History and exam
Key diagnostic factors
Reported in approximately 78% of patients. Prevalence has been higher in some case series. 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. In children, fever may be absent or brief and rapidly resolving.
Reported in approximately 57% of patients. Prevalence has been higher in some case series. The cough is usually dry; however, a productive cough has been reported in some patients.
Reported in approximately 23% of patients. Prevalence has been higher in some case series. The World Health Organization estimates the range to be 31% to 40%. Median time from onset of symptoms to development of dyspnea is 5 to 8 days. It is less common in children, but the most common sign in neonates. May last weeks after initial onset of symptoms. Wheeze has been reported in 17% of patients.
The pooled prevalence of olfactory dysfunction (anosmia/hyposmia) is 53%, with a pooled prevalence of 44% for gustatory dysfunction (ageusia/dysgeusia). Prevalence appears to be higher in European studies; 87% of patients self-reported loss of smell and 56% reported taste dysfunction in one study.
Initial findings from the American Academy of Otolaryngology - Head and Neck Surgery’s COVID-19 anosmia reporting tool found that 73% of patients reported anosmia prior to diagnosis, and it was the initial symptom in 26.6% of patients.
There is anecdotal evidence that altered sense of smell/taste may be an early symptom of COVID-19 before the onset of other symptoms, or may be the only symptom in patients with mild to moderate illness.
The UK government now includes altered sense of taste/smell in the general clinical case definition, and recommends that patients self-isolate if they develop an altered sense of smell/taste. However, the current evidence base is of poor quality due to the mainly retrospective and cross-sectional nature of studies available.
Complete resolution or improvement in symptoms was reported in 89% of patients 4 weeks after onset.
Other diagnostic factors
Reported in approximately 31% of patients. Prevalence has been higher in some case series. 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. Prevalence has been higher in some case series.
Reported in approximately 23.7% of patients. Prevalence has been higher in some case series.
Reported in approximately 12% of patients. Usually presents early in the clinical course.
Diarrhea has been reported in approximately 10% of patients, nausea in 6%, vomiting in 4%, and abdominal pain in 4%. The pooled prevalence of gastrointestinal symptoms is 15%, and patients with severe illness have a higher prevalence. Around 10% of patients present with gastrointestinal symptoms alone. Gastrointestinal symptoms are more prevalent outside of China.
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.
Hematochezia has been reported.
Reported in approximately 11% of patients.
Reported in approximately 13% of patients.
Confusion has been reported in approximately 11% of patients. Prevalence of confusion/delirium and agitation is high (65% and 69%, respectively) in patients in the intensive care unit. Delirium is associated with an increased risk of mortality, and rapid onset may indicate clinical deterioration. Anxiety, depression, and sleep problems have also been reported.
Reported in 7.8% of hospitalized adults in one observational cross-sectional study in Italy.
Various manifestations have been reported in adults and children including a erythematous or maculopapular or morbilliform rash, a varicella-like papulovesicular exanthem on the trunk, petechiae, urticaria, vesicles, ischemic and ecchymotic acral lesions as a manifestation of clotting disorders, pityriasis rosea, digitate papulosquamous eruption, and erythema multiforme-like lesions.
A case collection survey of images and clinical data classified lesions as: maculopapular eruptions (47%); acral areas of erythema with vesicles or pustules, or pseudo‐chilblain (19%); urticarial lesions (19%); other vesicular eruptions (9%); and livedo or necrosis (6%). Vesicular lesions often appear early in the course of disease before other symptoms, and the pseudo-chilblain pattern frequently appears later in the course after the appearance of other symptoms.
Chilblains, particularly on the toes or foot, have been reported especially in younger patients who lack a history of chilblains, Raynaud phenomenon, or collagen vascular diseases (e.g., systemic lupus erythematosus). However, based on data from small case series, chilblains do not appear to be directly associated with COVID-19.
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 skin involvement.
Rhinorrhea has been reported in approximately 8% of patients, and nasal congestion has been reported in approximately 5% of patients.
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.
Diagnosis should be suspected in patients with acute respiratory illness (i.e., fever and at least one sign/symptom of respiratory disease such as cough or shortness of breath) and a history of travel to or residence in a location reporting community transmission of COVID-19 during the 14 days prior to symptom onset.
