How to identify the prognosis of lung function in patients with severe COVID-19

Introduction

In December 2019, the detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a rapid global spread of pulmonary infections within a few months, affecting patients of all ages and regions. On January 30, 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) an international public health emergency (1). As of June 8, 2024, global confirmed COVID-19 cases reached 775,552,205, with 7,050,201 deaths (2). Among these cases, 14% are severe, and 5% are critical, often accompanied by acute respiratory distress syndrome (ARDS) (3). Another potential complication in severe COVID-19 patients is pulmonary fibrosis, leading to chronic respiratory dysfunction, affecting prognosis and quality of life (4). Reliable data on the incidence and severity of COVID-19-induced pulmonary fibrosis are not yet available. As an intensive care unit (ICU) physician, it is crucial to analyze high-risk factors for COVID-19-induced ARDS and pulmonary fibrosis, accurately assess pulmonary prognosis, and propose prevention and treatment methods based on pathophysiology, respiratory mechanics, and immune response mechanisms in severe COVID-19 patients.

Insights into the pathological changes in the lungs of severe COVID-19 patients

The primary cause of death in COVID-19 patients is respiratory and other vital organ failure due to severe lung damage. The first global postmortem pathological findings of COVID-19 indicate that the lung undergoes the most significant pathological changes following SARS-CoV-2 infection. These changes include exudation, degeneration, and proliferative mixed changes, such as diffuse alveolar damage, extensive alveolar exudation of serous/fibrinous material, massive macrophage exudation, lung consolidation, type I alveolar epithelial cell injury, type II alveolar epithelial cell proliferation, formation of a transparent membrane on the alveolar surface, proliferation of interstitial fibrous tissue, and lung consolidation due to fibrous tissue proliferation (5). Another feature of the lesion is the retention of mucous secretions in the small airways, leading to the formation of mucous plugs. The aggregation and activation of alveolar macrophages, along with the retention of mucous secretions in the small airways, distinguish COVID-19 from atypical pneumonia (SARS) and Middle East respiratory syndrome (MERS) (6). Pathological changes indicate that ARDS and secondary pulmonary fibrosis are critical in the final stages of severe COVID-19 (7), necessitating early identification and appropriate intervention.

Mechanisms of pulmonary pathological changes in COVID-19 patients

Upon entering the human body, SARS-CoV-2 initially causes pulmonary interstitial damage by utilizing angiotensin-converting enzyme 2 (ACE2) as a cellular receptor, subsequently leading to lung parenchymal injury (8). Pulmonary fibrosis results from acute and chronic interstitial lung diseases. It is characterized by failed reconstruction of damaged alveolar epithelium, persistent fibroblasts, excessive collagen and extracellular matrix deposition, and destruction of normal lung structure (9). The progression of pulmonary fibrosis increases the width of the pulmonary interstitium, compressing and damaging normal lung parenchyma, disrupting capillaries, and causing respiratory failure. The etiology of pulmonary fibrosis is multifactorial, involving age, smoking, viral infections, drug exposure, and genetic susceptibility (10). Another mechanism may involve oxidative stress, excessive production of reactive oxygen species (ROS), and improper clearance (11).

When lung tissue is damaged, cells excessively express and release a series of growth factors and cytokines, including monocyte-1 chemoattractant protein (MCP-1), transforming growth factor β1 (TGF-β1), tumor necrosis factor α (TNF-α), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), interleukin-1β (IL-1β), and interleukin-6 (IL-6) (12). Dysregulation of matrix metalloproteinase release leads to epithelial and endothelial injury and uncontrolled fibrous proliferation, which are the most important pathological changes during the inflammatory phase of ARDS. TGF-β regulates fibrosis and along with vascular endothelial growth factor, IL-6, TNF-α, and vascular dysfunction, participates in the progression of fibrosis (13).

