History and exam
Key diagnostic factors
Reported in approximately 77% of patients. In one case series, only 44% of patients had a fever on presentation, but it developed in 89% of patients after hospitalization. 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. In children, fever may be absent or brief and rapidly resolving.
Presence of anosmia and/or ageusia may be useful as a red flag for diagnosis, particularly in countries with older circulating SARS-CoV-2 variants. However, loss of smell, a pathognomonic feature of previous SARS-CoV-2 variants, was present in only <20% of cases of people infected with the Omicron variant.
Anosmia or hyposmia has been significantly associated with an enhanced risk of testing positive for COVID-19, and may be a good predictor of infection. Olfactory dysfunction (anosmia/hyposmia) has been reported in approximately 55% of patients, and gustatory dysfunction (ageusia/dysgeusia) has been reported in approximately 41% of patients in the context of previously circulating SARS-CoV-2 variants. Prevalence appears to be higher in European studies. May be an early symptom before the onset of other symptoms, or may be the only symptom in patients with mild to moderate illness. 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%.
Olfactory recovery was found to occur as early as 7 days, with the majority of patients recovering within 30 days. Persistent anosmia has an excellent prognosis with nearly complete recovery at 1 year. In one cohort study, 12.8% of previously hospitalized patients in the UK reported persistent problems with smell or taste up to 1 year after infection. Parosmia (misperception of an odor) is a late-onset symptom that may develop approximately 3 months after infection. It may occur without any preceding apparent smell loss, or it may follow a short recovery period from initial anosmia.
Many drugs are associated with taste and smell changes (e.g., antibiotics, ACE inhibitors) and should be considered in the differential diagnosis.
Smell and taste dysfunction are common in children.
Other diagnostic factors
Reported in approximately 25% of patients. Headache is twice as prevalent in COVID-19 patients compared with patients with non-COVID-19 viral respiratory tract infections.
Data from the UK COVID Symptom Study report that headache is one of the most common symptoms in fully vaccinated people and unvaccinated people in the context of the Delta and Omicron variants.
Reported in approximately 16% of patients. Usually presents early in the clinical course.
Data from the UK COVID Symptom Study report that sore throat is one of the most common symptoms in fully vaccinated people and unvaccinated people in the context of the Delta and Omicron variants.
Rhinorrhea has been reported in approximately 8% of patients, and nasal congestion has been reported in approximately 5% of patients.
Data from the UK COVID Symptom Study report that rhinorrhea is one of the most common symptoms in fully vaccinated people and unvaccinated people in the context of the Delta and Omicron variants.
Reported in approximately 30% of patients. Patients may also report malaise. Fatigue and exhaustion may be extreme and protracted, even in patients with mild disease.
Data from the UK COVID Symptom Study report that mild to severe fatigue is one of the most common symptoms in the context of the Omicron variant.
Reported in approximately 18% of patients.
Reported in approximately 22.9% of patients.
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. 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. The presence of gastrointestinal symptoms may be a predictor of progression to severe disease. However, the presence of these symptoms does not appear to affect intensive care unit admission rate or mortality. The presence of diarrhea has been associated with a severe clinical course in children. Hematochezia has been reported.
Reported in approximately 11% of patients.
Confusion has been reported in approximately 11% of patients.
The overall prevalence of delirium is 24.3%, with an increased prevalence in adults >65 years of age (28%). Delirium has been associated with a 3-fold increase in mortality. Benzodiazepine use and the lack of family visitation (virtual or in-person) have been identified as risk factors for delirium.
The pooled prevalence of anxiety, depression, and insomnia is 15.2%, 16%, and 23.9%, respectively.
Altered mental status was as common in younger hospitalized patients (<60 years) as it was in older patients in one study.
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%). Most symptoms are mild and last for 4 to 14 days with no complications. Prodromal symptoms occur in 12.5% of patients. 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. Patients with severe disease are more likely to have ocular symptoms. Retinal complications that may lead to vision loss have also been reported.
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.
Reported in approximately 7% of patients. May indicate pneumonia.
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.
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. 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. Cutaneous signs may be the only, or the first, presenting sign. Cutaneous symptoms have been reported in children. 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 and whether there is a causal relationship. No direct link between COVID-19 and chilblains has been established, and there is conflicting evidence.