Diagnosis should be suspected in patients with any acute respiratory illness if they have been in contact with a confirmed or probable COVID-19 case in the last 14 days prior to symptom onset.
Older age is a risk factor for infection. Data from a cross-sectional study in the UK indicate that people aged 40 to 64 years are at greatest risk of infection, followed by patients 75 years and older, and then people aged 65 to 74 years. The risk of severe illness in adults increases with age, with older people (ages 65 years and older) at highest risk. The highest mortality rate has been 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, 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.
Widespread transmission has been reported in long-term care facilities. People who live in a nursing home or long-term care facility are at higher risk for severe illness. Care home residents represent approximately one third of the total number of deaths in England and Wales; other countries have reported a similar experience. This is likely due to shortages in personal protective equipment, a vulnerable population, and a lack of testing. More than one third of care homes in England have had cases. A study across four nursing homes in the UK found that 26% of residents died over a 2-month period, with all-cause mortality increasing by 203% compared with previous years. Approximately 40% of residents tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and of these, 43% were asymptomatic and 18% had atypical symptoms.
Male sex is a risk factor for infection. Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in males (18.4%) compared with females (13.3%). Male sex is also a risk factor for severe disease, disease progression, need for mechanical ventilation, and increased mortality. It has been hypothesized that this may be due to the presence of androgens, or a lower level of SARS-CoV-2 antibodies compared with females; however, further research is required.
People from Black, Asian, and minority ethnic (BAME) groups are at a higher risk of infection and worse outcomes, including an increased risk of mortality, compared with the general population. The reasons for this are unclear and require further research. Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in Black people (62.1%) compared with White people (15.5%). The average age of patients from ethnic minorities was significantly lower than that of White patients. 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. There is also evidence from the US that supports this. Age-adjusted data from the Centers for Disease Control and Prevention (as of 25 June) show that non-Hispanic American Indian, Alaska Native, and non-Hispanic Black people have approximately 5 times the rate of hospitalizations of non-Hispanic White people, and Hispanic or Latino people have approximately 4 times the rate of hospitalizations of non-Hispanic White people. In a study of over 10,000 deceased patients in the US, 35% of Hispanic and 30% of non-White decedents were ages <65 years, compared with 13% of White, non-Hispanic decedents.
People with comorbidities are at higher risk for severe illness and mortality. The more comorbidities a person has, the greater their risk for severe illness. The most prevalent comorbidities in adults with COVID-19 are hypertension, cardiovascular disease, diabetes, chronic respiratory disease, malignancy, chronic kidney disease, cerebrovascular disease, and obesity. In a prospective observational cohort study of more than 20,000 hospitalized patients in the UK, the most common comorbidities were chronic cardiac disease (31%), uncomplicated diabetes (21%), nonasthmatic chronic pulmonary disease (18%), and chronic kidney disease (16%). Similarly, in the US the most common comorbidities were cardiovascular disease (32%), diabetes (30%), and chronic lung disease (18%). Hospitalizations were six times higher and deaths were 12 times higher in patients with comorbidities compared with those without. It has been estimated that approximately 56% of adults in the US are at risk for requiring hospitalization from COVID-19 because of the presence of at least one comorbidity. These underlying conditions are associated with modifiable risk factors, which, if improved through lifestyle changes, may improve a person’s risk status.
Among 345 pediatric cases with information on underlying conditions, 23% had at least one underlying condition, most commonly chronic lung disease, cardiovascular disease, or immunosuppression. Approximately 39% of hospitalized children had an underlying condition in another study. The most prevalent comorbidities were asthma, neurologic disorders, diabetes, obesity, cardiovascular disease, and malignancy/hematologic conditions.
Around 32% of young adults (ages 18-25 years) in the US had underlying conditions that put them at risk for severe disease including heart conditions, diabetes, asthma, immune conditions, liver conditions, and obesity. Smoking (including e-cigarette use) in the past 30 days also increased the risk. The rate of young adults at risk for severe disease decreased to 16% when considering nonsmokers only.
