Introduction
The clinical spectrum of COVID-19 is highly variable, ranging from asymptomatic to critical disease. The objective of this article is to analyze the identified risk factors for severe disease and to establish the clinical approach to patients presenting with severe and critical COVID-19. Severe disease is defined when the patient presents with fever, dyspnea, or cough, accompanied by any of the following criteria: respiratory rate > 30 breaths per minute, severe respiratory distress, or oxygen saturation (SpO2) ≤ 90% on room air.1 Other guidelines include a pulse oxygen saturation (spO2 < 93% on room air at sea level, or pulmonary opacities with involvement greater than 50%.2
Critical COVID-19 is considered when the patient develops moderate or severe acute respiratory distress syndrome (ARDS), septic shock, and/or multiorgan dysfunction. The World Health Organization (WHO) Clinical Progression Scale, scored from 0 to 10, provides a standardized severity stratification, where scores of 5 to 6 represent severe disease requiring oxygen support and scores of 7 to 9 indicate critical disease requiring mechanical ventilation.3,4
As with any patient in the intensive care unit, success depends on treating both the initial medical condition and the underlying comorbidities and complications.2
Risk factors
The precise determinants remain unknown, but the principal factors appear to be host-related rather than attributable to viral mutations.5 Certain demographic factors are associated with a severe clinical course.6 Advanced age (particularly > 65 years) is an important predictor of mortality, and male sex is independently associated with disease severity; a body mass index (BMI) > 30 kg/m2 and a history of smoking are considered additional risk factors for severe COVID-19.7,8,9,10,11,12
Comorbidities significantly increase the risk of disease progression. The strongest associations include chronic kidney disease (CKD) (odds ratio [OR]: 2.97), chronic obstructive pulmonary disease (COPD) (OR: 2.88), coronary artery disease (OR: 2.87), diabetes mellitus (OR: 2.40-3.68), systemic arterial hypertension (OR: 2.42-2.72), malignant neoplasm (OR: 2.60), and cerebrovascular disease (OR: 2.47).10,11,12,13 Kidney disease emerges as a particularly high-risk factor, with an adjusted OR of 7.71 for critical illness and 6.48 for mortality.13
Clinical manifestations predictive of deterioration include dyspnea or difficulty breathing (OR: 4.16), fever, and oxygen requirement upon hospital admission (OR: 2.9).12,14 The development of ARDS (OR: 39.59), shock (OR: 21.5), and acute kidney injury (AKI) (OR: 8.84) are the strongest predictors of unfavorable outcomes.10
Prognostic factors
An increase in the case fatality rate has been documented among patients with pre-existing conditions, with higher mortality recorded in individuals with cardiovascular disease (10.5%), diabetes (7.3%), COPD (6.3%), arterial hypertension (6.0%), and cancer – particularly hematologic and pulmonary malignancies (5.6%). In contrast, patients without pre-existing conditions had a case fatality rate of < 1%.15 Solid organ transplant recipients also appear to be at higher risk of complications.16
Chest imaging is indicated in patients with respiratory deterioration or in those considered at risk of disease progression. While chest radiography may be useful for detecting disease progression, computed tomography (CT) is more sensitive early in the course of the disease.17 The majority of patients who died from COVID-19 exhibited consolidation and air bronchograms. The CT score is based on the degree of attenuation and consolidation in specific pulmonary regions and was higher in patients who died.18 Other findings with prognostic significance include traction bronchiectasis, extensive distribution, lymph node involvement, and increased pulmonary artery diameter.19
Likewise, inflammatory markers demonstrate strong prognostic value. Elevated interleukin (IL)-6 is the most precise inflammatory biomarker, with cutoff values of 42 pg/ml predicting severity with an area under the curve (AUC) of 0.97, and 83 pg/ml predicting mortality with an AUC of 0.94.20,21 Elevation of C-reactive protein (CRP), procalcitonin > 0.5 ng/ml (OR: 43.24), and elevated ferritin are consistently associated with severe disease and mortality.20,22,23,24
