# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 4 Comparisons to Other Etiologies
### Bacterial Pneumonia  
Compared to viral pathogens, bacterial pneumonias are typically characterized by more rapid disease onset. Bacterial pneumonia is classified as community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) and can be caused by diverse gram-negative or gram-positive species, each of which possess different virulence factors that drive infection and lung injury [146]. CAP is most often caused by _Streptococcus pneumoniae_, a gram-positive bacterium. _S. pneumoniae_ is an extracellular pathogen and can induce damage to host cells through several mechanisms. Like many other bacteria, _S. pneumoniae_ uses biofilm formation to modulate host inflammatory responses and evade phagocytosis [147]. Additionally, its pore-forming toxins such as pneumolysin and hemolysin compromise the epithelial barrier through induction of alveolar type 2 epithelial cell death and release of pro-inflammatory cytokines [15]. Similar to COVID-19, inflammosome activation appears to play an important role in pathogenesis, and NLRP3-deficient mice were shown to have better outcomes. IFN-I production has been shown to be beneficial to the host, although through an apparently different mechanism than COVID-19, involving protection of AEC2 cells [148,149]. _Mycoplasma pneumoniae_ is an atypical bacteria and common cause of CAP, responsible for up to 40% of CAP in children over the age of 5 [149]. _M. pneumoniae_ is predominantly an extracellular pathogen that binds to respiratory epithelial cells using a polarized attachment organelle [150]. This allows it to bind respiratory cilia, where it produces hydrogen peroxide and superoxide, promoting sloughing of epithelial cells injury. M. pneumonia also produces a unique exotoxin termed community-acquired respiratory distress syndrome (CARDS) toxin, which induces a potent inflammatory response, resulting in cell swelling, nuclear lysis, mucous proliferation, and cellular vacuolization [151]. _Legionella pneumophila_, a less common cause of CAP, is clinically distinct from other causes of bacterial pneumonia as well as COVID 19 ALI [152]. The presence of certain symptoms, mainly diarrhea and mental confusion, are much more common in _L. pneumoniae_ infection compared to other bacterial pneumonias [152]. _L. pneumoniae_ is a facultative intracellular bacterium that has a high propensity to invade alveolar macrophages. Its Dot/Icm type IV secretion system delivers effector proteins into the host, inhibiting phagosome-lysosomal fusion, therefore facilitating bacterial proliferation [153]. Interestingly, Legionnaires disease produces distinctive histopathological findings. Erythroleukoplagocytosis is a hallmark finding, which reflects the intravascular hemolysis and leukopenia caused by infection [154]. Moreover, the scarcity of neutrophils in the alveolar exudate contrasts with the abundance of neutrophils that is commonly seen in other types of bacterial pneumorias [154]. HAP, which includes ventilator-associated pneumonia (VAP), can become a severe complication of pre-existing infections or illnesses in health care settings. The most common causative pathogens of HAP include _Pseudomonas aeruginosa_ and _Staphylococcus aureus_[146]. _P. aeruginosa_ is a gram-negative opportunistic bacterium that secretes several products that play a key role in its pathogenesis. These include exotoxins and exoenzymes that impair intercellular junctions in the epithelium and endothelium, as well as alkaline protease, which decreases the airway surface liquid through the activation of ENaC [147; 155]. _S. aureus_ is a gram-positive opportunistic aerobe which induces host epithelial damage through several mechanisms including hemolysis pore-forming toxins and a leukocytolytic exotoxin known as Panton-Valentine leukocidin (PVL). PVL is particularly insidious in the development of ALI and can induce epithelial necrosis of AEC1s as well as recruitment and degranulation of neutrophils [147].