Clinical Manifestations of COVID-19


Clinical Manifestations of COVID-19

Based on the severity of presenting illness that includes clinical symptoms, laboratory and radiographic abnormalities, hemodynamics, and organ function. The National Institutes of Health (NIH) issued guidelines that classify COVID-19 into five distinct types.

  • Asymptomatic or Presymptomatic Infection: Individuals with positive SARS-CoV-2 test without any clinical symptoms consistent with COVID-19.
  • Mild illness: Individuals who have any symptoms of COVID-19 such as fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, anosmia, or dysgeusia but without shortness of breath or abnormal chest imaging
  • Moderate illness: Individuals who have clinical symptoms or radiologic evidence of lower respiratory tract disease and who have oxygen saturation (SpO2) ≥ 94% on room air
  • Severe illness: Individuals who have (SpO2) ≤ 94% on room air; a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, (PaO2/FiO2) <300 with marked tachypnea with respiratory frequency >30 breaths/min or lung infiltrates >50%.
  • Critical illness: Individuals who have acute respiratory failure, septic shock, and/or multiple organ dysfunction. Patients with severe COVID-19 illness may become critically ill with the development of acute respiratory distress syndrome (ARDS) which tends to occur approximately one week after the onset of symptoms.

ARDS is characterized by a severe new-onset respiratory failure or worsening of an already identified respiratory picture. The diagnosis requires a set of clinical and ventilatory criteria such as chest imaging utilized includes chest radiograph, CT scan, or lung ultrasound demonstrating bilateral opacities (lung infiltrates > 50%), not fully explained by effusions, lobar, or lung collapse.

If there are clinical and radiologic findings of pulmonary edema, heart failure, or other causes such as fluid overload, they should be excluded before assessing it to be ARDS. The Berlin definition classifies ARDS into three types based on the degree of hypoxia, with the reference parameter being PaO2/FiO2 or P/F ratio[83]:

  • Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg in patients not receiving mechanical ventilation or in those managed through non-invasive ventilation (NIV) by using positive end-expiratory pressure (PEEP) or a continuous positive airway pressure (CPAP) ≥ 5 cmH2O.
  • Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg
  • Severe ARDS: PaO2/FiO2 ≤ 100 mmHg. 

When PaO2 is not available, a ratio of SpO2/FiO2 ≤ 315 is suggestive of ARDS. A multicenter prospective observational study that analyzed 28-day mortality in mechanically ventilated patients with ARDS concluded that COVID-19 ARDS patients had similar ARDS features from other causes. The risk of 28-day mortality increased with ARDS severity.[84]

Extrapulmonary Manifestations 

Although COVID-19, the illness caused by SARS-CoV-2, predominantly affects the respiratory system, COVID-19 can be considered a systemic viral illness given the multiple organ dysfunction associated with this illness.

