History and exam

Key diagnostic factors

Reported in approximately 77% of patients.[138] In one case series, only 44% of patients had a fever on presentation, but it developed in 89% of patients after hospitalization.[589] The course may be prolonged and intermittent, and some patients may have chills/rigors. The prevalence of fever is higher in adults compared with children; approximately 54% of children do not exhibit fever as an initial presenting symptom.[590] In children, fever may be absent or brief and rapidly resolving.[591]

Reported in approximately 68% of patients.[138] The cough is usually dry; however, a productive cough has been reported in some patients. Can persist for weeks or months after infection.[592]

Reported in approximately 38% of patients.[138] Median time from onset of symptoms to development of dyspnea is 5 to 8 days.[49][50][593] May last weeks after initial onset of symptoms. Wheeze has been reported in 17% of patients.[594]

Presence of anosmia and/or ageusia may be useful as a red flag for diagnosis.[476] 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.[138] Prevalence appears to be higher in European studies.[595] May be an early symptom before the onset of other symptoms, or may be the only symptom in patients with mild to moderate illness.[596] Prevalence of anosmia/ageusia presenting before other symptoms was 13% to 73%, at the same time as other symptoms was 14% to 39%, and after other symptoms was 27% to 49%.[597] Complete resolution or improvement in symptoms was reported in 89% of patients 4 weeks after onset.[598] Anosmia or hyposmia is significantly associated with an enhanced risk of testing positive for COVID-19, and is a good predictor of infection.[599] Many drugs are associated with taste and smell changes (e.g., antibiotics, ACE inhibitors) and should be considered in the differential diagnosis.[600]

Other diagnostic factors

Reported in approximately 30% of patients.[138] 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.[594] Arthritis has been reported rarely.[601]

Reported in approximately 18% of patients.[138]

Reported in approximately 22.9% of patients.[516] 

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.[602] 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.[603] The presence of gastrointestinal symptoms may be a predictor of progression to severe disease.[604][605] However, the presence of these symptoms does not appear to affect intensive care unit admission rate or mortality.[606] Hematochezia has been reported.[607]

Reported in approximately 16% of patients.[138] Usually presents early in the clinical course.

Reported in approximately 16% of patients.[138]

Reported in approximately 11% of patients.[594]

Confusion has been reported in approximately 11% of patients.[594] Prevalence of confusion/delirium and agitation is high (65% and 69%, respectively) in patients in the intensive care unit.[608] Delirium is associated with an increased risk of mortality in hospitalized older patients.[609] Benzodiazepine use and the lack of family visitation (virtual or in-person) have been identified as risk factors for delirium.[610] The pooled prevalence of anxiety, depression, and insomnia is 15.2%, 16%, and 23.9%, respectively.[611] Altered mental status was as common in younger hospitalized patients (<60 years) as it was in older patients in one study.[612][613]

Reported in 11% of patients. The most common ocular symptoms include dry eye or foreign body sensation (16%), redness (13.3%), tearing (12.8%), itching (12.6%), eye pain (9.6%), and discharge (8.8%). Conjunctivitis was the most common ocular disease in patients with ocular manifestations (88.8%).[614] Most symptoms are mild and last for 4 to 14 days with no complications. Prodromal symptoms occur in 12.5% of patients.[615] 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.[616]

Rhinorrhea has been reported in approximately 8% of patients, and nasal congestion has been reported in approximately 5% of patients.[594]

Sudden sensorineural hearing loss, tinnitus, and rotatory vertigo have been reported in 7.6%, 14.8%, and 7.2% of patients, respectively. Otalgia has also been reported.[617]

Reported in approximately 7% of patients.[594] 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.[618] 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.[619] 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

There is emerging evidence that patients may rarely have signs, symptoms, and radiologic and laboratory features indicative of involvement of the lower urinary tract and male genital system. This may include scrotal discomfort, swelling, or pain (acute orchitis, epididymitis, or epididymo-orchitis), low-flow priapism, impaired spermatogenesis, bladder hemorrhage, acute urinary retention, and worsening of existing lower urinary tract symptoms. Further research is required.[620]

Reported in approximately 2% of patients.[594] May be a symptom of pulmonary embolism.[621]

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 who have been in contact with a probable or confirmed case are at increased risk of infection.

