Epidemiology

Adults

  • In China, 87% of confirmed cases were aged 30 to 79 years and 3% were aged 80 years or older. Approximately 51% of patients were male.[4]

  • In Italy, the median age and prevalence of comorbidities was higher compared with China.[5]

  • In the UK, the median age of patients was 73 years and males accounted for 60% of admissions in a prospective observational cohort study of more than 20,000 hospitalised patients.[6]

  • In the US, older patients (aged ≥65 years) accounted for 31% of all cases, 45% of hospitalisations, 53% of intensive care unit admissions, and 80% of deaths, with the highest incidence of severe outcomes in patients aged ≥85 years.[7]

Children

  • Evidence suggests that children have a lower susceptibility to infection compared with adults, with an odds ratio of 0.56 for being an infected contact compared with adults. Adolescents appear to have similar susceptibility to adults.[8]

  • The mean age of children with infection is 6.5 years.[9] Infection rates in children and adolescents vary according to geographical location:[4][10][11][12][13][14][15]

  • In the UK, a prospective observational cohort study found that children and young adults represented 0.9% of all hospitalised patients at the time. The median age of children admitted to hospital was 4.6 years, 56% were male, 35% were under 12 months of age, and 42% had at least one comorbidity. In terms of ethnicity, 57% were White, 12% were South Asian, and 10% were Black. Age under 1 month, age 10 to 14 years, and Black race were risk factors for admission to critical care.[16]

  • In the US, a retrospective cohort study of over 135,000 children found that the mean age of infected children was 8.8 years, and 53% were male. In terms of ethnicity, 59% were White, 15% were Black, 11% were Hispanic, and 3% were Asian. Only 4% of children tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this population, and clinical manifestations were typically mild.[17]

  • Most cases in children are from familial clusters, or children who have a history of close contact with an infected patient. It is rare for children to be the index case in household transmission clusters.[18] Unlike adults, children do not seem to be at higher risk for severe illness based on age or sex.[19]

Pregnant women

  • A meta-analysis of over 2500 pregnant women with confirmed COVID-19 found that 73.9% of women were in the third trimester; 50.8% were from Black, Asian, or minority ethnic groups; 38.2% were obese; and 32.5% had chronic comorbidities.[20]

  • In the UK, the estimated incidence of admission to hospital with confirmed SARS-CoV-2 infection in pregnancy is 4.9 per 1000 maternities. Most women were in the second or third trimester. Of these patients, 41% were aged 35 years or older, 56% were from Black or other ethnic minority groups, 69% were overweight or obese, and 34% had pre-existing comorbidities.[21]

  • In the US, 53,641 cases have been reported in pregnant women (as of 4 January 2021), with 9619 hospitalisations and 62 deaths.[22] According to an analysis of approximately 400,000 women aged 15 to 44 years with symptomatic disease, Hispanic and non-Hispanic Black pregnant women appear to be disproportionately affected during pregnancy.[23]

Healthcare workers

  • The incidence of infection in healthcare workers ranged from 0% to 49.6% (by polymerase chain reaction), and the prevalence of SARS-CoV-2 seropositivity ranged from 1.6% to 31.6%. The wide ranges are likely related to differences in settings, exposures, rates of community transmission, symptom status, use of infection control measures, and other factors.[24][25]

  • A systematic review and meta-analysis of nearly 130,000 healthcare workers estimated the overall seroprevalence of SARS-CoV-2 antibodies to be 8.7%, with higher seroprevalence reported in North America (12.7%) compared with Europe (8.5%), Africa (8.2%), and Asia (4%). Risk factors for seropositivy included male sex; Black, Asian, or Hispanic ethnicity; working in a COVID-19 unit; patient-facing work; and frontline healthcare work.[26]

  • Approximately 14% of the cases reported to the World Health Organization are in healthcare workers (range 2% to 35%).[27]

  • The majority of healthcare workers with COVID-19 reported contact in the healthcare setting. In a study of over 9000 cases reported in healthcare workers in the US, 55% had contact only in a healthcare setting, 27% only in a household, 13% only in the community, and 5% in more than one setting.[28]

