History and exam

Key diagnostic factors

Reported in approximately 77% of patients.[120] In one case series, only 44% of patients had a fever on presentation, but it developed in 89% of patients after hospitalization.[459] The course may be prolonged and intermittent, and some patients may have chills/rigors. In children, fever may be absent or brief and rapidly resolving.[460]

Reported in approximately 68% of patients.[120] The cough is usually dry; however, a productive cough has been reported in some patients.  

Reported in approximately 38% of patients.[120] Median time from onset of symptoms to development of dyspnea is 5 to 8 days.[35][36][461] It is less common in children, but the most common sign in neonates.[370] May last weeks after initial onset of symptoms. Wheeze has been reported in 17% of patients.[462]

Olfactory dysfunction (anosmia/hyposmia) has been reported in approximately 41% of patients, and gustatory dysfunction (ageusia/dysgeusia) has been reported in approximately 35% of patients.[120] Prevalence appears to be higher in European studies.[463] May be an early symptom before the onset of other symptoms, or may be the only symptom in patients with mild to moderate illness.[464] Complete resolution or improvement in symptoms was reported in 89% of patients 4 weeks after onset.[465]

Other diagnostic factors

Reported in approximately 30% of patients.[120] Patients may also report malaise. Fatigue and exhaustion may be extreme and protracted, even in patients with mild disease. 

Reported in approximately 17% (myalgia) and 11% (arthralgia) of patients.[462] Arthritis has been reported rarely.[466]

Reported in approximately 18% of patients.[120]

Reported in approximately 22.9% of patients.[403] 

Reported in 20% of patients. The weighted pooled prevalence of specific symptoms is as follows: loss of appetite 22.3%; diarrhea 2.4%; nausea/vomiting 9%; and abdominal pain 6.2%. Gastrointestinal symptoms appear to be more prevalent outside of China, although this may be due to increased awareness and reporting of these symptoms as the pandemic progressed.[467] Gastrointestinal symptoms are not associated with an increased likelihood for testing positive for COVID-19; however, anorexia and diarrhea, when combined with loss of smell/taste and fever, were 99% specific for COVID-19 infection in one prospective case-control study.[468] Children may present with gastrointestinal symptoms more commonly than adults, particularly newborns and infants, and these may be the only symptom.[370] Hematochezia has been reported.[469]

Reported in approximately 16% of patients.[120] Usually presents early in the clinical course.

Reported in approximately 16% of patients.[120]

Reported in approximately 11% of patients.[462]

Confusion has been reported in approximately 11% of patients.[462] Prevalence of confusion/delirium and agitation is high (65% and 69%, respectively) in patients in the intensive care unit.[470] Delirium is associated with an increased risk of mortality, and rapid onset may indicate clinical deterioration.[471] The pooled prevalence of anxiety, depression, and sleep disturbances is 47%, 45%, and 34%, respectively.[472] Altered mental status was as common in younger hospitalized patients (<60 years) as it was in older patients in one study.[473][474]

Reported in 11.2% of patients. The most common ocular symptom is unilateral or bilateral conjunctivitis. Other reported symptoms include ocular pain, dry eye, and floaters. Most symptoms are mild and last for 4 to 14 days with no complications. Prodromal symptoms occur in 12.5% of patients.[475] Mild ocular symptoms (e.g., conjunctival discharge, eye rubbing, conjunctival congestion) were reported in 22.7% of children in one cross-sectional study. Children with systemic symptoms were more likely to develop ocular symptoms.[476]

Rhinorrhea has been reported in approximately 8% of patients, and nasal congestion has been reported in approximately 5% of patients.[462]

Reported in approximately 7% of patients.[462] May indicate pneumonia. 

The pooled prevalence of overall cutaneous lesions is 5.7%. The most common symptoms are a viral exanthem-like presentation (4.2%), maculopapular rash (3.8%), and vesiculobullous lesions (1.7%). Other manifestations include urticaria, chilblain-like lesions, livedo reticularis, and finger/toe gangrene.[477] In the UK COVID Symptom Study, 17% of respondents reported rash as the first symptom of disease, and 21% of respondents reported rash as the only clinical sign.[478] It is unclear whether skin lesions are from viral infection, systemic consequences of the infection, or drugs the patient may be on. Further data is required to better understand cutaneous involvement. 

British Association of Dermatologists: Covid-19 skin patterns external link opens in a new window

Reported in approximately 2% of patients.[462] May be a symptom of pulmonary embolism.[479]

May indicate pneumonia.

May be present in patients with acute respiratory distress.

May be present in patients with acute respiratory distress.

May be present in patients with acute respiratory distress.

May be present in patients with acute respiratory distress.

