Clinical Spectrum of SARS-CoV-2 Infection
Last Updated: December 17, 2020
Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can experience a range of clinical manifestations, from no symptoms to critical illness. This section of the Guidelines discusses the clinical presentation of patients according to illness severity.
In general, adults with SARS-CoV-2 infection can be grouped into the following severity of illness categories. However, the criteria for each category may overlap or vary across clinical guidelines and clinical trials, and a patient’s clinical status may change over time.
- Asymptomatic or Presymptomatic Infection: Individuals who test positive for SARS-CoV-2 using a virologic test (i.e., a nucleic acid amplification test or an antigen test) but who have no symptoms that are consistent with COVID-19.
- Mild Illness: Individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging.
- Moderate Illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have saturation of oxygen (SpO2) ≥94% on room air at sea level.
- Severe Illness: Individuals who have SpO2 <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, respiratory frequency >30 breaths/min, or lung infiltrates >50%.
- Critical Illness: Individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction.
Patients with certain underlying comorbidities are at a higher risk of progressing to severe COVID-19. These comorbidities include being 65 years or older; having cardiovascular disease, chronic lung disease, sickle cell disease, diabetes, cancer, obesity, or chronic kidney disease; being pregnant; being a smoker; and being a recipient of transplant or immunosuppressive therapy.1 Health care providers should monitor such patients closely until clinical recovery is achieved.
The optimal pulmonary imaging technique has not yet been defined for people with symptomatic SARS-CoV-2 infection. Initial evaluation for these patients may include chest X-ray, ultrasound, or, if indicated, computerized tomography. An electrocardiogram should be performed if indicated. Laboratory testing includes a complete blood count with differential and a metabolic profile, including liver and renal function tests. While not part of standard care, measuring the levels of inflammatory markers such as C-reactive protein (CRP), D-dimer, and ferritin may have prognostic value.2-4
The definitions for the severity of illness categories listed above also apply to pregnant patients. However, the threshold for certain interventions may be different for pregnant patients and nonpregnant patients. For example, oxygen supplementation is recommended for pregnant patients when SpO2 falls below 95% on room air at sea level to accommodate physiologic changes in oxygen demand during pregnancy and to ensure adequate oxygen delivery to the fetus.5 If laboratory parameters are used for monitoring and for interventions, clinicians should be aware that normal physiologic changes during pregnancy can alter several laboratory values. In general, leukocyte cell count increases throughout gestation and delivery and peaks during the immediate postpartum period. This is mainly due to neutrophilia.6 D-dimer and CRP levels also increase during pregnancy and are often higher in pregnant patients than nonpregnant patients.7 Detailed information on treating COVID-19 in pregnant patients can be found in Special Considerations in Pregnancy and in the pregnancy considerations subsection of each individual section of the Guidelines.
In pediatric patients, radiographic abnormalities are common and, for the most part, should not be the only criteria used to determine the severity of illness category. The normal values for respiratory rate also vary with age in children; thus, hypoxia should be the primary criterion used to define severe illness, especially in younger children. In a small number of children and in some young adults, SARS-CoV-2 infection may be followed by a severe inflammatory condition called multisystem inflammatory syndrome in children (MIS-C).8,9 This syndrome is discussed in detail in Special Considerations in Children.
Asymptomatic or Presymptomatic Infection
Asymptomatic SARS-CoV-2 infection can occur, although the percentage of patients who remain truly asymptomatic throughout the course of infection is variable and incompletely defined. It is unclear what percentage of individuals who present with asymptomatic infection progress to clinical disease. Some asymptomatic individuals have been reported to have objective radiographic findings that are consistent with COVID-19 pneumonia.10,11 The availability of widespread virologic testing for SARS-CoV-2 and the development of reliable serologic assays for antibodies to the virus will help determine the true prevalence of asymptomatic and presymptomatic infection. See Therapeutic Management of Patients With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy.
