# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 2 Pathophysiology of Acute Lung Injury
### Clinical Pathophysiology and Findings  
Hypoxemia in ARDS fundamentally results from inadequate gas exchange between ventilated lung regions and perfused lung regions, and vice versa. A major driver of this failure is ventilation-perfusion (V/Q) mismatch, which occurs secondary to insufficient air or blood flow to a given lung region [1]. Insufficient ventilation results from alveolar edema or atelectasis, reducing the fraction of alveoli available to participate in gas exchange. These non-ventilated regions cause intrapulmonary shunts as unoxygenated blood bypasses the lungs and enters systemic circulation, contributing to an elevated V/Q ratio in that region [11]. Conversely, capillary microthrombi and pulmonary emboli reduce the fraction of perfused capillaries [4]. Since local alveoli are ventilated but unable to participate in gas exchange, increased pulmonary dead space decreases the V/Q ratio in the region. Overall, the presence of multiple regions of V/Q mismatch increases hypoxemia and hypercapnia resulting in respiratory acidosis and critically reducing the ability of supplemental oxygen to restore normal PaO\({}_{2}\) levels. Additionally, loss of compliance in edematous lung regions decreases total lung compliance and increases work of breathing (under non-invasive ventilation support) and regional overdistension (under mechanical ventilation), which can contribute to VILI. Consistent with this, increased pulmonary dead space and decreased compliance are predictive of mortality in ARDS [25]. Diffuse alveolar damage (DAD) is the prototypical histological finding associated with ALI [26]. The acute (exudative) phase of DAD is characterized by edema, formation of hyaline membranes, and infiltration of immune cells, and may last approximately 7 days. Following this, an organizing (proliferative) phase occurs which may last weeks to months in survivors [11]. Proliferation of alveolar type 2 epithelial cells is the defining feature of this phase. Importantly, while these two phases are sequential, they may display regional heterogeneity, with different tissue areas undergoing acute and organizing phases simultaneously as ALI progresses [11; 26]. Furthermore, heterogeneity exists among ARDS patients. It has been reported that approximately half or less of autopsy and biopsy specimens from patients with ARDS fulfill criteria for DAD, while most others display histologic patterns of alveolar inflammation consistent with acute pneumonia [27; 28]. The presence of DAD, however, was associated with higher mortality attributable to refractory hypoxemia [28]. Biomarker analyses of bronchoalveolar larvae fluid (BALF) and plasma in ARDS patients has provided insight into the mechanisms contributing to lung injury. Elevated plasma levels of surfactant protein D and RAGE are consistent with disruption and cell death, respectively, within the alveolar epithelial barrier [29; 30]. Similarly, endothelial activation and coagulation are supported by plasma elevations in angiopoeitin 2 and vWF and decreases in Protein C [31]. Most notably, elevated levels of the cytokines IL-1\(\beta\), IL-6, IL-8, and TNF in plasma and BALF correlate with poorer outcomes, demonstrating the role of dysregulated inflammation in ARDS [32; 33; 34; 35]. Cytokine analysis has played an important role in determining the role of low tidal volume lung-protective ventilation strategies in decreasing VILI-induced inflammation and improving outcomes [36]. The failure of any one pharmacotherapy to broadly improve outcomes in all ARDS patients has necessitated identification of subphenotypes that might respond differently to treatment. The most promising of these proposes a hyperinflammatory subphenotype, characterized by high levels of pro-inflammatory mediators and comprising approximately one-third of patients, and a hypoinflammatory subphenotype, with lower levels of pro-inflammatory mediators and comprising approximately two-thirds of patients.