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.[189]

The Centers for Disease Control and Prevention defines a close contact 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).[190]

People who live or work in, or travel to, a location with a high risk of transmission are at increased risk of infection.

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.[189]

People at risk of infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern include: those who have been in, or transited through, any countries with transmission of variants of concern (consult local guidance for lists of affected countries) and who develop symptoms within 10 days of departure or transit (or date of sampling for a positive SARS-CoV-2 test if asymptomatic); those known to be infected with a variant of concern based on sequencing results, regardless of travel history; contacts of these individuals.[191]

Older people are at increased risk for infection and severe disease.[192]

In the UK, data from a cross-sectional study indicated 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.[193] The highest mortality rate was observed in patients 80 years and older.[194]

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 early in the pandemic, 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. The higher prevalence of malnutrition in older patients may also contribute to poor outcomes.[195]

Males are at increased risk for infection and severe disease.[196]

In the UK, data from a cross-sectional study found that the adjusted odds of a positive test were greater in males (18.4%) compared with females (13.3%).[193]

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, women mounting a stronger immune response compared with men, genetic factors, or a higher prevalence of alcohol consumption and smoking; however, further research is required.[197][198]

People who belong to Black, Asian, and minority ethnic (BAME) groups are at increased risk of infection and severe disease.[199][200]

In the UK, data from a cross-sectional study found that South Asian and Black patients had 1.93 and 1.47 the odds of suspected infection, respectively.[201] The average age of patients from ethnic minorities was significantly lower than that of White patients.[202] 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.[203]

In the US, the proportion of hospitalized patients was highest for Hispanic or Latino patients, and these racial and ethnic disparities were largest during May–July 2020 and became less pronounced as the pandemic spread throughout the country.[204] Cumulative age-adjusted data from the Centers for Disease Control and Prevention (as of 3 April 2021) indicate that Hispanic or Latino people, non-Hispanic American Indian or Alaska Native people, and non-Hispanic Black people have approximately 1.8, 2.7, and 2.1 times the rate of hospitalizations of non-Hispanic White people, respectively.[205] However, cohort studies in the US have found no difference in outcomes between non-Hispanic Black and Hispanic patients compared with White patients after adjusting for sociodemographic factors (e.g., age, sex, insurance) and comorbidities. These patients may have an increased risk of mortality and morbidity due to their disproportionate representation among hospitalizations.[206][207][208] 

Racial disparities in outcomes may be partially attributed to higher rates of comorbidities in certain ethnic groups.[209]

People in a long-term care facility are at increased risk for infection and severe disease.[122][210] 

In the UK, care home residents represented approximately one third of the total number of deaths in England and Wales during the first wave of the pandemic; other countries reported a similar experience. This was likely due to shortages in personal protective equipment, a vulnerable population, and a lack of testing.[211] A study across four nursing homes 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 SARS-CoV-2, and of these, 43% were asymptomatic and 18% had atypical symptoms.[212]

In the US, the 30-day all-cause mortality rate was 21% in a cohort study of more than 5000 nursing home residents. Older age, male sex, and impaired cognitive and physical function were independently associated with mortality.[213]

People with comorbidities are at increased risk for severe disease, and the more comorbidities, the greater the risk.[214][215]

In the UK, the most common comorbidities reported in a cohort study of more than 20,000 hospitalized patients were cardiac disease (31%), uncomplicated diabetes (21%), nonasthmatic chronic pulmonary disease (18%), and chronic kidney disease (16%).[6]