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 traveling 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.[172]

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 3 feet (1 meter) 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.[172]

The Centers for Disease Control and Prevention has redefined what it considers to be a close contact in October 2020. A close contact is now defined as someone who has been within 6 feet (2 meters) 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.[173] The change was triggered by one study of a correctional facility officer who tested positive after having multiple brief encounters with six positive prisoners totaling over 17 minutes during an 8-hour shift, despite the officer wearing a mask and goggles.[174]

Older age is a risk factor for infection.[175] 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.[176] The risk of severe illness in adults increases with age, with older people (ages 65 years and older) at highest risk.[177][178] The highest mortality rate has been observed in patients 80 years and older.[179] In the US, patients ≥65 years accounted for 31% of all cases, 45% of hospitalizations, 53% of intensive care unit admissions, and 80% of deaths, with the highest incidence of severe outcomes in patients ages ≥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.[106] People who live in a nursing home or long-term care facility are at higher risk for severe illness.[178] 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.[180] More than one third of care homes in England have had cases.[181] 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.[182]

Male sex is a risk factor for infection, more severe disease, and mortality. The higher prevalence of alcohol consumption and smoking contributed to the higher prevalence of infection among men.[183] 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%).[176] It has been hypothesized 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.[184][185][186] 

People from Black, Asian, and minority ethnic (BAME) groups are at a higher risk of infection and worse outcomes, including an increased risk of mortality, compared with the general population. The reasons for this are unclear and require further research.[187] 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.[188] The average age of patients from ethnic minorities was significantly lower than that of White patients.[189] 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.[190] Age-adjusted data from the US Centers for Disease Control and Prevention (as of 19 September) show that non-Hispanic American Indian and Alaska Native people have approximately 4.5 times the rate of hospitalizations of non-Hispanic White people, and Hispanic, Latino, and non-Hispanic Black people have approximately 4.6 times the rate of hospitalizations of non-Hispanic White people.[191] 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).[192][193] In a study of over 10,000 deceased patients in the US, 35% of Hispanic and 30% of non-White decedents were ages <65 years, compared with 13% of White, non-Hispanic decedents.[194] 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.[195]

People with comorbidities are at higher risk for severe illness and mortality.[196] The more comorbidities a person has, the greater their risk for severe illness.[197] In the US, approximately 91% of hospitalized patients had at least one reported underlying medical condition (data reported as of 17 October 2020).[191] The most prevalent comorbidities in adults with COVID-19 are hypertension, diabetes, chronic respiratory disease, cardiovascular disease, and other chronic diseases such as cancer.[198] In a prospective observational cohort study of more than 20,000 hospitalized patients in the UK, the most common comorbidities were chronic cardiac disease (31%), uncomplicated diabetes (21%), nonasthmatic 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%). Hospitalizations were six times higher and deaths were 12 times higher in patients with comorbidities compared with those without.[199] It has been estimated that approximately 56% of adults in the US are at risk for requiring hospitalization 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.[200]

Among 345 pediatric cases with information on underlying conditions, 23% had at least one underlying condition, most commonly chronic lung disease, cardiovascular disease, or immunosuppression.[201] Approximately 39% of hospitalized children had an underlying condition in another study. The most prevalent comorbidities were asthma, neurologic disorders, diabetes, obesity, cardiovascular disease, and malignancy/hematologic conditions.[202]

Around 32% of young adults (ages 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 nonsmokers only.[203]

People with serious heart conditions (e.g., heart failure, coronary artery disease, cardiomyopathy, pulmonary hypertension) are at increased risk of severe illness.[197] Cardiovascular disease is associated with a 3-fold increased odds of severe infection, and an 11-fold increase in all-cause mortality.[204] People with heart failure are at increased risk of hospitalization, poor outcome, and death.[205]

People with hypertension may be at increased risk of severe illness.[197] 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.[206] 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.[207]

People with 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.[197] A pooled analysis found that people with obesity are at a 46% higher risk of infection, a 113% higher risk of hospitalization, a 74% higher risk of intensive care admission, and 48% higher risk of mortality.[208] Patients with a body mass index ≥30 kg/m² have a 2.35-fold risk for critical disease, and a 2.68-fold risk of in-hospital mortality compared with patients with a body mass index <30 kg/m².[209] Obesity plays a significant role in the risk of death from COVID-19, particularly in males and younger people (<60 years of age).[210] Increased body mass index is a significant risk factor for severe disease in pregnant women.[211] Obesity was the most common comorbidity in children, and was significantly associated with mechanical ventilation in children 2 years and older in a single-center retrospective study in New York.[212]

