more data becomes available. For example, at the start of the 2009 H1N1 influenza pandemic the CFR varied from 0.1% to 5.1% (depending on the country), but the mortality rate ended up being around 0.02%.[776] Centre for Evidence-Based Medicine: global COVID-19 case fatality rates external link opens in a new window

Factors that affect the CFR include:

  • Increased case detection of patients with severe disease

  • Testing limitations (some countries are only testing patients who have severe symptoms)

  • Testing rates in each country

  • Delays between symptom onset and death

  • Local factors (e.g., patient demographics, availability and quality of health care, other endemic diseases).

Also, the CFR is based on the number of detected cases and there is currently no set definition of a case. 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 equal COVID-19, or mean that a person is necessarily infected or infectious.[777]

It is important to note that daily death counts need to be interpreted with caution. 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.[778]

In Italy, the CFR may be higher because Italy has the second oldest population in the world, the highest rates of antibiotic resistance deaths in Europe, and a higher incidence of smoking (a known risk factor for more severe disease). The way COVID-19 related deaths are identified and reported in Italy may have also resulted in an overestimation of cases. Patients who die ‘with’ COVID-19 and patients who die ‘from’ COVID-19 are both counted towards the death toll. Only 12% of death certificates have shown direct causality from COVID-19, while 88% of patients who have died had at least one comorbidity.[776][779]

The overall CFR appears to be less than that reported for severe acute respiratory syndrome coronavirus (SARS) (10%) and Middle East respiratory syndrome (MERS) (37%).[31] Despite the lower CFR, COVID-19 has so far resulted in more deaths than both SARS and MERS combined.[780]

Infection fatality rate

The infection fatality rate (IFR) is the proportion of deaths among all infected individuals including confirmed cases, undiagnosed cases (e.g., mildly symptomatic or asymptomatic cases), and unreported cases. While the CFR is subject to selection bias as more severe/hospitalised cases are tested, the IFR gives a more accurate picture of the lethality of a disease, especially as testing becomes more rigorous within a population. The Centers for Disease Control and Prevention’s current best estimate of the overall IFR is 0.65%.[107]

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 could be much lower.[781]

Evidence from seroprevalence studies suggests that the prevalence of infections is much higher than the official figures suggest, and that the virus is much less lethal than the current global case and death counts indicate.

  • UK: data from the first round of results of the UK Biobank COVID-19 antibody study indicate that 7.1% of participants had been infected previously overall. 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).[782] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies were measured in the community at an overall adjusted prevalence of 6% in England (20 June to 13 July 2020).[783]

  • US: seroprevalence estimates for 10 sites in the US (Connecticut, Louisiana, Minnesota, Missouri, New York City metro area, Philadelphia, San Francisco Bay Area, South Florida, Utah, and Western Washington State) are available from the Centers for Disease Control and Prevention. In the New York City metro area, the number of estimated infections is at least 7 times higher than the number of cases reported according to the latest figures reported for the period 15 to 21 June.[784] CDC: commercial laboratory seroprevalence survey data external link opens in a new window

  • Spain: seroprevalence estimates from a nationwide study indicate a seroprevalence of around 5%, with the prevalence in hotspots (e.g., Madrid) being five times higher than that in low-risk regions.[785]

  • Switzerland: seroprevalence data from Geneva indicate an IFR of 0.64% for the total population, and an IFR of 0.0092% for people aged 20 to 49 years, 0.14% for people aged 50 to 64 years, and 5.6% for people aged 65 years and older.[786]

  • Iran: the seroprevalence estimate after adjusting for population and test performance characteristics in Guilan province was 22% to 33%, resulting in an estimated IFR of 0.08% to 0.12%.[787]

  • Denmark: a seroprevalence study in blood donors estimates the IFR to be approximately 0.08% in people aged under 70 years.[788]

  • Los Angeles county, California: based on results of the first round of testing, a research team estimates that approximately 2.8% to 5.6% of the county’s adult population has antibodies to the virus, an estimated IFR of 0.1% to 0.2% based on current deaths in the county.[789] Published seroprevalence data from adults in Los Angeles county found that the community prevalence of SARS-CoV-2 antibodies was 4.65% in early April. Based on this figure, the authors estimate that approximately 367,000 county residents had SARS-CoV-2 antibodies. This is much higher than the number of confirmed infections at this time, which was 8430. They conclude that fatality rates based on the number of confirmed cases may be much higher than the rates based on the actual number of infections.[790]

