# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 3 Pathogenesis of COVID-19-Induced Lung Injury
### Clinical Pathophysiology  
Similar to the general pathophysiology of ARDS, hypoxemia in severe COVID-19 results from inadequacy in gas exchange between ventilated and perfused lung regions [1]. However, clinical observations have inspired the hypothesis that COVID-19 follows a distinct pattern of respiratory features that occur in chronological order. As proposed by [PERSON] and colleagues, early COVID-19 presents a type \"L\" phenotype characterized by low degrees of elastance (i.e., high compliance), V/Q ratio, lung weight, and recruitability, while deterioration leads to a type \"H\" phenotype characterized by a high degree of elastance, intrapulmonary shunting, lung weight, and recruitability [118]. As such, type H is typically consistent with a diagnosis of severe ARDS. In the early stages of severe COVID-19, tissue injury appears to localize to the periphery of the lungs, consistent with coagulopathy and microvascular alterations observed in lung biopsies at this stage [119, 120, 121, 122]. Conversely, a lack of hyaline membranes and preservation of lung weight, compliance, and recruitability at this stage is suggestive of a relative lack of alveolar edema [118]. Of note, alveolar type 2 epithelial hyperplasia hasbeen observed at this stage as well, likely replacing cytopathy within the alveolar epithelium [80]. Interestingly, patients in this stage may also present with profound hypoxemia but a notable lack of dyspnea, a paradoxical finding which has come to be termed \"silent hypoxia\" [123; 124]. The mechanism for this phenomenon is proposed to involve impaired oxygen-sensing in the carotid body, and case reports of SARS-CoV-2 within the carotid body have emerged [124]. Progression of COVID-19 to critical stages may occur due to combined impacts of evolving pneumonia as well as patient self-inflicted lung injury (P-SILI) related to neurologically driven respiratory efforts during mechanical ventilation [125; 126]. At this stage, increasing barrier dysfunction drives the development of alveolar edema, leading to reduced compliance while increasing lung weight and intrapulmonary shunting [118]. These features are consistent with findings on autopsy specimens which report DAD as the predominant histopathological finding of COVID-19 [80]. Notably, lymphocytes have been shown to be the primary inflammatory cell in lung specimens, and while neutrophils were observed in a percentage of cases, their presence may have been related to bacterial superinfection [80]. Microvascular dysfunction appears to be a key driver of respiratory failure at this stage as well. Functional respiratory imaging demonstrated that COVID-19 ARDS patients have markedly reduced blood volume in small caliber vessels relative to matched non-COVID-19 ARDS patients [127]. These factors contribute to the high mortality seen in the H-type phenotype. Beyond lung injury, diverse extrapulmonary manifestations have been reported in COVID-19 patients. Myocardial dysfunction, including myocardial injury, acute coronary syndromes, arrhythmias, and other manifestations have been reported in 20-30% of hospitalized patients [47; 97]. Renal injury is reported in up to 29% of cases and is often characterized by acute tubular injury and microvascular occlusions [80]. Neurological complications are among the most diverse and frequently reported manifestations, ranging from common mild symptoms, such as anosmia and fatigue, to rare and severe presentations, such as stroke and Guillain-Barre syndrome [47]. The mechanisms of these effects have been hypothesized to involve viral cytotoxicity, endothelitis, immune dysregulation, and/or RAAS dysregulation [47]. COVID-19 is also associated with long-term complications which have been termed \"long COVID\" or post-acute sequelae of COVID-19 [128]. Long COVID encompasses a range of symptoms including gastrointestinal symptoms, memory loss, shortness of breath, and others.