Aphthous, hemorrhagic, and necrotic ulcers have been reported in 36.3% of patients. Other lesions include pustules, macules, bullae, maculopapular enanthema, and erythema multiforme-like lesions. SARS-CoV-2–associated reactive infectious mucocutaneous eruption has also been reported. Severe and potential life-threatening mucocutaneous dermatologic manifestations have also been reported. It is unclear whether oral lesions are from viral infection, systemic consequences of the infection, secondary to existing comorbidities, or drugs the patient may be on.
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 (including exacerbation of benign prostatic hyperplasia). Further research is required.
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: 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. Exposure must have occurred during the infectious period of the case. For symptomatic cases, this means 2 days before and 10 days after symptom onset of the case, plus at least 3 additional days without symptoms, for a minimum of 13 days total after symptom onset. For asymptomatic cases, this means 2 days before and 10 days after the date on which the sample that led to confirmation was taken.
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).
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.
Older people are at increased risk for infection and severe disease.
The risk of hospitalization and death increases with age. An increased age-related risk of in-hospital mortality, case mortality, and hospitalization of 5.7%, 7.4%, and 3.4% per age year, respectively, has been observed, based on high-quality of evidence. No increased risk was observed for intensive care unit admission and intubation by age year. There was no evidence of a specific age threshold at which the risk accelerates considerably.
According to US data, the risk of hospitalization is 10 times higher and the risk of death is 340 times higher in people ages 85 years and older compared with 18- to 29-year-olds.
In the UK, data from a cross-sectional study indicated that people ages 40 to 64 years are at greatest risk of infection, followed by patients 75 years and older, and then people ages 65 to 74 years. The highest mortality rate was observed in patients 80 years and older.
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.
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.
Males are at increased risk for infection and severe disease.
A meta-analysis found that men have a higher risk for infection, hospitalization, disease severity, intensive care unit admission, and death.
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, a higher prevalence of alcohol consumption and smoking, or higher circulating levels of inflammatory cytokines; however, further research is required.
People who belong to racial/ethnic minority populations are at increased risk of infection, severe disease, hospitalization, and death. However, studies are inconsistent, particularly in regards to the definitions of racial/ethnic minority groups and socioeconomic status.
In the UK, data indicate that South Asian, Black, and mixed ethnicity populations have an increased risk for testing positive and of adverse outcomes (i.e., hospitalization, intensive care unit admission, death) compared with the White population, even after accounting for differences in sociodemographic, clinical, and household characteristics. Race may play an important role in adverse outcomes in children as well as adults.
In the US, American Indian or Alaskan Native, Latino, Black, and Asian or Pacific Islander people were more likely than White people to test positive, be hospitalized, be admitted to the intensive care unit, or die during the first year of the pandemic.
Risk factors in these patients include poverty, low level of education, poor housing conditions, low family income, speaking in a language other than the national language, and household overcrowding.
While the risk of diagnosis was higher in most ethnic minorities, once hospitalized, no clear inequalities in outcomes existed (except for the high risk of mortality in ethnic minorities in Brazil). This suggests that ethnic minority status is an important social determinant of COVID-related health outcomes, likely through association with other social determinants (e.g., housing, socioeconomic status, employment, general health status). Racial disparities in outcomes may also be partially attributed to higher rates of comorbidities in certain ethnic groups.
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. 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.
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.
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%). Among 65,000 patients hospitalized in the UK, 68% reported at least one cardiometabolic condition on admission. Baseline cardiometabolic conditions were associated with an increased risk of in-hospital complications, and this risk increased in the presence of cardiometabolic multimorbidity.
In the US, approximately 95% of hospitalized adults had at least one reported underlying medical condition, with the most common being hypertension, disorders of lipid metabolism, and obesity. Approximately 99% of patients who died had at least one underlying health condition. The strongest risk factors for death were obesity, anxiety and fear-related disorders, and diabetes, as well as the total number of underlying conditions. 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.
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. Metabolic syndrome is also significantly associated with a higher risk of mortality.
Children with comorbidities including obesity, diabetes, chronic lung disease (not including asthma), heart disease, seizure disorders, and immunocompromised status had a high prevalence of severe disease.
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.