  • The most frequently affected healthcare workers were nurses. Only 5% of healthcare workers developed severe disease and 0.5% died.[29] The incidence of severe or critical disease and mortality in healthcare workers was lower than the incidence of severe or critical disease and mortality in all patients.[30]

  • Patient-facing healthcare workers were three times more likely to be admitted to hospital compared with non-patient-facing workers according to a study in Scotland. In the same study, healthcare workers and their household members accounted for 17% of hospitalisations.[31]

  • Analysis of hospitalisation data from 13 sites in the US found that 6% of hospitalised adults were healthcare workers, and 36% of these people were in nursing-related roles. Around 90% of hospitalised healthcare workers had at least one underlying condition, the most common conditions being obesity, hypertension, and diabetes.[32]

Resources

Risk factors

People residing or working in an area with a high risk of transmission (e.g., closed residential settings, humanitarian setting), people residing in or travelling to an area with community transmission, and people working in a health setting (including within health facilities and households) at any time within the 14 days prior to symptom onset are at higher risk of infection.[178]

The World Health Organization defines a contact as a person who has experienced any one of the following exposures during the 2 days before and the 14 days after the onset of symptoms of a probable or confirmed case: face-to-face contact with a probable or confirmed case within 1 metre (3 feet) and for at least 15 minutes; direct physical contact with a probable or confirmed case; direct care for a patient with probable or confirmed COVID-19 without using recommended personal protective equipment; or other situations as indicated by local risk assessments.[178]

The US Centers for Disease Control and Prevention defines a close contact as someone who has been within 2 metres (6 feet) of an infected person for at least 15 minutes over a 24-hour period, beginning 2 days before symptom onset (or 2 days before testing in asymptomatic patients). In the previous definition, the 15-minute exposure window was continuous.[179] This is based on one study of a correctional facility officer who tested positive after having multiple brief encounters with six positive prisoners totalling over 17 minutes during an 8-hour shift, despite the officer wearing a mask and goggles.[180]

Older age is a risk factor for infection.[181] Data from a cross-sectional study in the UK indicate that people aged 40 to 64 years are at greatest risk of infection, followed by patients 75 years and older, and then people aged 65 to 74 years.[182] The risk of severe illness in adults increases with age, with older people (aged 65 years and older) at highest risk.[183][184] The highest mortality rate has been observed in patients 80 years and older.[185] In the US, patients ≥65 years accounted for 31% of all cases, 45% of hospitalisations, 53% of intensive care unit admissions, and 80% of deaths, with the highest incidence of severe outcomes in patients aged ≥85 years.[7] While age is an independent risk factor, the risk in older people is also partly related to the likelihood that older adults are more likely to have comorbidities.

Widespread transmission has been reported in long-term care facilities.[113] People who live in a nursing home or long-term care facility are at higher risk for severe illness.[184] Care home residents represent approximately one third of the total number of deaths in England and Wales; other countries have reported a similar experience. This is likely due to shortages in personal protective equipment, a vulnerable population, and a lack of testing.[186] More than one third of care homes in England have had cases.[187] A study across four nursing homes in the UK found that 26% of residents died over a 2-month period, with all-cause mortality increasing by 203% compared with previous years. Approximately 40% of residents tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and of these, 43% were asymptomatic and 18% had atypical symptoms.[188] In a cohort study of more than 5000 nursing home residents in the US, the 30-day all-cause mortality rate was 21%. Increased age, male sex, and impaired cognitive and physical function were independently associated with mortality.[189]

Male sex is a risk factor for severe disease, intensive care admission, and mortality.[190] Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in males (18.4%) compared with females (13.3%).[182] It has been hypothesised that this may be due to the presence of androgens, a lower level of SARS-CoV-2 antibodies compared with females, or women mounting a stronger immune response compared with men; however, further research is required.[191][192][193] The higher prevalence of alcohol consumption and smoking may also contribute to the higher prevalence of infection among men.[194]

People from Black, Asian, and minority ethnic (BAME) groups are at a higher risk of infection and worse outcomes, including an increased risk of intensive care unit admission and mortality, compared with White people.[195][196]