In the US, approximately 92% of hospitalized adults had at least one reported underlying medical condition, with the most common being hypertension, obesity, metabolic disease, and cardiovascular disease. Approximately 53% of children had at least one reported underlying medical condition, with the most common being obesity, neurologic disease, and asthma.[205] It has been estimated that approximately 56% of adults, and 32% of young adults (ages 18-25 years), are at risk for severe disease because of the presence of at least one comorbidity.[216][217]

Globally, hypertension (21%), obesity (18%), and diabetes (18%) were the most prevalent comorbidities. Cancer, chronic kidney disease, diabetes, and hypertension were independently associated with mortality. Chronic kidney disease was statistically the most prominent comorbidity leading to death.[218]

People with obesity are at increased risk for infection and severe disease.[219]

Of the 2.5 million deaths reported globally by the end of February 2021, 2.2 million were in countries where more than half the population is classified as overweight. In countries where less than half the adult population is classified as overweight, the likelihood of death is around one tenth of the level seen in countries where more than half the population is classified as overweight.[220]

People with obesity (≥30 kg/m²) or severe obesity (≥40 kg/m²) and people who are overweight (25-30 kg/m²) are at increased risk of severe disease.[215] Evidence from a meta-analysis suggests a linear dose-response association between body mass index and disease severity and mortality.[221] However, another meta-analysis demonstrated a J-curve relationship between body mass index and mortality, indicating that both underweight and obese patients had a higher risk of mortality compared with those of normal weight.[222] A cohort study in the US found a nonlinear relationship between body mass index and disease severity, with the lowest risk at body mass indexes near the threshold between healthy weight and overweight, then increasing with higher body mass index.[223]

Obesity is associated with an increased risk for disease progression, hospitalization, intensive care unit admission, need for invasive mechanical ventilation, complications (e.g., venous thromboembolism and renal failure), and in-hospital mortality, especially among younger patients.[219][224][225]

People with cardiovascular disease are at increased risk for severe disease.[215]

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.[226]

People with risk factors for cardiovascular disease (e.g., hypertension, diabetes) are also at increased risk for severe disease and mortality (see below).[227][228]

People with type 1 or type 2 diabetes are at increased risk for severe disease.[215]

Diabetes is associated with an increased risk for disease progression, intensive care admission, acute respiratory distress syndrome, need for invasive mechanical ventilation, and mortality.[229][230]

In the UK, one third of all deaths in hospitalized patients occured in patients with diabetes.[231] An analysis of more than 19,000 patients admitted to critical care over the entire first wave of the pandemic 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.[232]

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/acute kidney injury, history of stroke or heart failure, higher glycosylated hemoglobin (HbA1c) levels, higher body mass index, elevated C-reactive protein, diabetic ketoacidosis, hyperglycemic hyperosmolar state, and insulin use.[233][234][235][236] However, HbA1c levels were not associated with mortality in a large US cohort of hospitalized patients.[237] Patients with newly diagnosed diabetes have a higher risk of all-cause mortality compared with patients with known diabetes, hyperglycemia, or normal glucose.[238] Metformin use has been associated with lower mortality.[239]

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.[240] 

People with chronic obstructive pulmonary disease COPD, including emphysema and chronic bronchitis, are at increased risk for severe disease. People with moderate to severe asthma, or other chronic lung diseases (e.g., interstitial lung disease, cystic fibrosis, idiopathic pulmonary fibrosis, pulmonary hypertension) may be at increased risk for severe disease; however, evidence is limited.[215]

COPD is associated with an increased risk of hospitalization, intensive care unit admission, and mortality.[241] A national, multicenter prospective cohort study in the UK (75,463 patients from 258 healthcare facilities) found that patients with COPD were less likely to receive critical care than patients without an underlying respiratory condition.[242]