Evidence from a meta-analysis found that patients who are obese have a significantly increased risk of infection, clinically severe disease, hospitalization, intensive care unit admission, need for mechanical ventilation, and mortality.
A cohort study in the UK found that the risk of severe outcomes (i.e., hospitalization, intensive care unit admission, death) increased progressively above a body mass index ≥23 kg/m², independent of the excess risks of related diseases (e.g., diabetes). The relative risk was particularly notable in people <40 years of age and those with Black ethnicity. Every unit increase in body mass index increased the risk of: hospital admission by 5% (above body mass index ≥23 kg/m²); intensive care admission by 10% (any body mass index); and death by 4% (body mass index ≥28 kg/m²).
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.
People with cardiovascular disease are at increased risk for severe disease.
Preexisting cardiovascular disease is associated with adverse outcomes including disease severity, disease progression, and mortality.
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. Preexisting atrial fibrillation/atrial flutter was associated with a higher risk of intensive care admission, in-hospital mortality, and worse outcomes. Coronary heart disease has also been associated with disease progression and severe/critical disease. The association is affected by the presence of hypertension; patients with coronary heart disease and hypertension had an increased risk of poor prognosis compared with those without hypertension.
People with type 1 or type 2 diabetes are at increased risk for severe disease.
Diabetes is associated with a more than 2-fold increase in the risk for severe disease, and a slightly less than 2-fold increase in the risk for death. Diabetes is also associated with an increased risk for intensive care unit admission. Individual studies show that type 1 diabetes is associated with a higher risk of death compared with type 2 diabetes. Higher blood glucose levels (in the immediate and longer terms) are associated with worse outcomes. There is no evidence of difference in risk between people with new-onset and preexisting diabetes. Data are insufficient to determine whether diabetes predisposes people to infection. There are no data to suggest that diabetes increases the risk of severe disease in children and adolescents. Variability across different regions in the world is significant and may skew overall trends.
Risk factors for poor prognosis and higher mortality in patients with diabetes are similar to risk factors that exist in the general population and include older age, male sex, non-White ethnicity, socioeconomic deprivation, acute kidney injury, history of stroke or heart failure, and higher body mass index. Other more specific risk factors include prediabetes, poor glycemic control, higher glycosylated hemoglobin level, diabetic ketoacidosis, hyperglycemic hyperosmolar state, diabetic retinopathy, and insulin use. Studies that adjusted for age, sex, ethnicity, deprivation, and geographic location still found an increased risk for death in people with diabetes. There is little evidence regarding the role of comorbidities in increasing the risk of poor outcomes.
Use of metformin, sodium–glucose cotransporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists was associated with lower mortality in patients with type 2 diabetes. Dipeptidyl peptidase-4 inhibitors and insulin have been associated with increased mortality. Sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors did not appear to increase or decrease risk of mortality. It is unclear whether these drugs have a protective effect, and further investigation is required.
Poor outcomes in these patients may be due to the syndromic nature of diabetes, the presence of comorbidities, impaired immune function, possible upregulation of enzymes that mediate viral invasion, and chronic inflammation coupled with the acute inflammatory reaction caused by SARS-CoV-2 resulting in a propensity for inflammatory storm.
People with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary embolism, pulmonary hypertension, tuberculosis, cystic fibrosis, and bronchiectasis are at increased risk for severe disease. People with asthma, bronchopulmonary dysplasia, and alpha-1 antitrypsin deficiency may be at increased risk for severe disease; however, evidence is limited. There is no clear evidence that people with asthma or COPD are at higher risk of infection.
COPD: associated with an increased risk of hospitalization, intensive care unit admission, and mortality. A national, multicenter prospective cohort study in the UK found that patients with COPD were less likely to receive critical care than patients without an underlying respiratory condition.
Asthma: associated with similar (if not slightly improved) clinical outcomes compared with those without asthma. Pooled results from a large systematic review showed that, overall, asthma was not associated with severe outcomes (hospitalization, intensive care unit admission, mortality). However, evidence was of very low certainty, and results were limited by a lack of reporting on asthma severity, unexplained statistical heterogeneity, and imprecision. People with allergic asthma appear to be at a lower risk of severe outcomes, while people with asthma and concurrent COPD appear to be at a high risk of severe outcomes. Previous systematic reviews and meta-analyses have generated conflicting conclusions. Whether asthma is associated with an increased risk of infection or severe outcomes remains unclear.
