REVIEW Aspiration Pneumonia and Related Syndromes Augustine S. Lee, MD, and Jay H. Ryu, MD Abstract Aspiration is a syndrome with variable respiratory manifestations that span acute, life-threatening illnesses, such as acute respiratory distress syndrome, to chronic, sometimes insidious, respiratory disorders such as aspiration bronchiolitis. Diagnostic testing is limited by the insensitivity of histologic testing, and although gastric biomarkers for aspiration are increasingly available, none have been clinically validated. The leading mechanism for microaspiration is thought to be gastroesophageal reflux disease, largely driven by the increased prevalence of gastroesophageal reflux across a variety of respiratory disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, and chronic cough. Failure of therapies targeting gastric acidity in clinical trials, in addition to increasing concerns about both the overuse of and adverse events associated with proton pump inhibitors, raise questions about the precise mechanism and causal link between gastroesophageal reflux and respiratory disease. Our review summarizes key aspiration syndromes with a focus on reflux-mediated aspiration and highlights the need for additional mechanistic studies to find more effective therapies for aspiration syndromes. ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2018;nn(n):1-11 ulmonary aspiration is the pathologic pas- unchallenged with empirical attempts at moder- From the Division of fl Pulmonary, Allergy and sage of uid or substances below the level ating aspiration, or more typically its prerequi- Sleep Medicine, Mayo P of the vocal cords into the lower airways. site, GER, by the use of acid suppressants. Clinic, Jacksonville, FL Typically, aspiration is considered an acute event The perception that aspiration is an impor- (A.S.L.); and Division of Pulmonary and Critical that can result in infectious pneumonia, chemical tant mechanism and contributor to respiratory Care Medicine, Mayo pneumonitis, or even respiratory failure from disorders is largely due to the apparent Clinic, Rochester, MN acute respiratory distress syndrome (ARDS).1 increase in the prevalence of gastroesophageal (J.H.R.). The pathologic consequence of aspiration has reflux disease (GERD) across both chronic and been mostly attributed to the acidity of gastric acute respiratory disorders. However, a fluid, but it should be noted that aspiration can well-validated tool to readily diagnose micro- occur from multiple sources in addition to the aspiration is lacking, and many clinicians stomach (eg, duodenal, oropharyngeal, exoge- have adopted the treatment of GERD, typically nous), and the aspirate material may contain other with a proton pump inhibitor (PPI), into injurious materials (eg, microbes, bile, pepsin, practice in hopes of improving their patient’s particulates). In this review, we will focus on aspi- respiratory condition. Although PPIs do little ration syndromes related to gastroesophageal to directly reduce reflux and are associated reflux (GER). with substantial health care costs and potential In contrast to the more established acute adverse events, large observational and aspiration syndromes, chronic occult pulmo- controlled studies have been increasingly nary aspiration, also referred to as silent aspiration reported in respiratory medicine, more often or microaspiration, is considered more often in with negative results. Nonetheless, aspiration the outpatient setting and is believed to remains a dominating concern as the linking contribute to the pathophysiology of multiple mechanism between GERD and chronic respi- respiratory disorders, including pulmonary ratory conditions, particularly with fibrotic fibrosis, asthma, bronchiectasis, bronchiolitis, lung diseases such as idiopathic pulmonary chronic bronchitis, pneumonia, chronic cough, fibrosis (IPF), and to a lesser extent in patients and lung transplant rejection (Table 1).2 Interest- with obstructive lung disorders, including ingly, these clinical suspicions often go asthma and chronic cough. Mayo Clin Proc. n XXX 2018;nn(n):1-11 n https://doi.org/10.1016/j.mayocp.2018.03.011 1 www.mayoclinicproceedings.org n ª 2018 Mayo Foundation for Medical Education and Research MAYO CLINIC PROCEEDINGS pressure gradient (TDPG) interact with the ARTICLE HIGHLIGHTS EGJ/LES complex to facilitate reflux. Specif- ically, because the striated crural muscles of d Reflux is prevalent across a variety of acute and chronic respi- the diaphragm are important to the competence ratory disorders and is considered a predisposing mechanism of the EGJ, this provides at least a potential for a variety of pulmonary aspiration syndromes. mechanistic link on how the respiratory system d Caution should be