Hematologic parameters include lymphopenia (OR: 1.91 for progression to severe presentation), elevated neutrophil count (OR: 2.62-6.25), neutrophil-to-lymphocyte ratio > 7.4, and thrombocytopenia.12,20,21,22,23,24 A neutrophil count > 3.74 × 109/l demonstrates a sensitivity of 100% and a specificity of 81% for identifying high-risk patients.24
Among biochemical markers with strong prognostic value, the following are included: lactate dehydrogenase (LDH) > 245 U/l (OR: 43.24), D-dimer > 0.5 mg/l (OR: 43.24 for progression; OR: 6.36 for mortality), elevated aspartate aminotransferase (AST) > 40 U/l (OR: 4.00), creatinine ≥ 133 μmol/l (OR: 5.30), and cardiac troponin I > 28 pg/ml (OR: 43.24).12,20,22,23,25
COVID-19 has been associated with reports of severe systolic dysfunction and fulminant myocarditis;26,27 ST-segment elevation is associated with poor prognosis. Elevated troponin (serum levels > 99th percentile; > 28 pg/ml) may be an independent risk factor for in-hospital mortality.28 Therefore, routine electrocardiography, troponin measurement, and transthoracic echocardiography may be important in evaluating the clinical course of COVID-19. Elevated glycated hemoglobin (HbA1c) values have been associated with inflammation, hypercoagulability, and high mortality (27.7%).29
Clinical prediction tools
Early identification of COVID-19 patients who may develop critical illness enables the implementation of an appropriate clinical approach. Clinical tools such as COVID-GRAM and the 4C Mortality Score evaluate risk factors including age, comorbidities (obesity, diabetes, and hypertension), and biochemical markers to estimate the probability of hospitalization, intensive care unit admission, or mortality.
The COVID-GRAM predictive risk score was developed by the Chinese National Health Commission using data from a retrospective cohort of patients diagnosed with COVID-19 to estimate the risk of developing critical illness (defined as requiring intensive care unit admission, mechanical ventilation, or death);30 it includes 10 variables for risk calculation, which are typically available at hospital admission. If the estimated risk of critical illness is low, the physician may opt for monitoring, whereas high-risk estimates may justify aggressive treatment or intensive care unit admission.
The 4C Mortality Score is a tool for stratifying in-hospital mortality risk in patients with COVID-19. It uses clinical variables at admission (age, sex, comorbidities, respiratory rate, SpO2, level of consciousness) to classify risk as low, intermediate, high, or very high, thereby facilitating therapeutic decision-making. It has demonstrated superior or comparable performance relative to other severity scales (such as CURB-65 or NEWS2) in predicting 30-day mortality and in-hospital mortality. It allows clinicians to identify which patients require more aggressive management and closer monitoring.31
The change in lymphocyte count has also been used as a prognostic scale and is classified as follows: 1) if the percentage was > 20% within 10 to 20 days after symptom onset, moderate disease can be predicted; 2) if the percentage decreased to 5-20% within 10 to 20 days after symptom onset, a severe disease presentation could be predicted; and 3) if the percentage decreased to < 5% within 17 to 19 days, a high risk of mortality could be predicted.32 Furthermore, there is a direct correlation between elevated CRP values – as a predictor of severity – and extensive involvement on CT.22
Recommended interventions in critically ill patients
Recommended interventions for critically ill patients with COVID-19 include oxygen therapy, invasive mechanical ventilation (IMV), and noninvasive mechanical ventilation (NIV), additional interventions such as prone positioning and extracorporeal membrane oxygenation (ECMO), as well as pharmacologic interventions. These interventions are summarized in table 1.