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.[197] The pooled prevalence of diabetes in COVID-19 patients is approximately 15%.[213] Diabetes is associated with an increased risk of disease progression, intensive care admission, acute respiratory distress syndrome, mechanical ventilation, and mortality.[214][215] 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).[213] One third of all deaths in hospitalized 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.[216] 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.[217] 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 hemoglobin (HbA1c) levels, higher body mass index, elevated C-reactive protein, diabetic ketoacidosis, and insulin use.[218][219][220] However, HbA1c levels were not associated with mortality in a large US cohort of hospitalized patients with diabetes and COVID-19, while insulin treatment and obesity were strong and independent risk factors for in-hospital mortality.[221] Hyperglycemia is also an independent risk factor for poor prognosis in hospitalized patients with or without known diabetes.[222][223] Patients with newly diagnosed diabetes have a higher risk of all-cause mortality compared with patients with known diabetes, hyperglycemia, or normal glucose.[224] The poor prognosis in these patients is likely due to the syndromic nature of diabetes, with factors such as hyperglycemia, older age, and the presence of comorbidities (e.g., obesity, hypertension, cardiovascular disease) all contributing to the increased risk.[225] 

There is no clear evidence that people with asthma or chronic obstructive pulmonary disease (COPD) are at higher risk of infection.[226][227] People with COPD (including emphysema and chronic bronchitis) are at increased risk of severe illness.[197] COPD is associated with a 5-fold increased risk of severe infection.[228] People with moderate to severe asthma may be at increased risk of severe illness; however, evidence is limited.[197] There is no statistically significant association between asthma and a higher risk of mortality in patients with COVID-19.[229] Asthma prevalence among hospitalized COVID-19 patients appeared to be similar to the asthma prevalence in the general population in one study, and asthma was not an independent risk factor for intubation.[230] 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.[197] There are no data on whether pediatric respiratory diseases (including childhood asthma) are risk factors for infection or severity.[231]

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%).[176] People with chronic kidney disease are also at increased risk of severe illness.[197] The prevalence of preexisting 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.[232]

People with cancer are at a higher risk of infection, likely due to immunosuppressive treatments and/or recurrent hospital visits.[233] The overall pooled prevalence of cancer in COVID-19 patients is approximately 2.3%.[234] People with cancer are also at increased risk of severe illness.[197] Patients with cancer are 76% more likely to get severe disease compared with those without cancer.[235] They also have an increased risk of worse clinical outcomes including intensive care unit admission and all-cause mortality (particularly those with metastatic disease, hematologic cancer, or lung cancer), and appear to deteriorate more quickly compared with patients without cancer.[236][237] The odds ratio of intensive care admission rates and mortality rates between cancer and noncancer groups was 2.88 and 2.25, respectively.[238] 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 hematologic malignancies have an increased risk of mortality compared with those with solid tumors. Recent anticancer treatments are not clearly associated with the mortality rate.[239] Children with cancer may be no more vulnerable to infection compared with children without cancer. Limited data show that the overall morbidity in pediatric patients with cancer is low, with only 5% requiring hospitalization for symptoms.[240] The pooled case fatality rate in patients with cancer is 25.6%.[241]

People with sickle cell disease are at increased risk of severe illness.[197] Among 178 patients with sickle cell disease and COVID-19 in the US (mean patient age <40 years), 69% were hospitalized, 11% were admitted to intensive care, and 7% died.[242] Infection can cause acute chest syndrome in patients with sickle cell disease.[243][244] 

People with an immunocompromised state from solid organ transplant are at increased risk of severe illness.[197] Organ transplant recipients may be at higher risk of severe illness or complications, more rapid clinical progression, and a prolonged clinical course compared with the general population due to chronic immunosuppression and the presence of coexisting conditions.[245][246][247][248][249][250] Hospitalization and mortality rates in liver transplant recipients are disproportionately high compared with nontransplant patients regardless of age or time after transplant. Older age and diabetes are significant risk factors for death among these patients.[251]

People who are current or former smokers are at increased risk of severe illness.[197] 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.[252] This may be due to increased airway expression of the angiotensin-converting enzyme-2 receptor in smokers.[253] The World Health Organization has reviewed the available evidence and concluded that smoking is associated with increased severity of disease and death in hospitalized patients.[254]

People with cerebrovascular disease may be at increased risk of severe illness; however, evidence is limited.[197] The pooled prevalence of preexisting cerebrovascular disease in COVID-19 patients is 4.4%.[255] Patients with a history of cerebrovascular disease are more likely to progress to adverse outcomes compared with patients without a history of cerebrovascular disease.[256] Patients with preexisting cerebrovascular disease have 2.67-fold higher odds of poor outcomes including intensive care admission, mechanical ventilation, and mortality.[255]

People with dementia may be at increased risk of severe illness; however, evidence is limited.[197] In the UK, over one quarter of people who died with COVID-19 from March to June 2020 had dementia. Dementia and Alzheimer disease was the most common main preexisting health condition in deaths involving COVID-19 between March and June 2020.[257]

People with chronic liver disease, especially cirrhosis, may be at increased risk of severe illness; however, evidence is limited.[197] 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.[258] 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.[259] 

