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01 Apr Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) Article

Posted at 12:27h in COVID-19 by

National Center for Immunization and Respiratory Diseases (NCIRD), Division of Viral Diseases

Clinical Presentation

Incubation period

The incubation period for COVID-19 is thought to extend to 14 days, with a median time of 4-5 days from exposure to symptoms onset.1-3 One study reported that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of SARS-CoV-2 infection.3

Presentation

The signs and symptoms of COVID-19 present at illness onset vary, but over the course of the disease, most persons with COVID-19 will experience the following1,4-9:

  • Fever (83–99%)
  • Cough (59–82%)
  • Fatigue (44–70%)
  • Anorexia (40–84%)
  • Shortness of breath (31–40%)
  • Sputum production (28–33%)
  • Myalgias (11–35%)

 

Atypical presentations have been described, and older adults and persons with medical comorbidities may have delayed presentation of fever and respiratory symptoms.10,11 In one study of 1,099 hospitalized patients, fever was present in only 44% at hospital admission but later developed in 89% during hospitalization.1 Headache, confusion, rhinorrhea, sore throat, hemoptysis, vomiting, and diarrhea have been reported but are less common (<10%).1,4-6 Some persons with COVID-19 have experienced gastrointestinal symptoms such as diarrhea and nausea prior to developing fever and lower respiratory tract signs and symptoms.9 Anosmia or ageusia preceeding the onset of respiratory symptoms has been anecdotally reported12, but more information is needed to understand its role in identifying COVID-19.

Several studies have reported that the signs and symptoms of COVID-19 in children are similar to adults and are usually milder compared to adults.13-17 For more information on the clinical presentation and course among children, see Information for Pediatric Healthcare Providers.

Asymptomatic and Pre-Symptomatic Infection

Several studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (pre-symptomatic).14,16,18-28

Since asymptomatic persons are not routinely tested, the prevalence of asymptomatic infection and detection of pre-symptomatic infection is not well understood.

One study found that as many as 13% of RT-PCR-confirmed cases of SARS-CoV-2 infection in children were asymptomatic.14

Another study of skilled nursing facility residents infected with SARS-CoV-2 from a healthcare worker demonstrated that half were asymptomatic or pre-symptomatic at the time of contact tracing evaluation and testing.26

Patients may have abnormalities on chest imaging before the onset of symptoms.20,21 Some data suggest that pre-symptomatic infection tended to be detected in younger individuals and was less likely to be associated with viral pneumonia.20,21

Asymptomatic and Pre-Symptomatic Transmission

Epidemiologic studies have documented SARS-CoV-2 transmission during the pre-symptomatic incubation period20,29-31, and asymptomatic transmission has been suggested in other reports.22,23,32

Virologic studies have also detected SARS-CoV-2 with RT-PCR low cycle thresholds, indicating larger quantities of viral RNA, and cultured viable virus among persons with asymptomatic and pre-symptomatic SARS-CoV-2 infection.19,24,26,33

The exact degree of SARS-CoV-2 viral RNA shedding that confers risk of transmission is not yet clear. Risk of transmission is thought to be greatest when patients are symptomatic since viral shedding is greatest at the time of symptom onset and declines over the course of several days to weeks.33-36

However, the proportion of SARS-CoV-2 transmission in the population due to asymptomatic or pre-symptomatic infection compared to symptomatic infection is unclear.37

Clinical Course

Illness Severity

The largest cohort of >44,000 persons with COVID-19 from China showed that illness severity can range from mild to critical38:

  • Mild to moderate (mild symptoms up to mild pneumonia): 81%
  • Severe (dyspnea, hypoxia, or >50% lung involvement on imaging): 14%
  • Critical (respiratory failure, shock, or multiorgan system dysfunction): 5%

In this study, all deaths occurred among patients with critical illness and the overall case fatality rate was 2.3%.38 The case fatality rate among patients with critical disease was 49%.38 Among children in China, illness severity was lower with 94% having asymptomatic, mild or moderate disease, 5% having severe disease, and <1% having critical disease.14 Among U.S. COVID-19 cases with known disposition, the proportion of persons who were hospitalized was 19%.39 The proportion of persons with COVID-19 admitted to the intensive care unit (ICU) was 6%.39

However, the proportion of SARS-CoV-2 transmission in the population due to asymptomatic or pre-symptomatic infection compared to symptomatic infection is unclear.37

Clinical Progression

Among patients who developed severe disease, the medium time to dyspnea ranged from 5 to 8 days, the median time to acute respiratory distress syndrome (ARDS) ranged from 8 to 12 days, and the median time to ICU admission ranged from 10 to 12 days.5,6,10,11