Data are insufficient to conclude whether asthma is a risk factor for infection, hospitalization, intensive care unit admission, or death.[243] According to meta-analyses, asthma is not associated with an increased risk for infection, severe disease, worse prognosis, or a higher risk of intubation or mechanical ventilation. Clinical outcomes were similar between patients with asthma and patients without asthma. Patients with asthma had a lower risk of death compared with nonasthmatic patients.[244][245] However, a national, multicenter prospective cohort study in the UK (75,463 patients from 258 healthcare facilities) found that patients with asthma were more likely to receive critical care than patients without an underlying respiratory condition. Severe asthma was associated with increased mortality compared with patients with nonsevere asthma in patients ages 16 years and older. Inhaled corticosteroid use in patients with asthma was associated with lower mortality compared with patients without an underlying respiratory condition in patients ages 50 years and older.[242]

People with obstructive sleep apnea may be at increased risk for severe disease independent of age, sex, body mass index, and comorbidities; however, evidence is limited. Obstructive sleep apnea has not been associated with an increased risk of infection.[246]

There are no data on whether pediatric respiratory diseases (including childhood asthma) are risk factors for infection or severity.[247] There is no clear evidence that people with asthma or COPD are at higher risk of infection.[248][249]

People with chronic kidney disease are at increased risk for severe disease, and may be at higher risk for infection.[193][215] 

Patients with chronic kidney disease had a significantly higher risk of hospitalization and all-cause mortality compared with people without chronic kidney disease. Patients with chronic kidney disease also had a higher risk of progressing to critical illness in the pooled analysis of included studies and subgroup analyses of studies with multivariable adjustment, although neither result achieved statistical significance.[250]

In the UK, data from a cross-sectional study 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%).[193]

Preexisting chronic kidney disease is an independent risk factor for developing acute kidney injury as a complication.[251]

Pregnant women are at increased risk for severe disease.[215]

According to an analysis of approximately 400,000 women ages 15 to 44 years with symptomatic disease, pregnant women were more likely to be hospitalized, be admitted to the intensive care unit, receive invasive mechanical ventilation or extracorporeal membrane oxygenation, and die compared with nonpregnant women.[27] 

See the Complications section for more information on pregnancy-related complications.

People who are current or former smokers are at increased risk for severe disease.[215]

Smoking is associated with severe or critical outcomes, and an increased risk of intensive care unit admission and mortality. The association appears to be more significant in former smokers compared with current smokers. Current smokers are at higher risk of developing severe disease compared with nonsmokers.[252] Smokers have double the mortality risk compared with nonsmokers.[253] This may be due to increased airway expression of the angiotensin-converting enzyme-2 receptor in smokers.[254]

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.[255]

People with cancer are at increased risk for infection and severe disease.[215][256]

A higher risk of infection is likely due to immunosuppressive treatments and/or recurrent hospital visits.[256] 

Patients with cancer are 76% more likely to get severe disease compared with those without cancer.[257] They also have an increased risk for deterioration, intensive care unit admission, and all-cause mortality (particularly those with metastatic disease, hematologic cancer, or lung cancer).[258][259] The odds ratio of intensive care admission rates and mortality rates between cancer and noncancer groups was 2.88 and 2.25, respectively.[260] The pooled in-hospital mortality risk in patients with cancer is 14.1%.[261]

Risk factors for mortality 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.[262] While active chemotherapy or chemotherapy within the last 30 days increased the risk of death, targeted therapies, immunotherapy, surgery, and radiation therapy did not appear to increase the risk for severe disease or death.[263][264] 

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.[265] Overall survival in children with cancer is very high (99.4%), and there was no significant difference in the risk of hospitalization or intensive care unit admission between hematologic malignancies and solid tumors in children.[266]

People with cerebrovascular disease are at increased risk for severe disease.[215]

Patients with a history of cerebrovascular disease were more likely to progress to adverse outcomes compared with patients without a history of cerebrovascular disease.[267] Patients with preexisting cerebrovascular disease had 2.67-fold higher odds of poor outcomes including intensive care admission, mechanical ventilation, and mortality.[268]

People with an immunocompromised state from solid organ or blood stem cell transplant may be at increased risk for severe disease; however, evidence is limited.[215]

Solid organ transplant recipients are at increased risk for hospitalization, intensive care unit admission, and mortality. However, the increased rate of hospitalization 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%.[269]

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.[270]

People with Down syndrome may be at increased risk for severe disease; however, evidence is limited.[215] 

In the UK, a cohort study found a 4-fold increased risk for hospitalization and a 10-fold increased risk for for mortality in people with Down syndrome.[271] This may possibly be due to the presence of immune dysfunction, congenital heart disease, and pulmonary pathology.