People with serious heart conditions (e.g., heart failure, coronary artery disease, cardiomyopathy, pulmonary hypertension) are at increased risk of severe illness. Cardiovascular disease is associated with a 3-fold increased odds of severe infection, and an 11-fold increase in all-cause mortality.
People with hypertension may be at increased risk of severe illness. 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 2.27-fold higher risk of severe disease, and a 3.48-fold higher risk of fatality compared with patients without hypertension.
People with type 2 diabetes are at increased risk of severe illness. People with type 1 diabetes or gestational diabetes may also be at increased risk of severe illness; however, evidence is limited for these patient groups. The pooled prevalence of diabetes in COVID-19 patients is approximately 10%. Prevalence is significantly higher in older patients and patients with severe disease. Diabetes is associated with increased risk of mortality, disease progression, and acute respiratory distress syndrome. Patients with diabetes have a 2-fold higher risk of developing severe disease, and a 2-fold higher risk of mortality. Risk factors for poor prognosis and higher mortality include older age, elevated C-reactive protein, and insulin use. One third of all deaths in hospitalized patients in England occur in patients with diabetes. People with type 1 diabetes have 3.50 times the odds of dying in hospital with COVID-19, while people with type 2 diabetes have 2.03 times the odds. Patients with poorly controlled hyperglycemia have an increased risk of disease severity and mortality. Body mass index is positively and independently associated with tracheal intubation and/or death within 7 days in patients with diabetes. Patients with newly diagnosed diabetes have a higher risk of all-cause mortality compared with patients with known diabetes, hyperglycemia, or normal glucose. 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.
There is no clear evidence that people with asthma or chronic obstructive pulmonary disease (COPD) are at higher risk of infection. People with COPD (including emphysema and chronic bronchitis) are at increased risk of severe illness. COPD is associated with a 5-fold increased risk of severe infection. It is unclear whether patients with asthma have a higher risk for severe disease; however, there is no statistically significant association between asthma and a higher risk of mortality in patients with COVID-19. People with other chronic lung diseases (e.g., cystic fibrosis, idiopathic pulmonary fibrosis) may be at increased risk of severe illness; however, the evidence is limited. There are no data on whether pediatric respiratory diseases (including childhood asthma) are risk factors for infection or severity.
People with chronic kidney disease may be at higher risk of infection. Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in patients with chronic kidney disease (32.9%) compared with those without (14.4%). People with chronic kidney disease are also at increased risk of severe illness. The prevalence of preexisting chronic kidney disease in COVID-19 patients was 5.2% (2.3% for end-stage kidney disease), and is an independent risk factor for developing acute kidney injury as a complication.
People with cancer are at a higher risk of infection, likely due to immunosuppressive treatments and/or recurrent hospital visits. The overall pooled prevalence of cancer in COVID-19 patients is approximately 2.3%, and it is significantly associated with severe disease. Patients with cancer are 76% more likely to get severe disease compared with those without cancer. They also have an increased risk of worse clinical outcomes including intensive care unit admission and all-cause mortality (particularly those with metastatic disease, hematologic cancer, or lung cancer), and appear to deteriorate more quickly compared with patients without cancer. Patients who underwent cancer surgery had higher mortality rates. Factors associated with an increased mortality rate in adults include older age, male sex, smoking status, number of comorbidities, Eastern Cooperative Oncology Group performance status of 2 or more, receiving chemotherapy within 4 weeks before symptom onset, and active cancer. However, a subgroup analysis of patients ages 65 years and older found that all-cause mortality was comparable to 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. Pooled case fatality rates of between 6.8% and 21% have been reported in adults with cancer, although these rates should be interpreted with caution.
People with obesity (body mass index ≥30) are at higher risk of infection. Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in patients with obesity (20.9%) compared with those without (13.2%). People with obesity are also at increased risk of severe illness. Data from France estimates that the prevalence of obesity is 1.35 times higher in patients with severe disease compared with the general population. Obesity is a risk factor for intensive care admission, respiratory failure leading to invasive mechanical ventilation, and mortality. Obesity may be a significant risk factor for the development of severe disease or mortality in younger people (defined as <50 years of age in some studies and <60 years of age in others). Increased body mass index is a significant risk factor for severe disease in pregnant women. Obesity was the most common comorbidity in children, and was significantly associated with mechanical ventilation in children 2 years and older in a single-center retrospective study in New York.