Idiopathic pulmonary fibrosis shares cytokine similarities with COVID-19, suggesting a potential common mechanism in their pathogenesis (14,15). Type II alveolar epithelial cells are among the primary fibrotic factors. These factors stimulate the excessive proliferation of type II alveolar cells, leading to fibroblast aggregation at fibrotic sites and inducing their differentiation and activation into myofibroblasts. Myofibroblasts cause excessive extracellular matrix accumulation in the basement membrane and interstitial tissue, ultimately resulting in pulmonary function loss, severely impairing gas exchange between alveoli and capillaries (16). Therefore, continuous monitoring of specific cytokines is essential in treating critically ill COVID-19 patients to assess lung prognosis through changes in their expression levels.

Insights into the alterations in respiratory mechanics of severe COVID-19 patients

ARDS can originate from either the gas side or the vascular side of the alveoli. Since COVID-19 is a systemic disease that primarily damages vascular endothelial cells, secondary ARDS management may differ from conventional methods. It is essential to consider the characteristics of vascular damage and provide personalized treatment to patients. Otherwise, even non-elderly individuals or those without underlying comorbidities who develop COVID-19-induced ARDS may experience adverse pulmonary outcomes and progress to multiple organ dysfunction syndrome.

Respiratory mechanics characteristics in typical ARDS patients

The characteristics of ARDS typically include non-cardiogenic pulmonary edema, shunting-related hypoxemia, and insufficient effective ventilation area, resulting in decreased lung compliance. High levels of positive end-expiratory pressure (PEEP), lung recruitment, or prone ventilation are typically used to improve the effective ventilation area of the lungs. Higher transpulmonary pressure can increase stress throughout the lungs, and ARDS lungs have poor tolerance to it. Therefore, relatively lower tidal volumes and, if permissible, hypercapnia help minimize ventilator-induced lung injury (17). In the early stage of ARDS, high transpulmonary pressure caused by patient-initiated vigorous inhalation may result in patient self-induced lung injury (P-SILI) (18).

Characteristics of respiratory mechanics in secondary ARDS associated with severe COVID-19

Despite severe COVID-19-induced ARDS causing poor oxygenation, patients initially maintain good lung compliance, normal minute ventilation, and limited lung infiltrates. These patients typically show ground-glass opacities on chest computed tomography (CT), indicating interstitial rather than alveolar edema (19). In simplified models, these patients are referred to as “L type” characterized by low pulmonary elastic resistance (high compliance), no pulmonary edema on CT, and a low response to PEEP. For many patients, the disease stabilizes at this stage without further deterioration. Other patients may progress to exhibit typical ARDS features due to disease severity, host response, or suboptimal disease management. These patients are defined as “H type” characterized by extensive lung consolidation, high pulmonary elastic resistance (low compliance), pulmonary edema, and a good response to PEEP. L and H types represent two extremes, with an intermediate stage overlapping characteristics of both (20-22).

A notable clinical feature is the highly activated coagulation cascade. Pathology has confirmed widespread microthrombi and large thrombi in the lungs and other organs, linking elevated serum D-dimer levels to poor prognosis (23). These findings suggest asymmetric endothelial injury, disrupting pulmonary vascular regulation, causing ventilation-perfusion imbalance, and promoting thrombosis. If unchecked, the respiratory drive in critically ill COVID-19 patients will significantly increase, and excessive transpulmonary pressure on fragile lung tissue is likely to induce P-SILI. Therefore, managing ARDS secondary to severe COVID-19 should focus more on pulmonary vasculature.

Management approaches for severe COVID-19 complicated by ARDS

The primary concern in the early stage of the disease is impaired vascular regulatory function. Endothelial damage prevents normal hypoxia-induced pulmonary vasoconstriction, resulting in a ventilation-perfusion mismatch and severe hypoxemia. Non-invasive mechanical ventilation, such as high-flow oxygen therapy or non-invasive positive pressure ventilation, is typically preferred if the patient does not exert excessive inspiratory effort. However, if these treatments fail to reduce the patient’s inspiratory drive, P-SILI may develop, causing progressive lung function deterioration (24).