People with sickle cell disease or thalassemia may be at increased risk for severe disease; however, evidence is limited.[215]

In the US, among 178 patients with sickle cell disease (mean patient age <40 years), 69% were hospitalized, 11% were admitted to intensive care, and 7% died.[272] Infection can cause acute chest syndrome in patients with sickle cell disease.[273][274] 

People with hypertension may be at increased risk for severe disease; however, evidence is limited.[215]

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.[275] Patients with hypertension have a 2.98-fold higher risk of severe disease, a 1.82-fold higher risk of critical disease, and a 2.17 to 2.88-fold higher risk of fatality compared with patients without hypertension.[276][277]

Initially, there was a concern that people on ACE inhibitors or angiotensin-II receptor antagonists may be at increased risk for infection or severe disease due to upregulation of ACE2 receptor expression.[278] 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.[279][280] 

People with dementia may be at increased risk for infection and severe disease; however, evidence is limited.[215][281]

Older adults with dementia are at a higher risk of mortality in the short term. Dementia patients are more likely to be vulnerable to having diseases such as hypertension, diabetes, and pneumonia, and be immunocompromised. The pooled mortality rate of patients with dementia was 39% compared with 20% in older adults without dementia.[282]

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.[283]

A retrospective case-control study of electronic patient health records in the US found that patients with dementia were at increased risk of infection compared with patients without dementia. They also had significantly worse outcomes (6‐month hospitalization risk and mortality risk) compared with patients with dementia but no COVID‐19 and patients with COVID‐19 but no dementia. The highest risk was seen in patients with vascular dementia.[284]

People with chronic liver disease, especially cirrhosis, may be at increased risk for severe disease; however, evidence is limited.[215]

Chronic liver disease has been associated with an increased risk for severe disease and mortality.[285] 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.[286] 

People with metabolic dysfunction-associated fatty liver disease (nonalcoholic fatty liver disease) are at increased risk for severe disease. Disease severity has been associated with age <60 years and intermediate or high fibrosis-4 (FIB-4) scores.[287][288][289]

People who are immunocompromised may be at increased risk for severe disease; however, evidence is limited.[215]

This includes people with a history of primary immune deficiencies or prolonged use of corticosteroids or other immunosuppressant medications.

Glucocorticoid exposure of ≥10 mg/day (prednisone) has been associated with a higher odds of hospitalization in patients with rheumatologic disease.[290] Patients treated with cyclosporine/tacrolimus also had an increased risk for 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.[291]

Immunosuppressed patients are not at significantly increased risk of infection compared with the general population.[292]

Also see HIV infection and Autoimmune disease below.

Children with certain underlying conditions may be at increased risk for severe disease; however, evidence is limited.[215]

These conditions include obesity, diabetes, asthma and chronic lung disease, immunosuppression, and sickle cell disease. Children may also be at risk if they are medically complex; have serious genetic, neurologic, or metabolic disorders; or have congenital heart disease.[215]

People with vitamin D deficiency may be at higher risk for infection and severe disease; however, evidence is limited.[293][294]

Multiple observational and retrospective studies have found an association between vitamin D deficiency and a higher risk for infection. A meta-analysis of available data concluded that low serum vitamin D level was significantly associated with a higher risk of infection, and people with vitamin D deficiency were 80% more likely to be infected.[295] A meta-analysis found that vitamin D deficiency increased the risk for hospitalization and mortality, and patients with severe disease were more likely to have vitamin D deficiency compared with patients with mild disease.[296] Despite these trends, another meta-analysis found that these associations were not statistically significant and the certainty of evidence was very low.[297]

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.[298] 