Data from a cross-sectional study in the UK found that South Asian and Black patients had 1.93 and 1.47 the odds of suspected infection, respectively.[197] The average age of patients from ethnic minorities was significantly lower than that of White patients.[198] Ethnic minorities in the UK (including South Asian, East Asian, Black, and other ethnic minorities) admitted to hospital were more likely to be admitted to intensive care and require invasive mechanical ventilation compared with White patients, despite similar disease severity at admission and being younger with fewer comorbidities.[199]

Age-adjusted data from the US Centers for Disease Control and Prevention (as of 2 January 2021) show that Hispanic or Latino people, non-Hispanic American Indian or Alaska Native people, and non-Hispanic Black people have approximately 3.4, 3.3, and 3 times the rate of hospitalisations of non-Hispanic White people, respectively.[200] However, cohort studies in the US have found no difference in outcomes between non-Hispanic Black and Hispanic people compared with White patients after adjusting for sociodemographic factors, and comorbidities (e.g., age, sex, insurance).[201][202] In a large national registry of COVID-19 hospitalisations, Black and Hispanic patients accounted for over 50% of hospitalisations. After adjusting for sociodemographic and clinical characteristics, mortality and major cardiovascular or cerebrovascular adverse events did not differ by ethnicity. This indicates that Black and Hispanic patients may have an increased risk of mortality and morbidity due to their disproportionate representation among hospitalisations.[203] In a study of over 10,000 deceased patients in the US, 35% of Hispanic and 30% of non-White decedents were aged <65 years, compared with 13% of White, non-Hispanic decedents.[204] An analysis of over 114,000 COVID-19–associated deaths in the US found that 51.3% of decedents were non-Hispanic White, 24.2% were Hispanic or Latino, and 18.7% were non-Hispanic Black.[205]

Racial disparities in outcomes may be partially attributed to higher rates of comorbidities in certain ethnic groups.[206]

People with comorbidities are at higher risk for severe illness and mortality.[207] The more comorbidities a person has, the greater their risk for severe illness.[208] In the US, approximately 90% of hospitalised patients had at least one reported underlying medical condition, with the most common being hypertension (56%), obesity (48%), metabolic disease (42%), and cardiovascular disease (33%).[200] In a prospective observational cohort study of more than 20,000 hospitalised patients in the UK, the most common comorbidities were chronic cardiac disease (31%), uncomplicated diabetes (21%), non-asthmatic chronic pulmonary disease (18%), and chronic kidney disease (16%).[6] Similarly, in the US the most common comorbidities were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Hospitalisations were six times higher and deaths were 12 times higher in patients with comorbidities compared with those without.[209] It has been estimated that approximately 56% of adults in the US are at risk for requiring hospitalisation from COVID-19 because of the presence of at least one comorbidity. These underlying conditions are associated with modifiable risk factors, which, if improved through lifestyle changes, may improve a person’s risk status.[210]

Among 345 paediatric cases with information on underlying conditions, 23% had at least one underlying condition, most commonly chronic lung disease, cardiovascular disease, or immunosuppression.[211] Approximately 39% of hospitalised children had an underlying condition in another study. The most prevalent comorbidities were asthma, neurological disorders, diabetes, obesity, cardiovascular disease, and malignancy/haematological conditions.[212] In the US, approximately 52% of children had at least one reported underlying medical condition, with the most common being obesity (39%), neurological disease (13%), and asthma (11%).[200] Children with comorbidities have a relative risk ratio of 1.79 for severe disease, and a relative risk ratio of 2.81 for mortality, compared with children without comorbidities.[213]

Around 32% of young adults (aged 18-25 years) in the US had underlying conditions that put them at risk for severe disease including heart conditions, diabetes, asthma, immune conditions, liver conditions, and obesity. Smoking (including e-cigarette use) in the past 30 days also increased the risk. The rate of young adults at risk for severe disease decreased to 16% when considering non-smokers only.[214]