People with metabolic dysfunction-associated fatty liver disease (MAFLD; also called nonalcoholic fatty liver disease) are at increased risk of severe illness, with a pooled odds ratio of 2.93.[260] 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.[261][262]

Surgical mortality and complications are higher in patients with COVID-19 compared with patients without COVID-19.[263] 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.[264] 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 ages 70 years and over.[265]

Pregnant women may be at increased risk of severe illness and adverse pregnancy outcomes; however, evidence is limited.[197] According to an analysis of 8200 infected pregnant women, pregnant women were more likely to be hospitalized, to be admitted to the intensive care unit, and to receive mechanical ventilation compared with nonpregnant women; however, mortality rates did not differ.[21]

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.[197] Patients with inflammatory bowel disease who were on long-term biologics or other immunomodulatory therapies did not have a higher risk of poor outcomes; however, recent corticosteroid use may be related to worse outcomes.[266] Glucocorticoid exposure of ≥10 mg/day (prednisone) has been associated with a higher odds of hospitalization in patients with rheumatologic disease.[267] Patients treated with cyclosporine/tacrolimus also had an increased risk of hospitalization; 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.[268] 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 tumor 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.[269] In patients with multiple sclerosis, neurologic disability, age, and obesity were risk factors for severe disease.[270] Weak evidence suggests that people with inflammatory bowel disease may be somewhat protected from infection, likely due to their ongoing treatment for the condition.[271] 

Limited evidence supports an association between vitamin D deficiency and the risk of infection and worse outcomes. Observational and retrospective studies have found an association between vitamin D deficiency and a higher risk for infection.[272][273][274][275][276] 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 hospitalization. The study concluded that low plasma vitamin D level appears to be an independent risk factor for COVID-19 infection and for hospitalization.[277] A cross-sectional study in 235 hospitalized 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.[278] 

Evidence suggests that there may be an association between long-term exposure to ambient air pollution and COVID-19.[279][280] 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.[281] 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.[282] 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.[283]

Distribution of community outbreaks along restricted latitude, temperature, and humidity measurements are consistent with the behavior of a seasonal respiratory virus.[284] 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.[285][286] However, there is other evidence that suggests ambient temperature has no significant impact on transmission, especially during the pandemic stage of an emerging pathogen.[287][288][289] 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.[290] 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.[291]

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%).[176]

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.[292] However, high-certainty evidence suggests that use of these drugs is not associated with severe disease, and moderate-certainty evidence suggests that there is no association between the use of these medications and a positive SARS-CoV-2 test result among symptomatic patients.[293][294] 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.[295] 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.[296] 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.[297] Professional societies recommend that patients who are already on these drugs continue to take them.[298][299][300] 

Dyslipidemia appears to be associated with an increased risk of severe disease; however, evidence is limited.[301][302]

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.[292] However, a retrospective study of nearly 14,000 patients found that statin use was associated with a lower risk of all-cause mortality in patients with COVID-19, possibly due to the immunomodulatory effects of statins. A meta-analysis of four retrospective studies also suggests a reduced risk for fatal or severe disease among statin users.[303] Further research into the potential therapeutic or detrimental effects of statins is required.[304]

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.[305] Patients taking PPIs may also be at increased risk of secondary infections, severe clinical outcomes, and death.[306][307]

It is still unclear whether HIV infection influences infection and disease course. However, males affected by antiretroviral therapy-related complications may be at greater risk of severe disease.[308] A cohort study found that HIV-positive patients receiving tenofovir disoproxil/emtricitabine had a lower risk for COVID-19 and related hospitalization than those receiving other antiretroviral therapies.[309]

People with thalassemia may be at increased risk of severe illness; however, evidence is limited.[197]

People with Down syndrome may be at increased risk for hospitalization 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 hospitalization and a 10-fold increased risk for COVID-19-related death in people with Down syndrome.[310]

Children may be at increased risk of severe illness if they have certain conditions (e.g., obesity, diabetes, asthma and chronic lung disease, immunosuppression); are medically complex; have serious genetic, neurologic, or metabolic disorders; or have congenital heart disease. However, evidence is limited.[197]

People with blood group A appear to be at increased risk of infection, while people with blood group O have a decreased risk (blood groups B and AB were not significantly associated with infection).[311] 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.[171]

There is some emerging evidence that gut microbiota dysfunction may be implicated in the pathogenesis of COVID-19, although this is yet to be confirmed. Patients appear to have a depletion of beneficial commensals (Eubacterium ventriosum, Faecalibacterium prausnitzii, Roseburia and Lachnospiraceae taxa) and an overgrowth of opportunistic pathogens (Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii) during hospitalisation. Gut microbiome configuration has been associated with disease severity.[312][313][314]

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