Patients with mild illness may exhibit a variety of signs and symptoms (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell). They do not have shortness of breath, dyspnea on exertion, or abnormal imaging. Most mildly ill patients can be managed in an ambulatory setting or at home through telemedicine or telephone visits. No imaging or specific laboratory evaluations are routinely indicated in otherwise healthy patients with mild COVID-19. Older patients and those with underlying comorbidities are at higher risk of disease progression; therefore, health care providers should monitor these patients closely until clinical recovery is achieved. See Therapeutic Management of Patients With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy.
Moderate illness is defined as evidence of lower respiratory disease during clinical assessment or imaging, with SpO2 ≥94% on room air at sea level. Given that pulmonary disease can progress rapidly in patients with COVID-19, patients with moderate disease should be closely monitored. If bacterial pneumonia or sepsis is suspected, administer empiric antibiotic treatment, re-evaluate the patient daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection. See Therapeutic Management of Patients With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy.
Patients with COVID-19 are considered to have severe illness if they have SpO2 <94% on room air at sea level, a respiratory rate of >30 breaths/min, PaO2/FiO2 <300 mm Hg, or lung infiltrates >50%. These patients may experience rapid clinical deterioration. Oxygen therapy should be administered immediately using a nasal cannula or a high-flow oxygen device. See Therapeutic Management of Patients With COVID-19 for recommendations regarding SARS-CoV-2–specific therapy. If secondary bacterial pneumonia or sepsis is suspected, administer empiric antibiotics, re-evaluate the patient daily, and de-escalate or stop antibiotics if there is no evidence of bacterial infection.
Critically ill patients may have acute respiratory distress syndrome, septic shock that may represent virus-induced distributive shock, cardiac dysfunction, elevation in levels of multiple inflammatory cytokines that provoke a cytokine storm, and/or exacerbation of underlying comorbidities. In addition to pulmonary disease, patients with critical illness may also experience cardiac, hepatic, renal, central nervous system, or thrombotic disease.
As with any patient in the intensive care unit (ICU), successful clinical management of a patient with COVID-19 includes treating both the medical condition that initially resulted in ICU admission and other comorbidities and nosocomial complications.
For more information, see Care of Critically Ill Patients With COVID-19.
Persistent Symptoms or Organ Dysfunction After Acute COVID-19
There have been an increasing number of reports of patients who experience persistent symptoms and/or organ dysfunction after acute COVID-19. At this time, there is limited information on the prevalence, duration, underlying causes, and effective management strategies for these lingering signs and symptoms.12 The nomenclature for this phenomenon is evolving, but it has been referred to as “postacute COVID-19 syndrome” or “long COVID,” and affected patients have been referred to as “long haulers.” The incidence, natural history, and etiology of these symptoms are currently unknown. Currently, there is no case definition for postacute COVID-19 syndrome, and no specific time frame has been established to define late sequelae of COVID-19. However, the Centers for Disease Control and Prevention (CDC) recently proposed defining late sequelae as sequelae that extend beyond 4 weeks after initial infection.13,14 Some of the symptoms overlap with the post–intensive care syndrome (PICS) that has been described in patients without COVID-19, but prolonged symptoms and disabilities after COVID-19 have also been reported in patients with milder illness, including outpatients (see General Considerations for information on PICS).15,16
Common persistent symptoms include fatigue, joint pain, chest pain, palpitations, shortness of breath, cognitive impairment, and worsened quality of life.17,18 The CDC conducted a telephone survey of a random sample of 292 adult outpatients who had positive polymerase chain reaction results for SARS-CoV-2. Among the 274 respondents who were symptomatic at the time of testing, 35% reported not having returned to their usual state of health 2 weeks or more after testing; 26% of these patients were aged 18 to 34 years (n = 85), 32% were aged 35 to 49 years (n = 96), and 47% were aged ≥50 years (n = 89).16 An age of ≥50 years and the presence of three or more chronic medical conditions were associated with not returning to usual health within 14 to 21 days. Moreover, one in five individuals aged 18 to 34 years who did not have chronic medical conditions had not achieved baseline health when interviewed at a median of 16 days from the testing date.