People taking proton-pump inhibitors (PPIs) may be at increased risk for severe disease; however, evidence is limited.[299][300]

Data on whether PPI use increases the risk for infection is conflicting. The largest meta-analysis to date found that PPI use was not associated with an increased risk for infection.[300]

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.[301]

Patients taking PPIs may also be at increased risk for secondary infections, severe clinical outcomes, and death.[302][303] 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 hospitalized 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.[304]

People with autoimmune disease may be at higher risk for infection and severe disease; however, evidence is limited.[305]

Autoimmune disease has been 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.[305]

In patients with inflammatory rheumatic and musculoskeletal diseases, use of rituximab was associated with more severe disease but not an increased risk of mortality.[306]

In patients with multiple sclerosis, neurologic disability, older age, Black race, cardiovascular comorbidities, recent treatment with corticosteroids, and obesity were risk factors for severe disease and mortality.[307][308]

In patients with inflammatory bowel disease, infection risk was comparable to the general population, and patient outcomes (hospitalization, intensive care unit admission, and mortality) were worse in ulcerative colitis and patients on corticosteroids, thiopurines, aminosalicylates, or combination therapy. Outcomes were better in patients on biologic agents.[309][310][311]

People living with HIV may be at increased risk for severe disease; however, evidence is limited.[215]

It is still unclear whether HIV infection influences infection and disease course. A retrospective cohort study in the UK found that people with HIV appear to be at increased risk for mortality.[312] A retrospective cohort study in New York found that while people with HIV do not appear to be at increased risk of infection, they are at increased risk for poor outcomes (mainly higher rates of severe disease requiring hospitalization) compared with people living without diagnosed HIV infection. Hospitalization risk increased with progression of HIV disease stage.[313]

Evidence from meta-analyses is conflicting. Some meta-analyses have found that HIV infection was not associated with composite poor outcome.[314][315] However, other meta-analyses have found that people living with HIV infection have an increased risk for infection and mortality compared with people without HIV. People on tenofovir disoproxil-based regimens may have a lower risk of infection and poor outcomes; however, evidence is inconclusive.[316][317]

People with substance use disorders may be at increased risk for severe disease; however, evidence is limited.[215] This includes alcohol, opioid, or cocaine use disorder.

People with substance abuse disorders, especially those using drugs that affect the respiratory and cardiovascular systems, may be vulnerable to the adverse respiratory effects of COVID-19. Cohort studies have found substance use disorders were associated with increased hospitalization, intensive care unit admission, ventilator use, and mortality.[318][319]

Dyslipidemia appears to be associated with an increased risk for severe disease and mortality; however, evidence is limited.[320][321][322]

The association was stronger in males, older age, and those with hypertension.[323]

Initially there was a concern that people on statins may be at increased risk of infection or more severe disease, as statins have been shown to increase ACE2 expression in animals and may promote the activation of the inflammatory pathway in acute respiratory distress syndrome.[278] However, so far, studies do not support this hypothesis, and some studies have shown a protective effect.[324][325][326][327]

Surgical mortality and complications may be higher in patients with COVID-19 compared with patients without COVID-19.[328]

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.[329]

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.[330]

People with blood group A may be at increased risk for infection and mortality, and people with blood group B may be at increased risk for infection; however, evidence is limited.[331]

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.[332]

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.[188] The SARS-CoV-2 receptor-binding domain directly binds the blood group A antigen expressed on respiratory epithelial cells, directly linking blood group A and SARS-CoV-2.[333]

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 hospitalization.[334][335][336] 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.[337]

Climate and latitude: limited evidence suggests that cold and dry conditions and higher latitude may increase transmission, and warm and humid conditions may reduce the rate of infections; however, evidence is conflicting and is not sufficient to prove causation.[338][339][340][341][342][343][344]

Air pollution: limited evidence suggests an association between exposure to ambient air pollution and COVID-19; however, evidence is not sufficient to prove causation.[345][346][347][348]

Residence in urban or deprived areas: limited evidence suggests 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%).[193] 

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