If pulmonary edema increases in L-type patients due to the disease itself and/or P-SILI, it reduces the gas exchange area of the lungs, gradually developing into an H-type. Concentrating the entire ventilation volume on the already overburdened lungs increases lung stress. As the condition progresses, the SARS-CoV-2 virus replicates further in the damaged lung tissue, exacerbating inflammation and edema. This promotes local and systemic thrombosis, leading to intense cytokine release, right ventricular overload, and systemic organ dysfunction (25). Therefore, COVID-19 can cause unique pulmonary damage. Classifying patients as L-type or H-type phenotypes may aid in prognosis. Different ventilation methods should be adopted based on the patient’s physiological condition.

Evaluating prognostic levels based on clinical characteristics of COVID-19 patients

The primary clinical manifestations of COVID-19 patients include fever, cough, dry cough, dyspnea, fatigue, and muscle pain. Severe cases may develop dyspnea and hypoxemia within one week of disease onset, rapidly progressing to ARDS or multiple organ failure. The prognosis is worse for elderly patients and those with underlying chronic diseases (26). Studies indicate that the incidence of ARDS in severe/critical COVID-19 patients is 67%, with 56% requiring invasive mechanical ventilation. A study of 201 confirmed patients reported the clinical characteristics and risk factors of those who developed ARDS after hospital admission and progressed to death (27). Compared to non-ARDS patients, ARDS patients are older (by 12 years), have higher body temperatures before admission (by 0.3 ℃), exhibit more respiratory distress symptoms (by 33.9%), have a higher prevalence of underlying diseases [including hypertension (by 13.7%) and diabetes (by 13.9%)], receive less antiviral therapy (by 14.4%), and are more likely to receive methylprednisolone treatment (by 49.3%). Univariate Cox regression analysis identified risk factors for ARDS occurrence and progression to death, including advanced age [hazard ratio (HR) of 3.26 and 6.17], elevated lactate dehydrogenase (HR of 1.61 and 1.30), and elevated D-dimer (HR of 1.03 and 1.02). Therefore, managing COVID-19 patients requires close monitoring of these clinical characteristics, early identification of critically ill patients, and assessment of their potential progression to ARDS and poor prognosis.

Evaluating the prognostic significance of imaging alterations in COVID-19 patients

Imaging is highly valuable for assessing lung injury and the extent of lung parenchymal involvement. The imaging features of COVID-19 patients are similar to those of other viral pneumonias. In the early stage, the lungs often exhibit single or multiple small patches and focal ground-glass opacities. As the disease progresses, the lesions increase and merge, expanding in range. Multiple lung lobes may show small patches or present as diffuse ground-glass opacities and consolidations (28). SARS-CoV-2 attacks the patient’s lymphocytic glial cells, leading to weakened immune function and virus replication, which can develop into severe and critical illness. At this stage, diffuse alveolar damage occurs, with the lesion range expanding and merging, resulting in bilateral consolidation (12). A study analyzing chest CT images of 63 COVID-19 patients suggested that the average number of affected lung lobes ranged from 1.8 to 3.3 (29). The most common change was patchy ground-glass opacities, with 17.5% of patients having fibrous stripes and 12.7% having irregular solid nodules. Approximately 85% of patients showed gradual enlargement of lung nodules and fibrous stripe lesions as the disease progressed, suggesting that pulmonary fibrosis may be a major complication of COVID-19. Close follow-up of imaging dynamics can help determine the lung prognosis of critically ill patients.