Obstructive sleep apnea: associated with an increased risk for severe disease, intensive care admission, mechanical ventilation, and mortality, but not an increased risk of infection; however, evidence is limited.
Cystic fibrosis: does not appear to be associated with an increased risk of infection; however, there is evidence that some patients may experience a more severe clinical course (e.g., post-transplantation).
Interstitial lung disease: appears to be associated with an increased risk of severe disease and mortality.
There are no data on whether pediatric respiratory diseases (including childhood asthma) are risk factors for infection or severity.
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.
Incidence appears to be higher in patients receiving dialysis compared with those not requiring renal replacement therapy. Patients with end-stage renal disease who were on renal replacement therapy also had an increased risk of intensive care unit admission, need for mechanical ventilation, and mortality.
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%).
Preexisting chronic kidney disease is an independent risk factor for developing acute kidney injury as a complication.
People with chronic liver disease such as cirrhosis, metabolic dysfunction-associated fatty liver disease, alcoholic liver disease, and autoimmune hepatitis are at increased risk for severe disease. People with hepatitis B or C may be at increased risk for severe disease; however, evidence is limited.
Chronic liver disease has been associated with an increased risk for severe disease and mortality, but not an increased risk of infection. Higher liver fibrosis scores are associated with worse prognosis.
People with cirrhosis are at an increased risk of mortality. Cirrhotic patients had a 2.48-fold increased odds of mortality compared with noncirrhotic patients. Mortality risk is potentially higher in patients with more advanced cirrhosis.
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.
Pregnant women are at increased risk for severe disease.
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.
Pregnant women with severe infection were more likely to have a preterm birth or pre-labor cesarean birth, or have a baby that was stillborn or require admission to a neonatal intensive care unit. Risk factors for pregnant women developing severe disease included age ≥30 years, gestational diabetes, overweight/obesity, and mixed ethnicity.
Pregnant women and neonates are more vulnerable to adverse outcomes in low- to middle-income countries compared with high-income countries.
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.
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, and in younger people. Current smokers are at higher risk of developing severe disease compared with nonsmokers. Smokers have double the mortality risk compared with nonsmokers. This may be due to increased airway expression of the angiotensin-converting enzyme-2 receptor in smokers. The risk of mortality in current smokers does not appear to vary by age; however, the risk drops significantly by age in former smokers.
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.
Patients with cancer have an increased risk of severe disease, increased ventilatory requirements, and mortality compared with the general population. Intensive care unit admission rates were not statistically significant between the two groups. Hematologic malignancies were associated with the highest risk of severe disease and mortality (possibly explained by the greater degree of immunosuppression used in the treatment of these patients), followed by lung cancer. There is no clear association between treatment modality and mortality. A higher risk of infection is likely due to immunosuppressive treatments and/or recurrent hospital visits.
The pooled in-hospital mortality risk in patients with cancer is 14.1%. The pooled mortality in cancer patients admitted to the intensive care unit is 60.2%. Mortality in cancer patients is affected by preexisting noncancer comorbidities, and is significantly higher in people with hypertension, cardiovascular disease, chronic obstructive pulmonary disease, and diabetes. A registry-based study suggests that mortality in patients with cancer has improved over time in Europe, and this improvement may be associated with earlier diagnosis, improved clinical management, and changes in community transmission over time.
Patients with recent cancer treatment (within 3 months before COVID-19 diagnosis) had a statistically significant increase in the risk of 30-day mortality, intensive care unit stay, and hospitalization compared with patients with COVID-19 without cancer. Patients with no recent cancer treatment had a similar risk of mortality and intensive care unit stay, and a lower risk of mechanical ventilation and hospitalization compared with patients without cancer.
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. In the largest international cohort study to date, 20% of children with cancer developed severe or critical disease, but most patients recovered without advanced support. Approximately 35% of children were asymptomatic. Lymphopenia and neutropenia were associated with more severe disease. 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. Limited evidence suggests that no severe complications were associated with continuation of chemotherapy in children who test positive for SARS-CoV-2.
People with cerebrovascular disease are at increased risk for severe disease.