People with serious heart conditions (e.g., heart failure, coronary artery disease, cardiomyopathies) are at increased risk of severe illness.[208] Arrhythmias, coronary artery disease, and cardiovascular disease are significantly associated with intensive care unit admission. Heart failure, arrhythmias, coronary artery disease, and cardiovascular disease are also significantly associated with an increased risk of mortality.[215] The relative risk of developing severe disease or dying was significantly higher in people with risk factors for cardiovascular disease (e.g., hypertension, diabetes) and those with cardiovascular disease.[216]

People with hypertension may be at increased risk of severe illness.[208] Hypertension has been associated with increased poor composite outcome, including mortality, severe disease, acute respiratory distress syndrome, need for intensive care admission, and disease progression.[217] Patients with hypertension have a 2.98-fold higher risk of severe disease, and a 2.88-fold higher risk of fatality compared with patients without hypertension.[218]

People with obesity (≥30 kg/m²) or severe obesity (≥40 kg/m²) are at increased risk of severe illness, and people who are overweight (25-30 kg/m²) may be at increased risk of severe illness; however, evidence is limited for the latter group.[208] Obesity is associated with an increased risk for infection, higher risk of hospitalisation, progression to severe or critical disease, need for invasive mechanical ventilation, and higher risk of in-hospital mortality.[219][220][221] Obesity plays a significant role in the risk of death from COVID-19, particularly in males and younger people (<60 years of age).[222] Obese patients are also at higher risk for venous thromboembolism and dialysis.[223] Increased body mass index is a significant risk factor for severe disease in pregnant women.[224] Obesity was the most common comorbidity in children, and was significantly associated with mechanical ventilation in children 2 years and older in a single-centre retrospective study in New York.[225]

People with type 2 diabetes are at increased risk of severe illness. People with type 1 diabetes or gestational diabetes may also be at increased risk of severe illness; however, evidence is limited for these patient groups.[208] The pooled prevalence of diabetes in COVID-19 patients is approximately 15%.[226] Diabetes is associated with an increased risk of disease progression, intensive care admission, acute respiratory distress syndrome, mechanical ventilation, and mortality.[227][228] The risk of intensive care admission and mortality is significantly higher in patients with diabetes compared with those without diabetes (pooled risk ratio of 1.88 and 1.61, respectively).[226] One third of all deaths in hospitalised patients in England occur in patients with diabetes. People with type 1 diabetes have 3.50 times the odds of dying in hospital with COVID-19, while people with type 2 diabetes have 2.03 times the odds.[229] An analysis of more than 19,000 patients admitted to critical care over the entire first wave of disease in England found that type 2 diabetes is associated with a 20% increase in mortality in patients with severe disease, independent of age, sex, ethnicity, obesity, or other major comorbidity.[230] Risk factors for poor prognosis and higher mortality in patients with type 1 or type 2 diabetes include older age, male sex, non-White ethnicity, socioeconomic deprivation, renal impairment, history of stroke or heart failure, higher glycosylated haemoglobin (HbA1c) levels, higher body mass index, elevated C-reactive protein, diabetic ketoacidosis, and insulin use.[231][232][233] However, HbA1c levels were not associated with mortality in a large US cohort of hospitalised patients with diabetes and COVID-19, while insulin treatment and obesity were strong and independent risk factors for in-hospital mortality.[234] Hyperglycaemia is also an independent risk factor for poor prognosis in hospitalised patients with or without known diabetes.[235][236] Patients with newly diagnosed diabetes have a higher risk of all-cause mortality compared with patients with known diabetes, hyperglycaemia, or normal glucose.[237] The poor prognosis in these patients is likely due to the syndromic nature of diabetes, with factors such as hyperglycaemia, older age, and the presence of comorbidities (e.g., obesity, hypertension, cardiovascular disease) all contributing to the increased risk.[238] Metformin use has been associated with lower mortality.[239]