Table 1. Interventions in critically ill patients with COVID-19
| Intervention | Main indications | Clinical objective | Key recommendations | Bibliography |
|---|---|---|---|---|
| Strategies for improved oxygenation | ||||
| Conventional oxygen therapy | Initial hypoxemia (SpO2 ≤ 90-93%) | Correct hypoxemia and reduce respiratory work | Use of nasal prongs, simple face mask, or reservoir mask with continuous monitoring | WHO1, Long et al.33 |
| Awake prone positioning | Persistent hypoxemia with conventional oxygen or HFNC | Improve ventilation/perfusion ratio | Recommended before escalating to invasive ventilatory support | Long et al.33 |
| HFNC | Acute hypoxemic respiratory failure | Improve oxygenation while avoiding intubation | Start FiO2 at 100% and flow at 20 l/min, adjustable according to response | Long et al.33 |
| NIV/CPAP | Persistent hypoxemia with increased respiratory work | Reduce respiratory effort and improve alveolar ventilation | CPAP improves alveolar recruitment and oxygenation | Long et al.33 |
| IMV | Failure of oxygen therapy/NIV or intubation criteria met | Advanced respiratory support | Do not delay intubation in the setting of clinical deterioration | Attaway et al.34 |
| Lung-protective ventilation | Moderate-to-severe ARDS | Reduce ventilator-induced lung injury | Tidal volume 4-8 ml/kg and plateau pressure < 30 cm H2O | Meyer et al.57 |
| Prone positioning on IMV | Refractory hypoxemia and moderate-to-severe ARDS | Improve oxygenation and pulmonary recruitment | 12-16 hours/day in selected patients | SSC Guidelines42 |
| Veno-venous ECMO | Refractory hypoxemia despite optimal management | Extracorporeal oxygenation support | Only at experienced centers and in selected patients | SSC Guidelines42 |
| Pharmacologic | ||||
| Dexamethasone | Patients requiring supplemental oxygen or IMV | Reduce systemic inflammation and mortality | 6 mg/day for up to 10 days; greatest benefit in IMV | SSC Guidelines42 |
| Remdesivir | Severe COVID-19 without IMV | Reduce clinical progression | May be combined with dexamethasone | NIH Guidelines2 |
| Tocilizumab/Sarilumab | Severe/critical patients with elevated inflammation | IL-6 modulation and mortality reduction | Add to systemic corticosteroids | RECOVERY39 REMAP-CAP36,40 IDSA 202535 |
| Baricitinib | Selected patients with rapid progression | Inhibition of inflammatory response | In combination with glucocorticoids | IDSA 202535 |
| Prophylactic anticoagulation | All hospitalized patients without contraindication | Prevent venous thromboembolism | LMWH or unfractionated heparin | SSC Guidelines42 |
| Therapeutic anticoagulation | Selected moderate cases with elevated D-dimer | Reduce thrombotic events | Not routinely recommended in critically ill patients | REMAP-CAP/ ATTACC/ACTIV-4a56 |
| Fluid resuscitation with crystalloids | Shock or hypoperfusion | Restore tissue perfusion | Prefer dynamic parameters and avoid starches | SSC Guidelines42 Attaway et al.34 |
| Vasopressors (norepinephrine) | Fluid-refractory shock | Maintain MAP 60-65 mmHg | Vasopressin as second-line agent | SSC Guidelines42 |
| Renal replacement | ||||
| CRRT | Acute kidney injury with dialytic indications | Renal support and metabolic control | Preferred over intermittent hemodialysis | Arabi et al.53 |
HFNC: high-flow nasal cannula; NIV/CPAP: noninvasive ventilation; IMV: invasive mechanical ventilation; CRRT: continuous renal replacement therapy.