Patients with a history of cerebrovascular disease were more likely to progress to adverse outcomes compared with patients without a history of cerebrovascular disease. Patients with preexisting cerebrovascular disease had 2.67-fold higher odds of poor outcomes including intensive care admission, mechanical ventilation, and mortality.
People with mental health disorders such as mood disorders (e.g., depression) and schizophrenia-spectrum disorders are at increased risk for severe disease.
People with preexisting schizophrenia may be at increased risk of mortality. Risk factors include older age and a history of smoking.
People with an immunocompromised state from solid organ or blood stem cell transplant are at increased risk for severe disease.
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. No increased risk in mortality was found compared with the general population when adjusted for demographic and clinical features and disease severity.
Hematopoietic stem cell transplant (HSCT) recipients are at increased risk for mortality. The mortality rate was slightly higher in allo-HSCT recipients compared with auto-HSCT recipients, but this difference was not statistically significant. Risk factors for higher mortality included older age, immunosuppressive therapy, graft-versus-host disease, and elevated inflammatory markers with lymphopenia.
People with disabilities including Down syndrome, cerebral palsy, congenital malformations, learning disabilities, attention deficit/hyperactivity disorder, intellectual and developmental disabilities, and spinal cord injuries are at increased risk for severe disease.
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. This may possibly be due to the presence of immune dysfunction, congenital heart disease, and pulmonary pathology.
Another study in the UK found that adults with learning disability and those with Down syndrome or cerebral palsy have markedly increased risks of hospital admission and death over and above the risks observed for non-COVID-19 causes of death.
The risk of death was higher for disabled people (including learning disability, neurologic conditions, and frailty) compared with nondisabled people during the first two waves of the pandemic. Relative risks were high among younger disabled people, disabled women, and people with greater levels of activity limitation. Adverse socioeconomic, demographic, and health-related risk factors accounted for some of the elevated risk.
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.
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.
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.
People who are immunocompromised are at increased risk for severe disease.
This includes people with a history of primary immune deficiencies or prolonged use of corticosteroids or other immunosuppressant medications.
Current data do not strongly suggest that medications associated with the treatment of immune-mediated inflammatory diseases increase the risk of infection or severe disease, with the exception of corticosteroids and rituximab.
Glucocorticoid exposure of ≥10 mg/day (prednisone) has been associated with a higher odds of hospitalization in patients with rheumatologic disease. 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.
Immunosuppressed patients are not at significantly increased risk of infection compared with the general population.
Also see HIV infection and Autoimmune disease below.
People living with HIV are at increased risk for severe disease.
Retrospective studies have found that while people with HIV do not appear to be at increased risk of infection, they are at increased risk for poor outcomes (i.e., severe disease, hospitalization, mortality) compared with people living without HIV infection. The risk of severe disease and hospitalization increased with progression of HIV disease stage. However, there is some evidence that suggests that HIV patients at advanced stages (stage 3 or 4) may manifest less severe symptoms and have reduced mortality. This may be due to the inability of HIV-positive individuals' immune systems to provoke the cytokine storm that usually causes poor clinical outcomes in COVID-19 patients.
Evidence from meta-analyses is conflicting. One meta-analysis found that HIV infection was not associated with composite poor outcome. 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.
The World Health Organization states that HIV infection appears to be a significant independent risk factor for severe or critical disease at hospital admission and in-hospital mortality. HIV infection was independently associated with a higher risk of mortality compared with the HIV-negative population after adjusting for age, sex, disease severity, and underlying conditions. Age >65 years, male sex, and the presence of diabetes or hypertension were risk factors for severe or critical illness at hospital admission, as well as in-hospital mortality. Data were predominantly from South Africa, which may limit the generalizability of the results. Other risk factors for severe illness include coexisting cardiovascular disease, respiratory disease, and chronic kidney disease.
People with sickle cell disease or thalassemia may be at increased risk for severe disease; however, evidence is limited.
Patients with hemoglobinopathy had an increased risk of severe disease and mortality compared with the general population. Mortality among patients with hemoglobinopathy was 6.9%. Respiratory and cardiovascular comorbidities were significant predictors of mortality.
In the UK, patients with sickle cell disease were found to have a 4-fold increased risk for hospitalization and a 2.6-fold increased risk for death. Sickle cell trait was also associated with increased risks for both outcomes, albeit to a lesser extent.