used when treating suspected pulmonary may anatomically and physiologically link with 7 aspiration syndromes with gastric acid neutralization alone GERD. Fundamentally, these 2 factors, the because standard treatment of reflux has not produced clear pressure gradient between the stomach and the esophagus (ie, TDPG) and the competency clinical benefit and may be of potential harm. of the EGJ and LES, are what define whether d Additional mechanistic studies are needed to understand the gastric fluid will abnormally enter into the causal role of reflux in aspiration and respiratory disorders to esophagus, including during physiologic 8 identify effective targets of interventions. transient LES relaxations. Second, the composition of gastric fluid is an important consideration. In animal models, MECHANISMS UNDERLYING GER AND it is readily recognized that acid is not the sole issue; gastric particulates also augment airway ASPIRATION 9,10 Mechanistically, it is inadequate and inappro- injury. Additionally, both pepsin and bile priate to assume that the presence of GER acids promote epithelial damage, not just to the esophageal mucosa but to airway epithe- implies that aspiration is occurring. There are 11,12 multiple factors that may promote reflux and lium as well. Thus, the constituency and eventual aspiration of gastric fluid into the volume of aspirate material are important in lower airways but also multiple defenses that the development of respiratory pathology must be bypassed before an aspiration event and perhaps help to account for vastly becomes pathologic (Table 2). different phenotypic expressions of gastric First, it is important to clarify what is meant aspiration (eg, pneumonitis, ARDS, broncho- fi by GERD. Gastroesophageal reflux is the retro- spasm, bronchiolitis, and lung brosis). fl grade movement of gastric fluid into the esoph- Next, if gastric contents do re ux into the agus and notably not a state of excess gastric esophagus, it must traverse the span of the acidity, which is the target of most GERD ther- esophagus up into the pharynx (ie, laryngo- fl apies. Furthermore, GERD is heterogeneous pharyngeal re ux) by bypassing the important and multifactorial, with multiple phenotypes barriers of not only the EGJ and LES but also identified in advanced esophageal testing and esophageal peristalsis, which act to clear any fl supported by the current Rome IV classification residual re uxate from the esophagus, further scheme (eg, erosive esophagitis, functional dyspepsia, nonerosive reflux disease, and 3 asymptomatic GERD). Additionally, standard- TABLE 1. Associated Aspiration Syndromes ization and advances in high-resolution esoph- fi Acute ageal manometry have identi ed differing Bronchospasm, asthma patterns in esophageal motility among patients Acute bronchitis, COPD exacerbation with GERD that may be particularly pertinent in Pneumonia, pneumonitis 4-6 patients with respiratory disorders. Finally, Foreign body obstruction novel techniques to image the esophagogastric Acute respiratory distress syndrome junction (EGJ) directly with fluoroscopic Chronic methods and simultaneously measure Bronchiectasis, chronic bronchitis pressures in the stomach, esophagus, and EGJ Exogenous lipoid pneumonia Interstitial lung disease and lower esophageal sphincter (LES) with ad- Organizing pneumonia aptations of the Dent sleeve catheter (Dent- Bronchiolitis obliterans syndrome sleeve International Ltd) have further Diffuse aspiration bronchiolitis facilitated our understanding of how the COPD ¼ chronic obstructive pulmonary disease. transdiaphragmatic (ie, gastric to esophageal) 2 Mayo Clin Proc. n XXX 2018;nn(n):1-11 n https://doi.org/10.1016/j.mayocp.2018.03.011 www.mayoclinicproceedings.org ASPIRATION SYNDROMES TABLE 2. Protective Reflexes to Aspiration and Potential Targets of Therapy Barriers to aspiration Potential therapeutic considerations Laryngopharyngeal Dietary/behavioral measures Swallow Speech therapy (swallow training) Epiglottis Increase cough sensitivity (eg, ACE inhibitors) Vocal cord closure Throat clearing, cough Esophagus Dietary/behavioral measures Upper esophageal sphincter Agents that reduce TLESRs Peristalsis (eg, postreflux swallow induced) Gastric acid neutralization Lower esophageal sphincter Promotility agents Crural diaphragm EGJ competence (eg, inspiratory muscle training) Lungs Increase cough sensitivity Cough Bronchial hygiene measures to enhance clearance Mucociliary barrier Prociliary agents Innate immune, inflammatory response b-Blockers Targeted blocking of aberrant inflammatory or fibrotic pathways ACE ¼ angiotensin-converting enzyme; EGJ ¼ esophagogastric junction; TLESRs ¼ transient lower esophageal sphincter relaxations. minimizing the possibility that it may