Oxygen therapy
Oxygen therapy should be initiated immediately using nasal prongs, a face mask, or an oxygen delivery device. Intensification of oxygen therapy involves a gradual progression of devices aimed at improving oxygenation and reducing the patient’s respiratory effort. At each stage of escalation, respiratory rate, oxygen saturation, and clinical signs of dyspnea (nasal flaring, thoracoabdominal dissociation, and/or use of accessory respiratory muscles) should be monitored. If these symptoms do not improve, repositioning the patient (awake prone positioning) is recommended. High-flow nasal cannula is also more comfortable than noninvasive mechanical ventilation (NIV) and its various ventilatory modes. Guidelines recommend its use as a first-line strategy for patients with acute hypoxemic respiratory failure despite conventional oxygen therapy. When used, the fraction of inspired oxygen should be set at 100% with an initial flow of 20 liters per minute. The flow can then be adjusted according to patient comfort, provided that oxygen saturation remains above 88%.33
NIV, along with high-flow nasal cannula, plays a role in the management of patients with hypoxemic COVID-19. Loss of pulmonary perfusion regulation, hypoxic vasoconstriction, and atelectasis are possible causes of hypoxemia in these patients. Continuous positive airway pressure may reduce respiratory effort and improve oxygenation, while positive airway pressure generally improves ventilation and may improve tidal volumes.33
Patients with greater respiratory effort and hypoxemia who do not respond to escalation of oxygen therapy and present with severe respiratory distress should undergo IMV.33 It is critically important to remember that at any point, if intubation criteria are met, the procedure should not be delayed.34
Pharmacologic treatment
Treatment decisions should be made based on local guidelines, drug availability, and patient comorbidities. In patients receiving supplemental oxygen without high-flow support or mechanical ventilation, one of the following treatments is recommended: remdesivir as monotherapy, or dexamethasone plus remdesivir (for patients requiring increasing amounts of oxygen), or dexamethasone alone (when combination therapy with remdesivir cannot be used or is unavailable). If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone may be used.2
Immunomodulatory therapies in critically ill COVID-19 patients have demonstrated benefits when combined with corticosteroids; for example, the 2025 Infectious Diseases Society of America (IDSA) guidelines recommend adding baricitinib or tocilizumab to systemic glucocorticoids in hospitalized adults with rapidly progressing severe or critical COVID-19, as both agents demonstrate equivalent efficacy.35 IL-6 receptor antagonists (tocilizumab, sarilumab) have a greater than 99.9% probability of improving 180-day survival compared with the control group, with an approximately 26% reduction in mortality.36 The combination of corticosteroids plus tocilizumab shows better survival outcomes compared with corticosteroids alone or standard care.37,38
The RECOVERY trial demonstrated that tocilizumab (an IL-6 receptor antagonist) improved survival and 28-day hospital discharge rates while reducing progression to IMV in patients with hypoxemia and elevated inflammatory markers (CRP ≥ 75 mg/l).39 The REMAP-CAP trial confirmed that both tocilizumab and sarilumab improve organ support-free days and survival in critically ill patients, with effects sustained over six months.36,40,41 Tocilizumab is currently approved by the Food and Drug Administration (FDA) for hospitalized patients receiving systemic corticosteroids who require supplemental oxygen, NIV or IMV, or ECMO.42,43,44 Remdesivir is recommended for patients with severe COVID-19 who do not require mechanical ventilation but is not recommended for critically ill patients receiving mechanical ventilation.42,(45 Baricitinib (a Janus kinase inhibitor) may be added to corticosteroids in selected patients.42,(46
Convalescent plasma and hydroxychloroquine are not recommended.44,(45
In patients requiring IMV or ECMO, one of the following treatments is recommended: dexamethasone as monotherapy or in combination; for patients who initially received remdesivir monotherapy and progressed to requiring IMV or ECMO, dexamethasone treatment should be initiated and remdesivir continued until the treatment course is completed; remdesivir or tocilizumab are not recommended as monotherapy in this patient group and should only be used in combination with corticosteroids.2
The use of systemic corticosteroids is recommended for severe and critical cases of COVID-19.45 Dexamethasone 6 mg daily for a maximum of 10 days reduces 28-day mortality (OR: 0.69; 95% CI: 0.55-0.86), with the greatest benefit observed in patients receiving IMV (29 vs. 41% mortality; relative risk [RR]: 0.64).45,(47,(48
Dexamethasone is the preferred corticosteroid based on available evidence, although hydrocortisone and methylprednisolone have also demonstrated benefits.45 Higher doses (equivalent to more than 6 mg of dexamethasone) do not provide additional benefit and may increase risk in patients requiring low-flow oxygen.48 Corticosteroids should not be used in hospitalized patients who do not require supplemental oxygen (mortality of 18 vs. 14% with standard care; RR: 1.19).48
