Several pulmonary defence mechanisms in the upper airway (e.g., nasopharynx) and the lower airway (e.g., bronchi and alveoli) function to prevent pulmonary infections. Particulate matter and microorganisms are eliminated through anatomic and mechanical barriers, humoral and cell-mediated immunity, and phagocytic activity. Details about these defence mechanisms are available in other reviews and will not be presented here. For an invasive infection to occur, the pathogens must gain access to the lungs by direct inoculation, hematogenous spread, inhalation of aerosolized inocula, or aspiration of bacteria that colonize mucosal surfaces. Bacterial colonization of the upper airway followed by aspiration of oropharyngeal contents into the lower respiratory tract is the most common cause of a respiratory tract infection. The bacterial load after colonization of the upper airway may be as high as 108 to 1010 organisms per millilitre in oropharyngeal secretions in the normal host. It has been estimated that 45% of the population experiences aspiration during sleep. Aspiration of oropharyngeal secretions is more common among patients with altered level of consciousness because of stroke, seizures, alcohol or sedative use, drug intoxication, or underlying diseases.

Other factors that may impair pulmonary host defences include immunosuppression, obstruction, and malnutrition. Exposure to chemical irritants such as tobacco smoke is known to impair mucociliary and macrophage activity, thus interfering with the clearance of particulate matter. Consumption of ethanol may also impair defences by inhibiting cough and epiglottic reflexes. In addition to these mechanisms, some pathogens such as Mycoplasma pneumoniae and Haemophilus influenzae may impair ciliary function, while viral infections (e.g., influenza) may damage the respiratory epithelium and impair neutrophil and macrophage activity. Furthermore, underlying diseases such as COPD, cystic fibrosis, and malignancy may predispose patients to pneumonia because of structural dysfunction or obstruction.
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In contrast, many patients in the ICU undergo intubation with an endotracheal tube and mechanical ventilation. These procedures bypass many of the natural pulmonary defences, placing the patient at greater risk of VAP by facilitating acquisition of and colonization by pathogenic organisms. An endotracheal tube, for example, bypasses the cough and mucociliary defences. Inoculation and colonization of the lower respiratory tract may also be facilitated by medical staff and ventilator equipment.