People with sickle cell disease are at increased risk of severe illness; people with other hemoglobin disorders (e.g., thalassemia) may be at increased risk of severe illness. Among 178 patients with sickle cell disease and COVID-19 in the US (mean patient age <40 years), 69% were hospitalized, 11% were admitted to intensive care, and 7% died. Infection can cause acute chest syndrome in patients with sickle cell disease.
People with an immunocompromised state from solid organ transplant are at increased risk of severe illness. Organ transplant recipients may be at higher risk of severe illness or complications, more rapid clinical progression, and a prolonged clinical course compared with the general population due to chronic immunosuppression and the presence of coexisting conditions.
Patients with any smoking history are at higher risk of severe disease and worse in-hospital outcomes. Current smokers have an increased risk of severe or critical disease. Patients with a smoking history have a significantly increased risk of severe or critical disease, in-hospital mortality, disease progression, and need for mechanical ventilation. This may be due to increased airway expression of the angiotensin-converting enzyme-2 receptor in 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.
People with cerebrovascular disease may be at increased risk of severe illness. Patients with a history of stroke are at increased risk of poor outcomes, including need for intensive care unit admission and mechanical ventilation, and increased risk of mortality compared with those without a history of stroke.
The prevalence of chronic liver disease in COVID-19 patients is approximately 3%. The presence of chronic liver disease is associated with more severe disease and overall mortality. 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.
Patients with severe COVID-19 may be more likely to have metabolic dysfunction-associated fatty liver disease (MAFLD; also called nonalcoholic fatty liver disease) compared with patients who have nonsevere COVID-19. MAFLD is associated with a 4- to 6-fold increase in severity of COVID-19. Severity of COVID-19 has been associated with younger age (<60 years) and intermediate or high fibrosis-4 (FIB-4) scores in patients with MAFLD.
Surgical mortality and complications are 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.
Pregnant women may be at increased risk of severe illness and adverse pregnancy outcomes. According to an analysis of 8200 infected pregnant women, pregnant women were more likely to be hospitalized, to be admitted to the intensive care unit, and to receive mechanical ventilation compared with nonpregnant women; however, mortality rates did not differ.
People who are immunocompromised (e.g., HIV, blood or bone marrow transplant, immune deficiencies, prolonged use of corticosteroids or other immunosuppressant medications) may be at increased risk of severe illness; however, evidence is limited. Patients with inflammatory bowel disease who were on long-term biologics or other immunomodulatory therapies did not have a higher risk of poor outcomes; however, recent corticosteroid use may be related to worse outcomes. Glucocorticoid exposure of ≥10 mg/day (prednisone) has been associated with a higher odds of hospitalization in patients with rheumatologic disease. HIV coinfection does not significantly impact presentation, hospital course, or outcomes of patients when compared with nonmatched non-HIV patients. People living with HIV who have well-controlled disease are not at risk of poorer disease outcomes compared with the general population. It is unclear whether those with poorly controlled disease or AIDS have poorer outcomes.
Evidence suggests that there may be an association between long-term exposure to ambient air pollution and COVID-19. The highest numbers of cases were recorded in the most polluted regions of Italy, with patients presenting with more severe disease requiring intensive care. The mortality was 2-fold higher in polluted regions compared with other regions. One study found that of deaths from COVID-19 across 66 administrative regions in Italy, Spain, France, and Germany, 78% of deaths occurred in just five regions, and these regions were the most polluted in terms of nitrogen dioxide levels. A preprint study from Harvard University found that people who live in US regions with high levels of air pollution were more likely to die from COVID-19 than those who live in less polluted areas. The researchers found that an increase of 1 microgram/m³ in fine particulate matter is associated with an 8% increase in the COVID-19 death rate.