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. Infection can cause acute chest syndrome in patients with sickle cell disease.
People with hypertension may be at increased risk for severe disease; however, evidence is limited.
Almost all available evidence suggests that hypertension increases the risk of severe disease or mortality, although it was sometimes unclear whether this was independent of other risk factors. There were no systematic reviews or meta-analyses studying whether people with hypertension were at greater risk of infection.
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. 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.
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. 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.
People with substance use disorders may be at increased risk for severe disease; however, evidence is limited. 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.
People with opioid use disorder had higher odds of hospitalization, maximum length of hospital stay, and invasive mechanical ventilation compared with those without an opioid use disorder. However, patients did not appear to have an increased risk of mortality. Patients treated with methadone or buprenorphine appeared to have worse outcomes in terms of hospitalization and length of hospital stay, but better outcomes in terms of mortality risk and need for invasive mechanical ventilation compared with patients not receiving opioid agonist treatment.
Children with certain underlying conditions may be at increased risk for severe disease; however, evidence is limited.
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.
A cross-sectional study of over 43,000 children in the US found that the most commonly documented underlying conditions were obesity, asthma, neurodevelopmental disorders, anxiety and fear-related disorders, and depressive disorders. Children with type 1 diabetes, cardiac and circulatory congenital anomalies, obesity, hypertension, epilepsy, neuropsychiatric disorders, and asthma as well as children with chronic disease had higher risk of hospitalization and severe disease. Limited data suggest that children with congenital heart disease might be at increased risk of severe disease.
People with vitamin D deficiency may be at higher risk for infection and severe disease; however, evidence is limited.
Meta-analyses have found that low serum vitamin D level is significantly associated with a higher risk of infection, and increased risk for severe disease, hospitalization, and mortality in both adults and children. However, it is unclear whether these associations were statistically significant and the certainty of evidence is very low.
A meta-analysis and GRADE assessment of cohort studies and randomized controlled trials found that current evidence suggests that vitamin D deficiency is not significantly linked to susceptibility to infection or death, and vitamin D supplementation did not significantly improve clinical outcomes. However, the overall quality of evidence was low.
People taking proton-pump inhibitors (PPIs) may be at increased risk for infection and severe disease; however, evidence is limited.
Data on whether PPI use increases the risk for infection is conflicting. The largest meta-analysis to date found that PPI use was marginally associated with a nominal, but statistically significant, increase in the risk of infection, as well as an increased risk of severe infection and mortality.
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.
Current data do not strongly suggest that the presence of an immune-mediated inflammatory disease increases the risk of infection or severe disease. The increased risk reported in some studies may be due to comorbidities associated with immune-mediated inflammatory diseases or medications the patient is taking (corticosteroids, rituximab). Increased rates of hospitalization in these patients were not associated with increased rates of death. Tumor necrosis factor (TNF)-alpha inhibitor monotherapy was associated with a lower risk of hospitalization or death among patients with immune-mediated inflammatory disorders compared with other treatment regimens (e.g., methotrexate, azathioprine, Janus kinase inhibitors). There was no increased risk of mechanical ventilation or in-hospital mortality for other rheumatologic, antineoplastic, or antimetabolite therapies examined in one cohort study, with the exception of rituximab.
Inflammatory arthritis: evidence does not show a strong association between inflammatory arthritis (e.g., rheumatoid arthritis, spondyloarthritis) and risk of infection or adverse outcomes such as hospitalization, intensive care unit admission, need for mechanical ventilation, or death. However, evidence is conflicting. Some studies do report an increased risk of adverse outcomes, but the studies had limitations.
Inflammatory bowel disease: prevalence in patients with inflammatory bowel disease appears to be low. Evidence suggests that the risk profile for infection and severe disease is similar to the general population if patients have good disease control and do not use corticosteroids. Corticosteroid use was associated with an increased risk for severe disease and intensive care unit admission, but not mortality. One third of patients with inflammatory bowel disease required hospitalization, and fewer than 4% required intensive care unit admission. Higher disease activity and flares may lead to increased susceptibility to infection and worse outcomes. 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. A risk calculator has been developed that predicts which patients with inflammatory bowel disease are at higher risk of adverse outcomes.
