Fig. 23.6  High resolution manometry with esophageal pressure topography. These are composite images of ten consecutive swallows. The y-axis represents distance along the catheter from the pharynx at the top to the stomach at the bottom. Pressure is displayed as a heat map with blue representing lower pressures and red to purple representing higher pressures. The x-axis represents time. The left panel (a) represents a

normal swallow with relaxation of the upper and lower esophageal sphincters (UES/LES) (a) with subsequent contraction along the length of the esophagus (b). The swallow ends with resumption of normal basal tone of the UES/LES (c). The right panel (b) represents an esophagus with 90% failed peristalsis (d) or severely impaired esophageal motility with normal resting UES/LES tone

tify patients who are at increased risk for refux of gastric and esophageal contents. Additionally, many surgeons incorporate manometry ndings as part of planning for any fundoplication procedures.

Esophagram/Barium Swallow

A barium swallow or esophagram is an inexpensive and readily available method of assessing swallowing function, esophageal motility, GER, and structural abnormalities of the esophagus and stomach [47]. Speci c protocols for performing the test are center speci c but generally involve a pharyngeal phase where a bolus of barium is swallowed with dynamic recordings to assess the swallowing mechanism and detect entry of barium into the pharynx and trachea. Next, additional boluses of barium are swallowed in the supine and upright positions to assess esophageal motility and the presence of any structural abnormalities including hiatal hernias.

Bronchoalveolar Lavage/Sputum: Biomarkers

Another area of interest has been the detection of biomarkers of microaspiration in samples from the distal airways. Both pepsin and bile acids have been quanti ed in bronchoalveolar lavage (BAL) samples as potential markers of gastric contents in the respiratory system [48, 49]. Starosta et al. demonstrated in a pediatric population the BAL pepsin level correlated with the degree of refux as measured by 24-h pH monitoring [50]. There was no signi cant correlation with the BAL concentration of bile acids. Examination of expectorated sputum of subjects with suspected GER and microaspiration has also been identi ed as a potential clinical tool.

Parameswaran et al. examined the sputum of 33 subjects with 24-h pH testing for the presence of intracellular lipids in macrophages. A higher concentration of intracellular lipids, calculated as a “lipid index,” was found to be both sensitive and speci c for the presence of GER [51]. While sputum and BAL biomarkers represent a promising avenue for con rming the occurrence of microaspiration additional work is needed to develop standardized methods of measurement and the relationship between the concentrations of the biomarkers and the risks of disease progression.

Treatment

The recommended approach to the management of GER in patients with IPF includes non-pharmacological, pharmacologic, and lifestyle modi cations. In patients with progressive disease without contraindications for general anesthesia, anti-refux surgical interventions are considerations for intractable GER/D despite strict adherence of conservative measures to decrease risks of GER. Most clinical practice guidelines suggest a stepwise approach to therapy which should be individualized based on the severity of symptoms and any esophageal or extraesophageal complications. Lifestyle modi cations are the cornerstone to the conservative treatment of GER and suggestions include weight loss in overweight or obese patients, smaller meals, avoidance of late meals, avoidance of precipitating factors, use of a sleep positioning device or elevating the head of the bed with sleep [52]. While these interventions are often proposed to patients

in a clinical setting only elevating the head of the bed and weight loss have been shown to be effective in reducing GER symptoms.

Anti-Acid Therapy (PPI/H2 Blocker)

From a pharmacologic perspective the treatment of GER is focused on the use of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA). It is important to note, however, that while both PPIs and H2RAs are effective at reducing the acidity of the refuxate they do not decrease the overall number or severity of refux events [53]. This highlights the need to consider the non-acid components of refux and their deleterious effects on the respiratory system.