  • Santa Clara county, California: an analysis of 3300 people in early April found that the seroprevalence of antibodies to SARS-CoV-2 in Santa Clara county was between 2.49% and 4.16%. Based on this, researchers estimate that between 48,000 and 81,000 people were infected with the virus at the time (out of the county’s population of approximately 2 million people). Researchers estimate an IFR of 0.1% to 0.2% based on this data.[791]

  • Germany: the overall seroprevalence in healthcare workers in a tertiary hospital was low (1.6%).[792]

  • Iceland: the country where the most testing per capita has occurred - the IFR lies between 0.01% and 0.19%.[776] A more recent study found that the incidence of infection in Iceland was 0.9%, and the IFR was 0.3%.[793]

  • China: seropositivity varied between 3.2% and 3.8% in Wuhan, and decreased in other Chinese cities as the distance to the epicentre increased.[794]

These estimates are likely to change as more data emerge.

Case fatality rate according to age and presence of comorbidities

The CFR increases with age.[774] The presence of comorbidities is associated with greater disease severity and poor clinical outcomes, and the risk increases with the number of comorbidities a patient has.[795]

The majority of deaths in China have been in patients aged 60 years and older and/or those who have pre-existing underlying health conditions (e.g., hypertension, diabetes, cardiovascular disease). The CFR was highest among critical cases (49%). It was also higher in patients aged 80 years and older (15%), males (2.8% versus 1.7% for females), and patients with comorbidities (10.5% for cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6% for hypertension, and 5.6% for cancer).[4] Another study found the CFR in China to be 6.4% in patients aged ≥60 years versus 0.32% in patients aged <60 years, and 13.4% in patients aged ≥80 years.[774]

In Italy, the CFR was 8.5% in patients aged 60 to 69 years, 35.5% in patients aged 70 to 79 years, and 52.5% in patients aged ≥80 years.[796] In a case series of 1591 critically ill patients in Lombardy, the majority of patients were older men, a large proportion required mechanical ventilation and high levels of positive end-expiratory pressure, and the mortality rate in the intensive care unit was 26%.[797]

In the US, the CFR was highest among patients aged ≥85 years (10% to 27%), followed by those aged 65 to 84 years (3% to 11%), 55 to 64 years (1% to 3%), 20 to 54 years (<1%), and ≤19 years (no deaths). Patients aged ≥65 years accounted for 80% of deaths.[7] The CFR among critically ill patients admitted to the intensive care unit reached 67% in one hospital in Washington state. Most of these patients had underlying health conditions, with congestive heart failure and chronic kidney disease being the most common.[798] The CFR in residents in a long-term care facility in Washington was reported to be 34%.[799]

The case fatality rate in patients with cancer was 37% for patients with haematological malignancies and 25% for solid malignancies in one study. Some 55% of lung cancer patients died from COVID-19.[800]

Children have a good prognosis and generally recover within 1 to 2 weeks, and deaths are rare.[17] In one study, approximately 75% of COVID-19-related deaths in young people under the age of 21 years in the US occurred in those with underlying health conditions, most commonly asthma, obesity, neurological/developmental conditions, and cardiovascular conditions. The majority of deaths occurred in those aged 10 to 20 years (70%), with 20% of deaths in those aged 1 to 9 years, and 10% in infants under 1 year of age. Hispanic, non-Hispanic Black, and non-Hispanic American Indian/Alaskan Native people accounted for 78% of deaths.[801]

Prognostic factors

The leading cause of death in patients with COVID-19 is respiratory failure from acute respiratory distress syndrome.[802] The overall pooled mortality rate from acute respiratory distress syndrome in COVID-19 patients is 39%; however, this varies significantly between countries (e.g., China 69%, Iran 28%, France 19%, Germany 13%).[803] Patients who required invasive mechanical ventilation had an 88% mortality rate in one study in New York, but it has been much lower (36% to 53%) in other studies.[804][805][806] The other most common complications in deceased patients are myocardial injury, liver or kidney injury, and multi-organ dysfunction.[807] The strongest predictor of in-hospital mortality was chronic pulmonary disease, followed by chronic cardiovascular disease, older age, and elevated interleukin-6 and D-dimer levels at admission in a New York study.[539] In one retrospective study of 52 critically ill patients in Wuhan City, 61.5% of patients died by 28 days, and the median time from admission to the intensive care unit to death was 7 days for patients who didn’t survive.[808]