Clinicians should be aware of the potential for some patients to rapidly deteriorate one week after illness onset. Among all hospitalized patients, a range of 26% to 32% of patients were admitted to the ICU.6,8,11

Among all patients, a range of 3% to 17% developed ARDS compared to a range of 20% to 42% for hospitalized patients and 67% to 85% for patients admitted to the ICU.1,4-6,8,11

Mortality among patients admitted to the ICU ranges from 39% to 72% depending on the study.5,8,10,11

The median length of hospitalization among survivors was 10 to 13 days.1,6,8

Risk Factors for Severe Illness

Age is a strong risk factor for severe illness, complications, and death.1,6,8,10,11,38-41 Among more than 44,000 confirmed cases of COVID-19 in China, the case fatality rate was highest among older persons: ≥80 years: 14.8%, 70–79 years: 8.0%, 60–69 years: 3.6%, 50–59 years: 1.3%, 40–49 years: 0.4%, <40 years: 0.2%.38,42

Early U.S. epidemiologic data suggests that the case fatality was highest in persons aged ≥85 years (range 10%–27%), followed by 3%–11% for ages 65–84 years, 1%–3% for ages 55–64 years, and <1% for ages 0–54 years.39

Patients in China with no reported underlying medical conditions had an overall case fatality of 0.9%, but case fatality was higher for patients with comorbidities: 10.5% for those with cardiovascular disease, 7.3% for diabetes, and approximately 6% each for chronic respiratory disease, hypertension, and cancer.42

Heart disease, hypertension, prior stroke, diabetes, chronic lung disease, and chronic kidney disease have all been associated with increased illness severity and adverse outcomes.1,6,10,11,38,42,43

Accounting for differences in age and prevalence of underlying condition, mortality associated with COVID-19 in the United States was similar to China.39,40,44

Medications

It has been hypothesized that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may increase the risk of SARS-CoV-2 infection and COVID-19 severity.45 ACE inhibitors and ARBs increase the expression of angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 uses the ACE2 receptor to enter into the host cell.

There are no data to suggest a link between ACE inhibitors or ARBs with worse COVID-19 outcomes. The American Heart Association (AHA), the Heart Failure Society of America (HFSA), and the American College of Cardiology (ACC) released a statement recommending continuation of these drugs for patients already receiving them for heart failure, hypertension, or ischemic heart disease.46

It has also been hypothesized that non-steroidal anti-inflammatory drugs (NSAIDs) may worsen COVID-19. Currently, there are no data suggesting an association between COVID-19 clinical outcomes and NSAID use. More information can be found at Healthcare Professionals: Frequently Asked Questions and Answers.

Reinfection

There are no data concerning the possibility of re-infection with SARS-CoV-2 after recovery from COVID-19.

Viral RNA shedding declines with resolution of symptoms, and may continue for days to weeks.11,33,34

However, the detection of RNA during convalescence does not necessarily indicate the presence of viable infectious virus. Clinical recovery has been correlated with the detection of IgM and IgG antibodies which signal the development of immunity.36,47-49

Diagnostic Testing

Diagnosis of COVID-19 requires detection of SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR).

Detection of SARS-CoV-2 viral RNA is better in nasopharynx samples compared to throat samples.33,50 Lower respiratory samples may have better yield than upper respiratory samples.33,50. SARS-CoV-2 RNA has also been detected in stool and blood.13,34,47,51

Detection of SARS-CoV-2 RNA in blood may be a marker of severe illness.52 Viral RNA shedding may persist over longer periods among older persons and those who had severe illness requiring hospitalization. (median range of viral shedding among hospitalized patients 12–20 days).11,33-36

Infection with both SARS-CoV-2 and with other respiratory viruses has been reported, and detection of another respiratory pathogen does not rule out COVID-19.53

For more information about testing and specimen collection, handling and storage, visit Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19) and Frequently Asked Questions on COVID-19 Testing at Laboratories.