Evaluating the prognosis of COVID-19 patients using laboratory tests

SARS-CoV-2 enters the pulmonary alveoli and infects alveolar epithelial cells. Following infection, macrophages release a large amount of inflammatory factors, mediating inflammation-induced damage and leading to an inflammatory storm. Therefore, dynamic monitoring of cytokines is crucial for COVID-19 patients. An observational study comparing cytokine levels between severe and non-severe patients showed that plasma levels of IL-2, IL-7, IL-10, granulocyte colony-stimulating factor (GSCF), interferon-inducible protein 10 (IP-10), monocyte chemotactic protein-1 (MCP1), macrophage inflammatory protein 1A (MIP1A), and TNF-α were higher in ICU patients than in non-ICU patients (30). Another study confirmed that increased pro-inflammatory cytokines (such as IL-1β, IL-6, IL-12, IFN-γ, IP-10, and MCP1) in severe COVID-19 patients are associated with inflammatory response and extensive lung injury (31,32).

ARDS in different stages result in different complications

Clinically, COVID-19-induced ARDS often presents with hypoxia disproportionate to lung mechanics. While the Berlin criteria classify ARDS severity as mild [arterial pressure of oxygen/inspiratory fraction of oxygen (PaO₂/FiO₂): 201–300 mmHg], moderate (PaO₂/FiO₂: 101–200 mmHg), and severe (PaO₂/FiO₂ ≤100 mmHg), the COVID-19-associated ARDS may not align neatly with these categories due to its distinct pathophysiology, like vascular endothelial injury, coagulation abnormalities, and interstitial edema. Elderly patients and those with underlying chronic diseases are at higher risk for developing severe COVID-19, secondary ARDS, and poor pulmonary outcomes. The reasons are as follows: (I) hypertension and diabetes are significantly more prevalent in COVID-19 patients who progress to ARDS and death; (II) advanced age (≥65 years) and elevated biomarkers correlate with worse prognosis; (III) these comorbidities exacerbate systemic inflammation, endothelial dysfunction, and coagulation cascades, accelerating lung injury and fibrosis. Thus, while traditional ARDS staging relies on PaO₂/FiO₂, COVID-19-associated ARDS requires additional consideration of vascular pathology and comorbidities for accurate prognosis assessment. Early identification of high-risk patients (older age, hypertension, diabetes) is crucial for tailored interventions (33,34).

Impact of SARS-CoV-2 variants (pre-Delta, Delta, Omicron) on prognosis of COVID-19-induced ARDS

Different strains of the coronavirus induce varying prognoses for ARDS. During the pre-Delta variants (original strain, Alpha, Beta) pandemic period, early variants were associated with moderate-to-severe pulmonary injury, particularly in older adults and those with comorbidities. ARDS incidence was significant, with mortality rates heavily influenced by limited therapeutic options and delayed vaccination. Higher rates of ARDS progression and mortality compared to later variants, likely due to limited immunity and less optimized clinical management.

During the Delta variant pandemic period, it exhibited higher viral loads and enhanced affinity for lung tissue, leading to more severe alveolar damage and systemic inflammation. Strongly associated with rapid progression to ARDS, particularly in unvaccinated individuals. Studies reported higher ICU admission rates and mortality compared to pre-Delta variants. Poorer outcomes due to exacerbated cytokine storms, endothelial injury, and coagulation disorders in severe COVID-19.

During the Omicron variant pandemic period, its mutations favor upper airway replication over lower respiratory tract invasion, resulting in milder lung pathology and lower ARDS incidence. The risk factor of ARDS significantly reduced compared to Delta, even among unvaccinated populations. However, immunocompromised or high-risk individuals may still develop severe diseases. Better overall survival rates due to attenuated virulence, widespread immunity, and improved therapeutics. However, high transmissibility may strain healthcare systems, indirectly affecting outcomes.

Delta posed the highest risk for severe ARDS and mortality due to its aggressive pulmonary involvement, while Omicron’s reduced lung affinity and population immunity led to better outcomes. Pre-Delta variants laid the groundwork for understanding COVID-19-induced ARDS, but Delta and Omicron highlighted the importance of viral evolution in shaping prognosis (35).