Persistent symptoms have also been reported in pregnant people.19 Systematic data on persistent symptoms in children following recovery from the acute phase of COVID-19 are not currently available.20 MIS-C is discussed in Special Considerations in Children.
The prevalence of fatigue among 128 individuals from Ireland who had recovered from the acute phase of COVID-19 was examined using the Chalder Fatigue Scale (CFQ-11). More than half of patients reported persistent fatigue at a median of 10 weeks after initial symptoms first appeared (67 of 128 patients; 52.3%). There was no association between illness severity and fatigue.21 A postacute outpatient service developed in Italy reported that 87% of 143 patients surveyed reported persistent symptoms at a mean of 60 days after symptom onset, with the most common symptom being fatigue (which occurred in 53.1% of these patients).22
A study from the United Kingdom reported that among 100 hospitalized patients (32 received care in the ICU and 68 received care in hospital wards only), 72% of the ICU patients and 60% of the ward patients experienced fatigue and breathlessness at 4 to 8 weeks after hospital discharge. The authors suggested that posthospital rehabilitation may be necessary for some of these patients.17 A retrospective study from China found that pulmonary function (as measured by spirometry) was still impaired 1 month after hospital discharge in 31 of 57 patients (54.4%).23 In a study from Germany that included 100 patients who had recently recovered from COVID-19, cardiac magnetic resonance imaging (MRI) performed a median of 71 days after diagnosis revealed cardiac involvement in 78% of patients and ongoing myocardial inflammation in 60% of patients.24 A retrospective study from China of 26 patients who had recovered from COVID-19 and who had initially presented with cardiac symptoms found abnormalities on cardiac MRI in 15 patients (58%).25 One should review these data and assess the prevalence of cardiac abnormalities in people with postacute COVID-19 syndrome with caution, however, as the results were likely biased by only including patients with cardiac symptoms.
Neurologic and psychiatric symptoms have also been reported among patients who have recovered from acute COVID-19. High rates of anxiety and depression have been reported in some patients using self-report scales for psychiatric distress.18,26 Younger patients have been reported to experience more psychiatric symptoms than patients aged >60 years.17,18 Patients may continue to experience headaches, vision changes, hearing loss, loss of taste or smell, impaired mobility, numbness in extremities, tremors, myalgia, memory loss, cognitive impairment, and mood changes for up to 3 months after diagnosis of COVID-19.27,28 One study in the United Kingdom administered cognitive tests to 84,285 participants who had recovered from suspected or confirmed cases of SARS-CoV-2 infection. These participants had worse performances across multiple domains than would be expected for people with the given age and demographic profiles; this effect was observed even among those who had not been hospitalized.29 However, the study authors did not report when the tests were administered in relation to the diagnosis of COVID-19.
More research and more rigorous observational cohort studies are needed to better understand the pathophysiology and clinical course of these postinfection sequelae and to identify management strategies for patients. More information about ongoing studies can be found at ClinicalTrials.gov.
- Centers for Disease Control and Prevention. COVID-19 (oronavirus disease): people with certain medical conditions. 2020. Available at https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed December 11, 2020.
- Tan C, Huang Y, Shi F, et al. C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early. J Med Virol. 2020;92(7):856-862. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32281668.
- Berger JS, Kunichoff D, Adhikari S, et al. Prevalence and outcomes of D-dimer elevation in hospitalized patients with COVID-19. Arterioscler Thromb Vasc Biol. 2020;40(10):2539-2547. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32840379.
- Casas-Rojo JM, Anton-Santos JM, Millan-Nunez-Cortes J, et al. Clinical characteristics of patients hospitalized with COVID-19 in Spain: results from the SEMI-COVID-19 Registry. Rev Clin Esp. 2020;220(8):480-494. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32762922.