There is no clear evidence that people with asthma or chronic obstructive pulmonary disease (COPD) are at higher risk of infection.[240][241] However, people with COPD (including emphysema and chronic bronchitis) are at increased risk of severe illness.[208] COPD is associated with a more than 3-fold increased risk of severe illness and mortality.[242] People with moderate to severe asthma may be at increased risk of severe illness; however, evidence is limited.[208] A meta-analysis found that asthma is not associated with severe disease, worse prognosis, or a higher risk of intubation or mechanical ventilation. Patients with asthma had a lower risk of death compared with non-asthmatic patients.[243] The prevalence of asthma in patients with COVID-19 is significantly lower (1.6%) than the global prevalence of asthma (4.4%).[244] People with other chronic lung diseases (e.g., cystic fibrosis, idiopathic pulmonary fibrosis) may be at increased risk of severe illness; however, the evidence is limited.[208] There are no data on whether paediatric respiratory diseases (including childhood asthma) are risk factors for infection or severity.[245]

People with chronic kidney disease may be at higher risk of infection. Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in patients with chronic kidney disease (32.9%) compared with those without (14.4%).[182] People with chronic kidney disease are also at increased risk of severe illness.[208] The prevalence of pre-existing chronic kidney disease in COVID-19 patients was 5.2% (2.3% for end-stage kidney disease), and is an independent risk factor for developing acute kidney injury as a complication.[246]

People with cancer are at a higher risk of infection, likely due to immunosuppressive treatments and/or recurrent hospital visits.[247] The overall pooled prevalence of cancer in hospitalised patients is approximately 2.6%, with a lower incidence in China compared with Western countries.[248] People with cancer are also at increased risk of severe illness.[208] Patients with cancer are 76% more likely to get severe disease compared with those without cancer.[249] They also have an increased risk of worse clinical outcomes including intensive care unit admission and all-cause mortality (particularly those with metastatic disease, haematological cancer, or lung cancer), and appear to deteriorate more quickly compared with patients without cancer.[250][251] The odds ratio of intensive care admission rates and mortality rates between cancer and non-cancer groups was 2.88 and 2.25, respectively.[252] The pooled in-hospital mortality risk in patients with cancer is 14.1%.[248] Risk factors for mortality in patients with cancer include male sex, older age, presence of one or more comorbidities, hypertension, COPD, and the presence of complications (e.g., acute respiratory distress syndrome, acute renal failure). Patients with haematological malignancies have an increased risk of mortality compared with those with solid tumours. Recent anticancer treatments are not significantly associated with an increased mortality rate.[253] While active chemotherapy or chemotherapy within the last 30 days increased the risk of death, targeted therapies, immunotherapy, surgery, and radiotherapy did not appear to increase the risk for severe disease or death.[254][255] Children with cancer may be no more vulnerable to infection compared with children without cancer. Limited data show that the overall morbidity in paediatric patients with cancer is low, with only 5% requiring hospitalisation for symptoms.[256]

People with sickle cell disease are at increased risk of severe illness.[208] Among 178 patients with sickle cell disease and COVID-19 in the US (mean patient age <40 years), 69% were hospitalised, 11% were admitted to intensive care, and 7% died.[257] Infection can cause acute chest syndrome in patients with sickle cell disease.[258][259]

People with an immunocompromised state from solid organ transplant are at increased risk of severe illness.[208] Solid organ transplant recipients are at higher risk of hospitalisation, intensive care unit admission, and mortality. However, the increased rate of hospitalisation may reflect a preferred management strategy of closer inpatient monitoring in these patients rather than being an indicator of disease severity. Overall mortality in solid organ transplant recipients was 20%.[260] Hospitalisation and mortality rates in liver transplant recipients are disproportionately high compared with non-transplant patients regardless of age or time after transplant. Older age and diabetes are significant risk factors for death among these patients.[261]

People who are current or former smokers are at increased risk of severe illness.[208] Current smokers have an increased risk of severe or critical disease. Patients with any smoking history have a significantly increased risk of severe or critical disease, in-hospital mortality, disease progression, and need for mechanical ventilation.[262] Smokers have double the mortality risk compared with non-smokers.[263] This may be due to increased airway expression of the angiotensin-converting enzyme-2 receptor in smokers.[264] The World Health Organization has reviewed the available evidence and concluded that smoking is associated with increased severity of disease and death in hospitalised patients.[265]