Laboratory and Radiographic Findings

Laboratory Findings

Lymphopenia is the most common lab finding in COVID-19 and is found in as many as 83% of hospitalized patients.1,5 Lymphopenia, neutrophilia, elevated serum alanine aminotransferase and aspartate aminotransferase levels, elevated lactate dehydrogenase, high CRP, and high ferritin levels may be associated with greater  illness severity.1,5,6,8,11,54

Elevated D-dimer and lymphopenia have been associated with mortality.8,11 Procalcitonin is typically normal on admission, but may increase among those admitted to the ICU.4-6

Patients with critical illness had high plasma levels of inflammatory makers, suggesting potential immune dysregulation.5,55

Radiographic Findings

Chest radiographs of patients with COVID-19 typically demonstrate bilateral air-space consolidation, though patients may have unremarkable chest radiographs early in the disease.1,5,56

Chest CT images from patients with COVID-19 typically demonstrate bilateral, peripheral ground glass opacities.4,8,38,56-65

Because this chest CT imaging pattern is non-specific and overlaps with other infections, the diagnostic value of chest CT imaging for COVID-19 may be low and dependent upon interpretations from individual radiologists.57,66

One study found that 56% of patients who presented within 2 days of diagnosis had a normal CT58. Conversely, other studies have also identified chest CT abnormalities in patients prior to the detection of SARS-CoV-2 RNA.56,67 Given the variability in chest imaging findings, chest radiograph or CT alone is not recommended for the diagnosis of COVID-19.

The American College of Radiology also does not recommend CT for screening or as a first-line test for diagnosis of COVID-19. (See American College of Radiology Recommendationsexternal icon).

Clinical Management and Treatment

Mild to Moderate Disease

Patients with a mild clinical presentation (absence of viral pneumonia and hypoxia) may not initially require hospitalization, and many patients will be able to manage their illness at home.

The decision to monitor a patient in the inpatient or outpatient setting should be made on a case-by-case basis. This decision will depend on the clinical presentation, requirement for supportive care, potential risk factors for severe disease, and the ability of the patient to self-isolate at home.

Patients with risk factors for severe illness (see People Who Are at Higher Risk for Severe Illness) should be monitored closely given the possible risk of progression to severe illness in the second week after symptom onset.5,6,10,11

For information regarding infection prevention and control recommendations, please see Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons Under Investigation for COVID-19 in Healthcare Settings.

Severe Disease

Some patients with COVID-19 will have severe disease requiring hospitalization for management. No specific treatment for COVID-19 is currently FDA approved.

Corticosteroids have been widely used in hospitalized patients with severe illness in China6,8,10,11; however, the benefit of corticosteroid use cannot be determined based upon uncontrolled observational data.

By contrast, patients with MERS-CoV or influenza who were given corticosteroids were more likely to have prolonged viral replication, receive mechanical ventilation, and have higher mortality.68-72

Therefore, corticosteroids should be avoided unless indicated for other reasons, such as management of chronic obstructive pulmonary disease exacerbation or septic shock.

More information can be found at Healthcare Professionals: Frequently Asked Questions and Answers.

Inpatient management revolves around the supportive management of the most common complications of severe COVID-19: pneumonia, hypoxemic respiratory failure/ARDS, sepsis and septic shock, cardiomyopathy and arrhythmia, acute kidney injury, and complications from prolonged hospitalization including secondary bacterial infections, thromboembolism, gastrointestinal bleeding, and critical illness polyneuropathy/myopathy.1,4-6,10,11,38,73-76

The Infectious Diseases Society of America has released guidelines on the treatment and management of patients with COVID-19.

For more information, please visit: Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19 Infection.external icon

The World Health Organization and the Surviving Sepsis Campaign have both released comprehensive guidelines for the inpatient management of patients with COVID-19, including those who are critically ill.

For more information visit: Interim Guidance on Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspectedexternal icon (WHO) and Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19)pdf iconexternal icon.

For more information on the management of children, see Information for Pediatric Healthcare Providers and the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Childrenexternal icon.

Investigational Therapeutics

No FDA-approved drugs have demonstrated safety and efficacy in randomized controlled trials for patients with COVID-19.

Use of investigational therapies for treatment of COVID-19 should ideally be done in the context of enrollment in randomized controlled trials.

Several clinical trials are underway testing multiple drugs with in-vitro antiviral activity against SARS-CoV-2 and/or immunomodulatory effects that may have clinical benefit.

For the latest information, see Information for Clinicians on Therapeutic Options for COVID-19 Patients. For the information on registered trials in the U.S., see ClinicalTrials.govexternal icon.

Discontinuation of Transmission-Based Precautions or Home Isolation

Patients who have clinically recovered and are able to discharge from the hospital but who have not been cleared from their Transmission-Based Precautions may continue isolation at their place of residence until cleared.

For recommendations on discontinuation of Transmission-Based Precautions or home isolation for patients who have recovered from COVID-19 illness, please see: Interim Guidance for Discontinuation of Transmission-Based Precautions and Disposition of Hospitalized Patients with COVID-19, Interim Guidance for Discontinuation of In-Home Isolation for Patients with COVID-19, and Discontinuation of In-Home Isolation for Immunocompromised Persons with COVID-19.

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