  • Renal manifestations: Patients hospitalized with severe COVID-19 are at risk for developing kidney injury, most commonly manifesting as acute kidney injury (AKI), which is likely multifactorial in the setting of hypervolemia, drug injury, vascular injury, and drug-related injury, and possibly direct cytotoxicity of the virus itself. AKI is the most frequently encountered extrapulmonary manifestation of COVID-19 and is associated with an increased risk of mortality.[85] A large multicenter cohort study of hospitalized patients with COVID-19 that involved 5,449 patients admitted with COVID-19 reported that 1993(36.6%) patients developed AKI during their hospitalization, of which 14.3% patients required renal replacement therapy(RRT).[86] Other clinical and laboratory manifestations include proteinuria, hematuria, electrolyte abnormalities such as hyperkalemia, hyponatremia, acid-base balance disturbance such as metabolic acidosis.[87][54][36]
  • Cardiac manifestations: Myocardial injury manifesting as myocardial ischemia/infarction (MI) and myocarditis are well-recognized cardiac manifestations in patients with COVID-19. Other common cardiac manifestations include ACS, arrhythmias, cardiomyopathy, and cardiogenic shock. A single-center retrospective study analysis of 187 patients with confirmed COVID-19 reported that 27.8% of patients exhibited myocardial injury indicated by elevated troponin levels. The study also noted that patients with elevated troponin levels had more frequent malignant arrhythmias and a high mechanical ventilation rate than patients with normal troponin levels.[87] A meta-analysis study of 198 published studies involving 159, 698 COVID-19 patients reported that acute myocardial injury and a high burden of pre-existing cardiovascular disease were significantly associated with higher mortality and ICU admission.[88]
  • Hematologic manifestations: Lymphopenia is a common laboratory abnormality in the vast majority of patients with COVID-19. Other laboratory abnormalities include thrombocytopenia, leukopenia, elevated ESR levels, C-reactive protein (CRP) lactate dehydrogenase (LDH), and leukocytosis. As previously discussed, COVID-19 is also associated with a hypercoagulable, evidenced by the high prevalence of venous and thromboembolic events such as PE, DVT, MI, ischemic strokes, and arterial thromboses that also occurred in patients despite being maintained on prophylactic or even therapeutic systemic anticoagulation. Notably, COVID-19 is associated with markedly elevated D-dimer, fibrinogen levels, prolonged prothrombin time (PT), and partial thromboplastin time(aPTT) in patients at risk of developing arterial and venous thrombosis.[54][87][54] Clinical trials are required to determine the benefit of therapeutic anticoagulation in patients with COVID-19, especially at what stage of the illness.
  • Gastrointestinal manifestations: GI symptoms such as diarrhea, nausea and/or vomiting, anorexia, and abdominal pain are seen in up to 1 in 5 patients with COVID-19 infection based on the results of a meta-analysis study by Tariq et al. that analyzed 78 studies involving 12, 797 patients. The weighted pool prevalence of diarrhea was 12.4% (95% CI, 8.2% to 17.1%), nausea and/or vomiting was 9% (95% CI, 5.5% to 12.9%), loss of appetite was 22.3% (95% CI, 11.2% to 34.6%) and abdominal pain was 6.2% (95% CI, 2.6% to 10.3%). The study also reported that the mortality rate among patients with GI symptoms was similar to the overall mortality rate.[89] Cases of acute mesenteric ischemia and portal vein thrombosis have also been described.[90]
  • Hepatobiliary manifestations: Elevation in liver function tests manifesting as an acute increase in aspartate transaminase(AST) and alanine transaminase(ALT) are frequently noted in 14% to 53% of patients with COVID-19 infection.[91] Hepatic dysfunction occurs more frequently in patients with severe COVID-19 illness.
  • Endocrinologic manifestations: Patients with underlying endocrinologic disorders such as diabetes mellitus who contract this virus are at increased risk of developing severe illness. Clinical manifestations such as abnormal blood glucose levels, euglycemic ketosis, and diabetic ketoacidosis have been noted in patients hospitalized with COVID-19.[87]
  • Neurologic manifestations: Besides anosmia and ageusia, other neurological findings include headache, stroke, impairment of consciousness, seizure disorder, and toxic metabolic encephalopathy. Five patients with COVID-19 developed Guillain-Barré syndrome (GBS) based on a case series report from Northern Italy.[92][64]
  • Cutaneous manifestations: Acral lesions resembling pseudo chilblains (40.4%) were the most common cutaneous manifestations noted in patients with COVID-19 based on the results of a meta-analysis study which included 34 published studies describing 996 patients with COVID-19. Other cutaneous manifestations described erythematous maculopapular rash (21.3%), vesicular rashes (13%), and urticarial rashes (10.9%). Notably, the appearance of a specific type was rash appeared to be dependent on the patient’s age. Other uncommon rashes described were vascular rashes (4%) resembling livedo or purpura, especially in elderly patients, and erythema multiforme-like eruptions (3.7%), mostly in children.[93]

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