People with cerebrovascular disease may be at increased risk of severe illness; however, evidence is limited.[208] The pooled prevalence of pre-existing cerebrovascular disease in COVID-19 patients is 3%.[266] Patients with a history of cerebrovascular disease are more likely to progress to adverse outcomes compared with patients without a history of cerebrovascular disease.[267] Patients with pre-existing cerebrovascular disease have 2.67-fold higher odds of poor outcomes including intensive care admission, mechanical ventilation, and mortality.[268]

Dementia is associated with increased risk of infection and increased mortality.[269] People with dementia are also at increased risk of severe illness; however, evidence is limited.[208] The incidence of dementia in COVID-19 patients is approximately 9%.[270] In the UK, over one quarter of people who died with COVID-19 from March to June 2020 had dementia. Dementia and Alzheimer's disease was the most common main pre-existing health condition in deaths involving COVID-19 between March and June 2020.[271]

People with chronic liver disease, especially cirrhosis, may be at increased risk of severe illness; however, evidence is limited.[208] The prevalence of chronic liver disease in COVID-19 patients is approximately 3%. The presence of chronic liver disease is associated with more severe disease and overall mortality.[272] The 30-day mortality rate is higher in patients with cirrhosis, with the main causes of death being respiratory complications and sudden worsening of liver function leading to end-stage liver disease.[273]

People with metabolic dysfunction-associated fatty liver disease (MAFLD; also called non-alcoholic fatty liver disease) are at increased risk of severe illness, with a pooled odds ratio of 2.93.[274] Severity of COVID-19 has been associated with younger age (<60 years) and intermediate or high fibrosis-4 (FIB-4) scores in patients with MAFLD.[275][276]

Surgical mortality and complications are higher in patients with COVID-19 compared with patients without COVID-19.[277] A retrospective study of 34 patients in China who underwent elective surgeries during the incubation period of COVID-19 found that all patients developed pneumonia after surgery. Approximately 44% of these patients required admission to the intensive care unit, and 20% died.[278] Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection, and are associated with higher mortality, particularly in men and those aged 70 years and over.[279]

Pregnant women are at increased risk of severe illness.[208] According to an analysis of approximately 400,000 women aged 15 to 44 years with symptomatic disease, pregnant women were more likely to be hospitalised, to be admitted to the intensive care unit, and to receive invasive mechanical ventilation or extracorporeal membrane oxygenation, and to die compared with non-pregnant women.[23]

People who are immunocompromised (e.g., blood or bone marrow transplant, immune deficiencies, prolonged use of corticosteroids or other immunosuppressant medications) may be at increased risk of severe illness; however, evidence is limited.[208] Patients with inflammatory bowel disease who were on long-term biologicals did not have a higher risk of poor outcomes; however, recent corticosteroid use, thiopurine use, or combination therapy may be related to an increased risk of severe disease and worse outcomes.[280][281] Glucocorticoid exposure of ≥10 mg/day (prednisolone) has been associated with a higher odds of hospitalisation in patients with rheumatological disease.[282] Patients treated with ciclosporin/tacrolimus also had an increased risk of hospitalisation; however, it was not clear whether the increased risk is related to the drug itself, the underlying condition for which the patient is treated, or other factors.[283] Also see HIV infection and Autoimmune disease, below.

Autoimmune disease is associated with an increased risk of infection. However, clinical outcomes were not considerably worse when compared with people without autoimmune disease. Use of corticosteroids increased the risk of infection and severe outcomes, and use of combination disease-modifying antirheumatic drugs (DMARDs) increased the risk of severe outcomes. DMARD monotherapy, particularly tumour necrosis factor inhibitors, reduced the risk of severe disease and mortality. Other factors associated with severe disease in this population include older age and the presence of comorbidities.[284] In patients with multiple sclerosis, neurological disability, age, and obesity were risk factors for severe disease.[285] In patients with inflammatory bowel disease, infection risk is comparable to the general population, and patient outcomes (hospitalisation, intensive care unit admission, and mortality) are worse in ulcerative colitis and patients on corticosteroids or aminosalicylates. Outcomes are better in patients on biological agents.[286]