Additional considerations
The use of dynamic parameters, body temperature, capillary refill time, and/or lactate levels – rather than static parameters – has been recommended for assessing fluid responsiveness. Fluid resuscitation is recommended to be initiated with crystalloids; the initial use of albumin or starches for resuscitation is not recommended.34 Approximately 20% of hospitalized COVID-19 patients have been reported to develop cardiac failure,49,50,51 which is associated with a variety of pre-existing cardiovascular conditions, including acute coronary syndrome, myocarditis, and arrhythmias.52 Norepinephrine remains the first-choice vasopressor for shock that is unresponsive to fluid resuscitation; thereafter, vasoactive agents should be titrated to achieve a mean arterial pressure (MAP) of 60 to 65 mmHg. Vasopressin (up to 0.03 units/min) or epinephrine is recommended as a second-line vasopressor to raise MAP to the target in cases where the patient shows evidence of cardiac dysfunction and persistent hypoperfusion despite adequate fluid resuscitation and vasopressor use.2 Critically ill patients are in a prothrombotic state, characterized by elevation of certain biomarkers, and there is an apparent increase in the incidence of venous thromboembolic disease.39
In patients with acute kidney injury who develop indications for renal replacement therapy, continuous renal replacement therapy (CRRT) is recommended if available. If CRRT is unavailable or not feasible due to limited resources, prolonged intermittent renal therapy is recommended rather than standard intermittent hemodialysis. In a case series of critically ill patients, more than 15% required continuous renal replacement therapy.53
Anticoagulation
Prophylactic anticoagulation with low-molecular-weight heparin or unfractionated heparin is recommended for all hospitalized COVID-19 patients without contraindications.45,47,54 In hospitalized patients with moderate severity (not requiring intensive care) and low bleeding risk, therapeutic-dose heparin may be considered instead of standard prophylaxis, particularly in those with significantly elevated D-dimer levels (2-4 times the upper limit of normal) or a history of venous thromboembolism.55 In critically ill patients, standard-dose prophylactic anticoagulation is recommended over therapeutic anticoagulation.45,54,55 The multiplatform REMAP-CAP/ACTIV-4a/ATTACC trial demonstrated no mortality benefit and an increased bleeding risk with therapeutic anticoagulation in intensive care unit patients.56
Ventilatory support
In patients with moderate to severe ARDS undergoing mechanical ventilation, lung-protective ventilation strategies are recommended, with a preference for intermittent neuromuscular blockade as needed over continuous infusion.45 Prone positioning should be used in cases of refractory hypoxemia.45 Veno-venous ECMO should be considered in carefully selected patients with refractory hypoxemia despite optimized ventilation and rescue therapies, when available at experienced centers.45
Ventilation strategies for critically ill COVID-19 patients follow the established principles for the management of acute respiratory distress syndrome (ARDS). Lung-protective ventilation with tidal volumes of 4-8 ml/kg of predicted body weight and plateau pressures < 30 cm H2O is recommended.45,(47,(57 For moderate to severe ARDS, additional strategies include prone positioning for 12-16 hours daily, higher PEEP strategies (> 10 cm H2O), conservative fluid management, and neuromuscular blockade as needed rather than continuous infusion.45,(58
Conclusion
The management of the critically ill patient with COVID-19 requires a comprehensive evaluation based on clinical factors, biomarkers, and prognostic prediction tools that enable timely identification of patients at highest risk of deterioration. The implementation of evidence-based therapeutic strategies – including stepwise respiratory support, appropriate use of corticosteroids and immunomodulatory agents, and intensive care unit supportive measures – is essential for reducing mortality. Favorable outcomes depend not only on the treatment of the viral infection but also on appropriate management of systemic complications and comorbidities, underscoring the importance of a multidisciplinary and dynamic approach to the care of the critically ill patient.
Funding
The present work received no funding.
Conflicts of interest
The authors declare no conflicts of interest.
Ethical considerations
Protection of persons and animals. The authors declare that no experiments on human beings or animals were performed for this research.
Confidentiality, informed consent, and ethical approval. The study does not involve personal patient data and does not require ethical approval. SAGER guidelines do not apply.
Statement on the use of artificial intelligence. The authors declare that they did not use any type of generative artificial intelligence for the writing of this article.