Prognostic factors that have been associated with increased risk of unfavourable outcomes and mortality include:[809]

  • Age ≥50 years

  • Male sex

  • Smoking

  • Presence of comorbidities (e.g., hypertension, diabetes, cardiovascular or cerebrovascular disease, COPD, obesity, malignancy)

  • Lymphopenia

  • Thrombocytopenia

  • Liver, kidney impairment, or cardiac injury

  • Elevated inflammatory markers (C-reactive protein, procalcitonin, ferritin)

  • Elevated D-dimer

  • Elevated interleukin-6.

The most common risk factors for death are age ≥65 years, male sex, hypertension, cardiovascular disease, diabetes, chronic obstrictive pulmonary disease, and cancer.[810]

Prognostic scores

The APACHE II score was found to be an effective clinical tool to predict hospital mortality in patients with COVID-19, and performed better than SOFA and CURB-65 scores in a small retrospective observational study. An APACHE II score of 17 or more was an early indicator of death and may help provide guidance to make further clinical decisions.[811] In another retrospective study, A-DROP (a modified version of CURB-65) showed better accuracy of in-hospital death prediction on admission compared with other widely used community-acquired pneumonia scores.[812] Further research is required to confirm these findings, and to validate the use of prognostic scores in patients with COVID-19.

New clinical risk scores to predict disease progression and the risk for critical illness in hospitalised patients with COVID-19 have been developed (e.g., COVID-GRAM, CALL score).[813][814] COVID-GRAM, a web-based calculator to estimate the probability that a patient will develop critical illness (defined as intensive care admission, invasive ventilation, or death) has been validated in a study of nearly 1600 patients in China. It relies on the following 10 variables at admission: chest radiographic abnormality, age, haemoptysis, dyspnoea, unconsciousness, number of comorbidities, cancer history, neutrophil-to-lymphocyte ratio, lactate dehydrogenase, and direct bilirubin. Additional validation studies, especially outside of China, are required.[814]

The 4C (Coronavirus Clinical Characterisation Consortium) Mortality Score was developed and validated in a UK prospective cohort study of nearly 60,000 adults admitted to hospital with COVID-19. The score uses patient demographics, clinical observations, and blood parameters commonly available at the time of hospital admission (i.e., age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, Glasgow Coma Scale score, urea, C-reactive protein), and can accurately characterise patients as being at low, intermediate, high, or very high risk of death. The score outperformed other risk stratification tools, showed clinical decision-making utility, and had similar performance to more complex models. The score should be further validated to determine its applicability in other populations.[815]

Refractory disease

Refractory disease (patients who do not reach obvious clinical and radiological remission within 10 days after hospitalisation) has been reported in nearly 50% of hospitalised patients in one retrospective single-centre study of 155 patients in China. Risk factors for refractory disease include older age, male sex, and the presence of comorbidities. These patients generally require longer hospital stays as their recovery is slower.[816]

Infectivity of recovered cases

Potential infectivity of recovered cases is still unclear. There have been case reports of patients testing positive again after being discharged. This suggests that some patients in convalescence may still be contagious, although this is yet to be confirmed.[817][818]

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%.[819] It is currently unclear whether this is due to reinfection, 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).[820]

More recently a man from Hong Kong is reported to have the first confirmed case of reinfection; the patient’s two symptomatic episodes (4.5 months apart) were caused by virus strains with different genomic sequences.[821]

Post-infection immunity

Evidence is currently insufficient to know whether individuals with SARS-CoV-2 antibodies have protective immunity.[399] A study in macaques suggests that infection with SARS-CoV-2 offers protection against reinfection.[822] Limited data suggest that recovery from COVID-19 might confer immunity against reinfection in humans, too.[823] Most convalescent patients have detectable neutralising antibodies and cellular immune responses.[824] In a study of over 1200 patients who recovered from confirmed COVID-19 in Iceland, over 90% of patients tested positive for SARS-CoV-2 antibodies; antibody levels increased during the 2 months after diagnosis and then plateaued, remaining stable over the next 2 months.[793] Among 175 patients who recovered from mild disease in China, neutralising antibody titres to SARS-CoV-2 varied substantially.[825]There are data to suggest that asymptomatic people may have a weaker immune response to infection; however, this is yet to be confirmed.[826]

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