Distribution of community outbreaks along restricted latitude, temperature, and humidity measurements are consistent with the behavior of a seasonal respiratory virus. Evidence suggests that cold and dry conditions may increase transmission, and warm and humid conditions may reduce the rate of infections; however, evidence is not yet sufficient to prove causation. However, there is other evidence that suggests ambient temperature has no significant impact on transmission, especially during the pandemic stage of an emerging pathogen. Further research is required on how weather conditions influence transmission as colder temperatures have been associated with increased transmission of other coronaviruses. Higher latitude may also be associated with an increased risk of cases and deaths in some countries. A positive correlation has been found between lower death rates and a country’s proximity to the equator, suggesting a correlation between sunlight exposure (and vitamin D levels) and reduced mortality.
Data from a cross-sectional study in the UK found that the adjusted odds of a positive test were greater in people living in urban areas (26.2%) compared with people living in rural areas (5.6%), and in people living in more deprived areas (29.5%) compared with people living in less deprived areas (7.7%).
A population-based study in Israel found that patients who tested positive for COVID-19 had significantly lower plasma vitamin D levels compared with those who tested negative. Univariate analysis demonstrated an association between low plasma vitamin D level and increased likelihood of hospitalization. The study concluded that low plasma vitamin D level appears to be an independent risk factor for COVID-19 infection and for hospitalization. A small retrospective observational preprint study (not peer reviewed) suggests a link between vitamin D insufficiency and COVID-19 severity. However, further research is needed.
There was originally concern that people on these drugs may be at increased risk of infection or more severe disease due to upregulation of angiotensin-converting enzyme-2 (ACE2) receptor expression. However, high-certainty evidence suggests that use of these drugs is not associated with severe disease, and moderate-certainty evidence suggests that there is no association between the use of these medications and a positive SARS-CoV-2 test result among symptomatic patients. A prospective cohort study of over 19,000 patients in England found that these drugs were associated with a significantly reduced risk of COVID-19, and were not associated with an increased risk of intensive care. However, variations between ethnic groups raise the possibility of ethnic-specific effects. The UK National Institute for Health and Care Excellence states that conclusion cannot be drawn on whether these drugs increase or decrease the risk of developing COVID-19 or severe disease based on the current available evidence. Professional societies recommend that patients who are already on these drugs continue to take them.
There is concern that people on these drugs may be at increased risk of infection or more severe disease as statins have been shown to increase the expression of ACE2 in laboratory animals, and may promote the activation of the inflammatory pathway in acute respiratory distress syndrome leading to more severe disease. However, a retrospective study of nearly 14,000 patients found that statin use was associated with a lower risk of all-cause mortality in patients with COVID-19, possibly due to the immunomodulatory effects of statins. Further research into the potential therapeutic or detrimental effects of statins is required.
Autoimmune disease, in general, does not appear to be associated with a higher risk of infection. Patients with autoimmune rheumatic disease may be more susceptible to infection compared with the general population, although data are scarce. Autoimmune disease has been associated with a slightly increased risk of disease severity and mortality; however, this was not statistically significant. Risk of mortality appears to be associated with older age and the presence of comorbidities even in patients with autoimmune disease, rather than the autoimmune disease itself or use of immunosuppressive medications. In patients with multiple sclerosis, neurologic disability, age, and obesity were risk factors for severe disease. Weak evidence suggests that people with inflammatory bowel disease may be somewhat protected from infection, likely due to their ongoing treatment for the condition. Further research is required as there is concern about the risk of infection in these patients.
People with neurologic conditions (e.g., dementia) may be at increased risk of severe illness; however, evidence is limited.
People with thalassemia may be at increased risk of severe illness; however, evidence is limited.
Children may be at increased risk of severe illness if they have certain conditions (e.g., obesity, diabetes, asthma and chronic lung disease, immunosuppression); are medically complex; have serious genetic, neurologic, or metabolic disorders; or have congenital heart disease. However, evidence is limited.
People with blood group A appear to be at increased risk of infection, while people with blood group O have a decreased risk. 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.
There is some emerging evidence that gut microbiota dysfunction may be implicated in the pathogenesis of COVID-19, although this is yet to be confirmed. Patients appear to have a depletion of beneficial commensals (Eubacterium ventriosum, Faecalibacterium prausnitzii, Roseburia and Lachnospiraceae taxa) and an overgrowth of opportunistic pathogens (Clostridium hathewayi, Actinomyces viscosus, Bacteroides nordii) during hospitalisation. Gut microbiome configuration has been associated with disease severity.
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