- Society for Maternal-Fetal Medicine. Management considerations for pregnant patients with COVID-19. 2020. Available at: https://s3.amazonaws.com/cdn.smfm.org/media/2336/SMFM_COVID_Management_of_COVID_pos_preg_patients_4-30-20_final.pdf. Accessed December 14, 2020.
- Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol. 2009;114(6):1326-1331. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19935037.
- Anderson BL, Mendez-Figueroa H, Dahlke JD, Raker C, Hillier SL, Cu-Uvin S. Pregnancy-induced changes in immune protection of the genital tract: defining normal. Am J Obstet Gynecol. 2013;208(4):321.e1-321.e9. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23313311.
- Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet. 2020;395(10237):1607-1608. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32386565.
- Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020;395(10239):1771-1778. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32410760.
- Zhang R, Ouyang H, Fu L, et al. CT features of SARS-CoV-2 pneumonia according to clinical presentation: a retrospective analysis of 120 consecutive patients from Wuhan city. Eur Radiol. 2020;30(8):4417-4426. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32279115.
- Inui S, Fujikawa A, Jitsu M, et al. Chest CT findings in cases from the cruise ship Diamond Princess with coronavirus disease 2019 (COVID-19). Radiology: Cardiothoracic Imaging. 2020;2(2). Available at: https://pubs.rsna.org/doi/10.1148/ryct.2020200110.
- Marshall M. The lasting misery of coronavirus long-haulers. Nature. 2020;585(7825):339-341. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32929257.
- Datta SD, Talwar A, Lee JT. A proposed framework and timeline of the spectrum of disease due to SARS-CoV-2 infection: illness beyond acute infection and public health implications. JAMA. 2020;324(22):2251-2252. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33206133.
- Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute COVID-19 in primary care. BMJ. 2020;370:m3026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32784198.
- Rawal G, Yadav S, Kumar R. Post-intensive care syndrome: an overview. J Transl Int Med. 2017;5(2):90-92. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28721340.
- Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32730238.
- Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32729939.
- Cai X, Hu X, Ekumi IO, et al. Psychological distress and its correlates among COVID-19 survivors during early convalescence across age groups. Am J Geriatr Psychiatry. 2020;28(10):1030-1039. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32753338.
- Afshar Y, Gaw SL, Flaherman VJ, et al. Clinical presentation of coronavirus disease 2019 (COVID-19) in pregnant and recently pregnant people. Obstet Gynecol. 2020;136(6):1117-1125. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33027186.
- Ludvigsson JF. Case report and systematic review suggest that children may experience similar long-term effects to adults after clinical COVID-19. Acta Paediatr. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33205450.
- Townsend L, Dyer AH, Jones K, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15(11):e0240784. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33166287.
- Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603-605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644129.
- Huang Y, Tan C, Wu J, et al. Impact of coronavirus disease 2019 on pulmonary function in early convalescence phase. Respir Res. 2020;21(1):163. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32600344.
- Puntmann VO, Carerj ML, Wieters I, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5(11):1265-1273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32730619.
- Huang L, Zhao P, Tang D, et al. Cardiac involvement in patients recovered from COVID-2019 identified using magnetic resonance imaging. JACC Cardiovasc Imaging. 2020;13(11):2330-2339. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32763118.
- Mazza MG, De Lorenzo R, Conte C, et al. Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors. Brain Behav Immun. 2020;89:594-600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32738287.
- Lu Y, Li X, Geng D, et al. Cerebral micro-structural changes in COVID-19 patients—an MRI-based 3-month follow-up study. EClinicalMedicine. 2020;25:100484. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32838240.
- Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020;12(1):69. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32498691.
- Hampshire A, Trender W, Chamberlain SR, et al. Cognitive deficits in people who have recovered from COVID-19 relative to controls: an N = 84,285 online study. medRxiv. 2020;[Preprint]. Available at: https://www.medrxiv.org/content/10.1101/2020.10.20.20215863v1.