Vitamin D deficiency may be associated with an increased risk of infection.[287] Observational and retrospective studies have found an association between vitamin D deficiency and a higher risk for infection.[288][289][290][291][292] A population-based study in Israel found that patients who tested positive for COVID-19 had significantly lower plasma vitamin D levels compared with those who tested negative. Univariate analysis demonstrated an association between low plasma vitamin D level and increased likelihood of hospitalisation. The study concluded that low plasma vitamin D level appears to be an independent risk factor for COVID-19 infection and for hospitalisation.[293] A meta-analysis found that vitamin D deficiency increased the risk of hospitalisation and mortality, and patients with severe disease were more likely to have vitamin D deficiency compared with patients with mild disease.[294] A cross-sectional study in 235 hospitalised patients in Iran found that patients who had sufficient serum vitamin D levels at admission, defined as serum 25(OH)D level ≥30 nanograms/mL, had significantly lower blood levels of C-reactive protein and a higher total blood lymphocyte count compared with those with insufficient vitamin D levels, suggesting that sufficient vitamin D levels improved immune function in these patients. Severe disease was less prevalent in patients with adequate vitamin D levels, and among those ages 40 years and over who died approximately 90% had insufficient vitamin D levels.[295]

Evidence suggests that there may be an association between long-term exposure to ambient air pollution and COVID-19.[296][297] The highest numbers of cases were recorded in the most polluted regions of Italy, with patients presenting with more severe disease requiring intensive care. The mortality was 2-fold higher in polluted regions compared with other regions.[298] One study found that of deaths from COVID-19 across 66 administrative regions in Italy, Spain, France, and Germany, 78% of deaths occurred in just five regions, and these regions were the most polluted in terms of nitrogen dioxide levels.[299] A preprint study from Harvard University found that people who live in US regions with high levels of air pollution were more likely to die from COVID-19 than those who live in less polluted areas. The researchers found that an increase of 1 microgram/m³ in fine particulate matter is associated with an 8% increase in the COVID-19 death rate.[300]

Distribution of community outbreaks along restricted latitude, temperature, and humidity measurements are consistent with the behaviour of a seasonal respiratory virus.[301] Evidence suggests that cold and dry conditions may increase transmission, and warm and humid conditions may reduce the rate of infections; however, evidence is not yet sufficient to prove causation.[302][303] However, there is other evidence that suggests ambient temperature has no significant impact on transmission, especially during the pandemic stage of an emerging pathogen.[304][305][306] Further research is required on how weather conditions influence transmission as colder temperatures have been associated with increased transmission of other coronaviruses. Higher latitude may also be associated with an increased risk of cases and deaths in some countries.[307] A positive correlation has been found between lower death rates and a country’s proximity to the equator, suggesting a correlation between sunlight exposure (and vitamin D levels) and reduced mortality.[308]

Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in people living in urban areas (26.2%) compared with people living in rural areas (5.6%), and in people living in more deprived areas (29.5%) compared with people living in less deprived areas (7.7%).[182]

There was originally concern that people on these drugs may be at increased risk of infection or more severe disease due to upregulation of angiotensin-converting enzyme-2 (ACE2) receptor expression.[309] However, high-certainty evidence suggests that use of these drugs is not associated with severe disease, and there is no association between the use of these medications and a positive SARS-CoV-2 test result among symptomatic patients.[310][311] Despite this reassuring evidence, another meta-analysis found that the use of angiotensin-II receptor antagonists, and not ACE inhibitors, may augment the risk of SARS-CoV-2 infection in adults <60 years of age.[312] A prospective cohort study of over 19,000 patients in England found that these drugs were associated with a significantly reduced risk of COVID-19, and were not associated with an increased risk of intensive care. However, variations between ethnic groups raise the possibility of ethnic-specific effects.[313] The UK National Institute for Health and Care Excellence states that conclusion cannot be drawn on whether these drugs increase or decrease the risk of developing COVID-19 or severe disease based on the current available evidence.[314] Professional societies recommend that patients who are already on these drugs continue to take them.[315][316][317]