There are several key factors that may influence the prognosis of COVID-19-induced ARDS. For example, vaccines drastically reduce ARDS risk across all variants, particularly for Delta and Omicron. Comorbidities like hypertension, diabetes, and advanced age remain critical predictors of poor prognosis. Antivirals, immunomodulators, and lung-protective ventilation have improved ARDS management (36).

Evaluating prognostic outcomes based on treatment experiences of SARS and MERS patients

Although the current COVID-19 epidemic is under control, the impact of recent and long-term complications on lung function in critically ill patients still requires proper prevention and management. The mechanism of pulmonary fibrosis due to secondary ARDS in critically ill COVID-19 patients is not fully understood, and targeted therapies are insufficient. Therefore, compared to the pulmonary complications of previous SARS and MERS, accurately assessing the pulmonary prognosis of critically ill patients is of great significance.

SARS is primarily transmitted through respiratory droplets. Besides avascular necrosis of the femoral head, pulmonary fibrosis during lung healing is its most severe long-term complication. SARS induces various morphological changes in the lungs, which can be categorized into three stages: (I) acute exudative inflammation (with localized fibroplasia and reticular fiber formation); (II) fibroplasia (resembling proliferative interstitial pneumonia, with interstitial cells differentiating into myofibroblasts and fibroblasts); and (III) late-stage fibrosis, characterized by extensive type I and type IV collagen fiber formation (37). Primitive interstitial cells, proliferating alveolar epithelial cells, epidermal growth factor receptor (EGFR), and macrophages are crucial in the pathogenesis of fibrosis during SARS. Patients initially develop atypical pneumonia, followed by acute lung injury and ARDS, eventually progressing to fibrosis (38). Fibrosis is more prevalent in elderly and severely ill patients and is associated with the disease course, though it may spontaneously regress. Similar observations are noted in MERS patients (39). The extent of pulmonary fibrosis correlates positively with the duration of SARS and MERS. Clinical data show that fibrous tissue is more common in late-stage patients than in early- and mid-stage patients. Notably, even SARS patients who recover and are discharged may develop pulmonary fibrosis. Additionally, the incidence of pulmonary fibrosis in SARS patients 9 months post-discharge is approximately 21.5% (67/311) (40-42). Therefore, for critically ill COVID-19 patients, long-term follow-up is essential to monitor lung function changes and enable early intervention to prevent secondary pulmonary fibrosis, which can lead to chronic respiratory dysfunction.

Conclusions

Severe COVID-19 patients are prone to progressing to ARDS and may develop long-term pulmonary fibrosis. However, ARDS caused by COVID-19 differs significantly from ARDS caused by other factors. Clinically, high lung compliance is often observed, which is inconsistent with the severity of hypoxia. Additionally, chest CT scans frequently do not show typical ARDS, and patients exhibit abnormal coagulation function, often with enhanced procoagulation. Pathological autopsies confirm that alveolar epithelial cells, rather than endothelial cells, are the primary site of injury. Therefore, we believe that the mechanism of secondary fibrosis caused by COVID-19 differs from that of previous interstitial fibrosis and other fibrotic lung diseases. These findings suggest that severe COVID-19 patients with concurrent ARDS require early identification. Patients at risk of deteriorating and developing pulmonary fibrosis should be assessed early and receive timely intervention to improve prognosis.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-79/prf

Funding: This work was supported by the Project of the Key Laboratory of Multiple Organ Failure, Ministry of Education (Nos. 2023KF07 and 2024KF03), the Key Laboratory of Intelligent Pharmacy and Individualized Treatment in Huzhou City (No. HZKF-20240101), the Guangxi Key Laboratory for Diagnosis and Treatment of Acute Respiratory Distress Syndrome (No. ZZH2020013-3), and the Collaborative Project on Major and Complex Diseases Between Traditional Chinese Medicine and Western Medicine in Clinical Settings.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-24-79/coif). Y.Y. serves as the Editor-in-Chief of Journal of Emergency and Critical Care Medicine from September 2024 to August 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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