Connective tissues diseases: several studies suggest an increased risk of infection in patients with connective tissue disorders (e.g., systemic lupus erythematosus, Sjogren syndrome, systemic sclerosis, polymyositis and dermatomyositis) compared with the general population and patients with other immune-mediated inflammatory diseases. This is possibly due to the widespread use of corticosteroids in these patients. There are a lack of data regarding outcomes and evidence is conflicting. Patients with lupus nephritis were at increased risk of developing severe or critical disease.
Psoriasis: data on risk and outcomes convincingly suggest a comparable risk profile as observed in the general population, with no increase in susceptibility to infection or severe disease reported in cohort studies.
Vasculitis: corticosteroid use, older age, male sex, moderate or severe disease activity, comorbidities (e.g., respiratory disease), and rituximab or cyclophosphamide use were associated with severe outcomes, based on limited data.
Multiple sclerosis: neurologic disability, older age, Black race, cardiovascular comorbidities, recent treatment with corticosteroids, and obesity were risk factors for severe disease and mortality. Current evidence does not suggest that multiple sclerosis significantly increases the mortality rate. Highest hospitalization and mortality rates were in patients who were not on disease-modifying therapies, followed by those who were on B cell-depleting therapies (e.g., rituximab, ocrelizumab).
Thyroid disorders (hypothyroidism and unspecified thyroid abnormalities, but not hyperthyroidism) are associated with a higher risk of poor outcomes including severe disease, hospitalization, intensive care unit admission, and mortality. This association was significantly associated with increasing age and presence of hypertension.
Risk factors for infection may include obesity, pulmonary disease, and hospitalization. Vitamin D supplementation was associated with a lower risk of infection.
Parkinson disease was associated with severe disease, poor in-hospital outcomes, and mortality in one meta-analysis. However, the evidence for an association is still unclear. The association was influenced by age, but not by sex or the presence of dementia, hypertension, or diabetes.
Patients may experience substantial worsening of parkinsonian symptoms.
Physical inactivity may be associated with a higher risk for severe disease; however, evidence is limited.
A retrospective observational study in nearly 50,000 patients found that patients with COVID-19 who were consistently inactive during the 2 years before the pandemic had a greater risk of hospitalization, intensive care unit admission, and death compared with patients who were consistently meeting physical activity guidelines or who were doing some level of physical activity. Other than older age and a history of organ transplant, physical inactivity was the strongest risk factor for severe disease outcomes in this study.
Gout appears to be associated with an increased risk for infection and mortality; however, evidence is limited.
A UK Biobank population-based study of over 15,000 people with gout found that gout was associated with an increased risk for diagnosis of COVID-19 and COVID-19-related death, independent of the metabolic comorbidities of gout. Women were at a higher risk of death compared with men. There were no significant differences in the risk of COVID-19-related death according to prescription of colchicine or urate-lowering therapy. Evidence is limited and further research is required.
The association was stronger in males, older age, and those with hypertension.
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. However, so far, studies do not support this hypothesis, and studies have shown a protective effect (lower risk of mortality or severe disease). Findings from the American Heart Association’s COVID-19 Cardiovascular Disease Registry report that patients taking statins prior to hospitalization had substantially lower odds of death, primarily among individuals with a history of cardiovascular disease and/or hypertension. Similar findings have been reported from a Swedish registry study.
Surgical mortality and complications may be higher in patients with COVID-19 compared with patients without COVID-19.
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.
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.
People with blood group A may be at increased risk for infection and mortality, and people with blood groups B and AB may be at increased risk for infection; however, evidence is limited.
Blood group O appears to be protective against infection; however, evidence is of low/very low quality. People who are Rh-positive were more vulnerable to infection compared with those who were Rh-negative.
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. 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.
There is limited evidence that gut and lung 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. 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.
Climate and latitude: higher temperatures may slow the progression of the epidemic based on low-certainty evidence and limited studies; however, climate variables alone don’t explain most of the variability in disease transmission. Temperature, humidity, wind speed, ultraviolet light, and latitude may play a role in the epidemic, but further research is required.
Residence in urban or deprived areas: limited evidence suggests that the prevalence was greater in people living in urban areas compared with people living in rural areas, and in people living in more deprived areas compared with people living in less deprived areas.
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