The use of anti-acid medications in IPF has been extensively studied and has been shown in multiple studies to improve outcomes (Table 23.2). The most recent ERS/ATS/ JRS/ALAT Clinical Guidelines for the Treatment of IPF give a conditional recommendation for the use of PPIs in patients with IPF (with a very low con dence in effect estimates) [54]. A large number of both prospective and retrospective studies have been completed investigating the relationship between GER and disease outcomes in IPF (summarized in Table 23.2). The results of these studies have been mixed and suffer from methodological limitations. In particular, the use of post-hoc, subgroup, and exploratory analyses is limited by a lack of pre-speci ed study design. This is important in determining the dosing of and compliance with anti-refux medications, adjudication of side effects, the infuence of confounding factors, and the impact of immortal time bias. While these studies have generated hypotheses for further testing only one randomized control trial has been performed to date which demonstrated safety with PPI use and a larger trial is currently underway [55].

Other E ects of PPI Therapy (Pleiotropic)

Aside from their anti-acid properties several studies have demonstrated PPIs have effects extending beyond the proton pump in the gastrointestinal system. These include an anti-­ oxidant effect by scavenging reactive oxygen species and promoting the activity of anti-oxidant enzymes and proteins [69]. PPIs have also been shown to have a pleiotropic effect in regulating processes that are involved in pulmonary infammatory and brotic cascades. Ghebremariam et al. have demonstrated in both in vitro and in vivo studies that esomeprazole suppresses the transcription of infammatory cytokines, adhesion molecules, and matrix metalloproteinases which attenuates infammation and brosis in a bleomycin mouse model [64].

Laparoscopic Anti-Refux Surgery (LARS)

In addition to the use of antacid therapy for the treatment of GER, surgical interventions are another option that have generated signi cant interest. Nissen laparoscopic fundoplication was rst performed in 1955 and has evolved to be considered the gold standard approach for the surgical management of GER and the repair of hiatal hernias. While techniques vary from center to center the procedure essentially involves reduction of the hiatal hernia (if present), plicating the gastric fundus 360° around the distal esophagus to mechanically reinforce the LES, and repair of the diaphragmatic hiatus. The procedure is generally well tolerated with the most common complications being dysphagia and abdominal bloating [70]. Other approaches have been developed including the Toupet fundoplication (a posterior 270° wrap) and the Dor fundoplication (an anterior 180° wrap). Recent studies have suggested that these techniques have similar ef - cacy to the Nissen fundoplication and may have lower rates of post-operative dysphagia and bloating [71, 72].

A large retrospective cohort study suggested improved survival in those patients who underwent refux surgery compared to those on antacid therapy alone [66]. A single center case series demonstrated an excellent safety pro le and stabilization of lung function in patients who underwent refux surgery [73]. The WRAP-IPF trial was a Phase II randomized, non-blinded, multicenter trial of laparoscopic anti-­ refux surgery. A total of 58 patients with a consensus diagnosis of IPF and GER con rmed with 24-h pH testing were randomized to surgery or medical management alone. Fundoplication was shown to be a safe procedure in patients with IPF and while no signi cant difference in rate of change of FVC was found between groups there was a signal for decreased rates of acute exacerbations and hospitalizations in the surgery group [74].

GER and Acute Exacerbations of IPF

While the typical natural history of IPF is described as a gradual and progressive decline in lung function, the disease course can be signi cantly affected by episodes of sudden deterioration which have been characterized as acute exacerbations (AE-IPF). These episodes are de ned as an acute worsening in clinical condition with associated radiographic changes and the absence of an alternative explanation [75]. The occurrence of AE-IPF have a marked impact on prognosis with median survival after an event being 3–4 months [76]. While the etiology of these events are most likely multifactorial, GER and microaspiration have been suggested to play an integral role in the development of acute lung injury. This hypothesis is supported indirectly by post-hoc analysis of the placebo arms from three separate clinical trials which

showed that AE-IPF only occurred in those patients not taking anti-acid medications [58].