Dyslipidaemia appears to be associated with an increased risk of severe disease; however, evidence is limited.[318][319]

There is concern that people on these drugs may be at increased risk of infection or more severe disease as statins have been shown to increase the expression of ACE2 in laboratory animals, and may promote the activation of the inflammatory pathway in acute respiratory distress syndrome leading to more severe disease.[309] A meta-analysis of four retrospective studies suggests a reduced risk for fatal or severe disease among statin users.[320] An observational cohort study found that recent statin exposure was not associated with an increased or decreased risk of severe infection or all-cause mortality.[321] Further research into the potential therapeutic or detrimental effects of statins is required.[322]

Proton-pump inhibitors (PPIs) are known to increase the risk of infections due to hypochlorhydria. There is evidence of an independent, dose-response relationship between the use of antisecretory medications and COVID-19 positivity. People taking PPIs had significantly increased odds for reporting a positive COVID-19 test when compared with those not taking PPIs. People taking H2 antagonists were not at elevated risk.[323] Patients taking PPIs may also be at increased risk of secondary infections, severe clinical outcomes, and death.[324][325] Current or regular users of PPIs were more likely to have severe outcomes compared with non-PPI users. Also, current PPI users were more likely to be hospitalised for longer compared with non-PPI users, although this was not statistically significant. Past use of PPIs is not associated with increased susceptibility to infection or severe outcomes.[326]

It is still unclear whether HIV infection influences infection and disease course. A retrospective cohort study found that people with HIV in the UK appear to be at increased risk of mortality.[327] However, the largest cohort study of HIV-positive patients with COVID-19 so far found that although crude mortality is higher in HIV-positive patients when compared with HIV-negative patients, propensity-matched analyses revealed no difference in outcomes, showing that this high mortality is driven by the higher burden of risk factors for severe disease in HIV-positive patients. Males affected by antiretroviral therapy-related complications may be at greater risk of severe disease.[328] Another cohort study found that HIV-positive patients receiving tenofovir disoproxil/emtricitabine had a lower risk for COVID-19 and related hospitalisation than those receiving other antiretroviral therapies.[329]

People with thalassaemia may be at increased risk of severe illness; however, evidence is limited.[208]

People with Down's syndrome may be at increased risk for hospitalisation and death, possibly due to the presence of immune dysfunction, congenital heart disease, and pulmonary pathology. A cohort study in the UK found a 4-fold increased risk for hospitalisation and a 10-fold increased risk for COVID-19-related death in people with Down's syndrome.[330]

Children may be at increased risk of severe illness if they have certain conditions (e.g., obesity, diabetes, asthma and chronic lung disease, immunosuppression, sickle cell disease, chronic kidney disease); are medically complex; have serious genetic, neurological, or metabolic disorders; or have congenital heart disease. However, evidence is limited.[208]

Blood groups A and B have been associated with an increase in the risk of infection compared with non-A and non-B blood groups. Blood group A may also be associated with an increased risk of mortality. There is no evidence for an association between blood group AB and the risk of infection. Blood group O appears to be protective against infection. People who are Rh-positive were more vulnerable to infection compared with those who were Rh-negative.[331] A genome-wide association study found that patients with blood group A are at 45% increased risk of respiratory failure compared with other blood groups. It also found a protective effect in blood group O. Two chromosomal loci were associated with respiratory failure, and one of these coincided with the ABO blood group locus.[177] 

There is limited evidence that gut microbiota dysfunction may be implicated in the pathogenesis of COVID-19. Patients appear to have a depletion of beneficial commensals (e.g., Eubacterium ventriosum, Eubacterium rectale, Faecalibacterium prausnitzii, Roseburia and Lachnospiraceae taxa) and an overgrowth of opportunistic pathogens (e.g., Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii) during hospitalisation.[332][333][334] Associations between gut microbiota composition, levels of cytokines, and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in disease severity, possibly via modulating host immune responses. Gut dysbiosis after disease resolution may contribute to persistent symptoms.[335]

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