In a small case-control study, Lee et al. found increased bronchoalveolar lavage (BAL) pepsin levels in the group of patients with AE-IPF. However, there was no survival advantaged noted and a small subgroup of patients had markedly elevated pepsin levels driving the difference

between groups [17]. This hypothesis is also supported by changes in the microbiome of patients diagnosed with AE-IPF. Molyneaux et al. discovered a signi cant increase in Campylobacter species, a well-established gastrointestinal pathogen, on bronchoalveolar lavage samples suggesting translocation of these bacteria as a result of the microaspiration of gastric contents [77].

Refux/GER/Microaspiration in Lung

Transplant

While the prevention of disease progression and improved survival is the principal goal in the management of patients with IPF many continue to decline and ultimately are considered for lung transplantation. The most signi cant limitation to long-term survival after lung transplant is chronic lung allograft dysfunction (CLAD) with bronchiolitis obliterans syndrome (BOS) being the most common subtype. While many possible causative factors of CLAD have been considered, the occurrence of GER and microaspiration have been proposed as signi cant contributors. Many of the proposed mechanisms of epithelial injury, infammation, and brosis are similar to those discussed in a previous section. Animal models have suggested that repeated exposure of the allograft to gastric contents may enhance allorecognition and accelerate the development of graft dysfunction/ rejection [78]. The prevalence of abnormal GER in lung transplant recipients is very high and it has been proposed that the process of lung transplantation itself can worsen pre-existing refux disease [79, 80].

The data regarding the detection of microaspiration in the respiratory system of lung transplant recipients is more robust than for patients with IPF; both the detection of bile acids and the use of oil red O stains have been proposed as effective screening tests [49, 81, 82]. While these biomarkers are useful in identifying those patients with abnormal GER and microaspiration, further research is needed to identify those patients at risk for development of CLAD that would bene t from more aggressive management of their GER.

As in patients with IPF there has been signi cant interest in anti-refux surgery in this patient population with regard to safety and the ef cacy of preventing CLAD. Overall existing data suggests that laparoscopic anti-refux surgery is safe in patients who are post-lung transplant with complication rates ranging from 5 to 14% comparable to those patients who have not undergone transplant with the most common complication being dysphagia [83, 84]. Several retrospective and prospective studies have been conducted to evaluate the ef cacy of anti-refux surgery with a strong signal that suggests early

surgery in patients with documented refux can reduce the risk of developing CLAD/BOS. For example, Hartwig et al. prospectively collected data on 297 LTX recipients and reported that early fundoplication appeared to preserve allograft function in those patients with abnormal 24-h pH testing [85].

Clinical Vignette

A 65-year-old former smoker presents for evaluation of a 2-year history of progressive dyspnea on exertion associated with a non-productive cough. He has no history of environmental or occupational exposures and no clinical ndings of a connective tissue disease. Pulmonary function testing reveals a moderate impairment in both forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO). The time course of pulmonary function changes is illustrated in Fig. 23.7. Computed tomographic imaging of the chest reveals subpleural reticular markings in a basal distribution with areas of traction bronchiectasis in the bilateral lower lobes in addition to a moderate sized hiatal hernia. Based on the clinical and radiographic criteria a diagnosis of idiopathic pulmonarybrosis is made consistent with the updated 2018 ATS/ ERS/JRS/ALAT criteria. He is started on antibrotic therapy and undergoes rigorous evaluation for abnormal GER with a barium esophagram, esophageal manometry, and 24-h pH monitoring. These reveal normal esophageal motility and sphincter function with a DeMeester score of 40.8 con rming the presence of abnormal refux. He is started on PPI therapy and counseled extensively about lifestyle modi cations and weight loss.

He returns to the clinic 18 months later with a 15% decrease in FVC despite regular adherence to his medications and lifestyle modi cations. Given this change he is referred and eventually undergoes a successful laparoscopic Nissen fundoplication. He is now 2 years post-fundoplication and has demonstrated stability of lung function and exercise tolerance.