Alimentary Pharmacology and Therapeutics

Oesophageal eosinophilic infiltration in patients with noncardiac chest pain S. R. Achem*, C. Almansa*, M. Krishna , M. G. Heckmanà, H. C. Wolfsen*, N. J. Talley* & K. R. DeVault*

*Gastroenterology Unit, Mayo Clinic Florida, Jacksonville, FL, USA.   Pathology Unit, Mayo Clinic Florida, Jacksonville, FL, USA. à Biostatistics Unit, Mayo Clinic Florida, Jacksonville, FL, USA.

Correspondence to: Dr S. R. Achem, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA. E-mail: [email protected]

Publication data Submitted 16 February 2011 First decision 6 March 2011 Resubmitted 13 March 2011 Accepted 19 March 2011 EV Pub Online 5 April 2011

SUMMARY Background Eosinophilic oesophagitis clinically presents with recurrent episodes of dysphagia and food impaction. Recently, we observed patients with noncardiac chest pain and eosinophilic oesophagitis.

Aims To estimate the prevalence of abnormal eosinophilic infiltration in noncardiac chest pain patients and examine diagnostic utility of demographic, clinical and endoscopic variables to predict eosinophilic oesophagitis.

Methods Retrospective study of 171 consecutive patients referred for EGD evaluation of noncardiac chest pain. Endoscopic signs consistent with eosinophilic oesophagitis were recorded. The histological findings were grouped as normal: 0–5 eosinophils ⁄ high power field (e ⁄ hpf), indeterminate: 6–20 e ⁄ hpf, and eosinophilic oesophagitis: ‡21 e ⁄ hpf. Abnormal eosinophilic infiltration was defined as ‡6 e ⁄ hpf.

Results Abnormal eosinophilic infiltrate was noted in 24 patients (14%). Thirteen (8%) had indeterminate counts, while 11 (6%) had eosinophilic oesophagitis. Compared with normal, those with abnormal oesophageal eosinophilic infiltration were more likely to be male (71% vs. 34%, P = 0.001), have allergies (29% vs. 12%, P = 0.050), have current GER symptoms (42% vs. 18%, P = 0.013), rings (54% vs. 22%, P = 0.002), furrows (21% vs. 1%, P < 0.001) and abnormal eosinophilic oesophagitis findings on endoscopy (67% vs. 32%, P = 0.001). Of the 24 abnormal patients, 23 (96%) were either male or had rings, furrows, or white specs. Conversely, 68 of 69 patients (99%) who were female did not have rings, furrows, or white specs, and endoscopy was normal. Eight patients (33%) with abnormal eosinophilic infiltration had a normal endoscopy.

Conclusions Eosinophilic oesophagitis should be considered in the evaluation of noncardiac chest pain. Our findings suggest that oesophageal biopsies should be obtained particularly in males with recurrent unexplained chest pain, whether endoscopy is normal or abnormal.

Aliment Pharmacol Ther 2011; 33: 1194–1201

1194

ª 2011 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2011.04652.x

Oesophageal eosinophilic infi filltration in noncardiac chest pain INTRODUCTION Eosinophilic oesophagitis (EoE) is a recently recognised disorder defined as an abnormal infiltration of the oesophagus sparing other areas of the gastrointestinal tract.1 The typical clinical presentation consists of recurrent episodes of dysphagia and food impaction.2, 3 In 1977, Dobbins et al. reported the first patient with abnormal oesophageal infiltration; this patient complained of noncardiac chest (NCCP) pain and dysphagia.4 In 1978, Landres et al. described a second case of eosinophilic oesophageal infiltration in a patient also complaining of NCCP and dysphagia.5 Since those early descriptions, EoE has been noted in only a few adult cases of patients with NCCP.6, 7 Noncardiac chest pain is a complex and heterogeneous disorder. The pathophysiology remains insufficiently understood.8, 9 Several potential factors have been associated with NCCP, including gastro-oesophageal reflux (GER), oesophageal motility disorders (EMD), visceral hyperalgesia and psychological disturbances.9 In a number of patients, no specific cause may be identified. We have observed several cases referred to our institution for evaluation of NCCP who had eosinophilic infiltration of the oesophagus. These observations, coupled with previous case reports of patients with oesophageal eosinophilic infiltration complaining of NCCP, raised the possibility that eosinophils may play a role in the genesis of chest pain, and led us to hypothesise that EoE causes NCCP in a subgroup of patients. The aims of this study were to determine the prevalence of abnormal eosinophilic infiltration in patients with NCCP and examine the utility of demographic, clinical and endoscopic variables in diagnosing patients with abnormal eosinophilic infiltration. MATERIALS AND METHODS We performed a computerised search to identify the medical records of patients referred for endoscopic evaluation of NCCP who had oesophageal biopsies for suspected eosinophilic oesophagitis from January 2006 to July 2007 at Mayo Clinic Florida. Chest pain had to be suspected of being oesophageal in origin after negative cardiac evaluation (either by non-invasive stress testing or coronary angiography). Patients with dysphagia were excluded from the study if this symptom was the main reason for endoscopy. Subjects who could not have biopsies of the gastrointestinal tract due to recent exposure to anticoagulants were also excluded. Oesophageal biopsies were obtained in all cases from at least two sites in the oesophagus: (i) distal, 5 cm above Aliment Pharmacol Ther 2011; 33: 1194–1201 ª 2011 Blackwell Publishing Ltd

the Z line and, (ii) middle, 10 cm above the Z line. Four quadrant distribution biopsies were obtained at each site. Several biopsies at different levels were obtained as EoE is a patchy disease and a recent study by Gonsalves et al. found that five biopsies were required to provide a 100% diagnostic sensitivity in EoE.10 Endoscopic signs consistent with eosinophilic oesophagitis (rings, furrows, white specs) and other relevant endoscopic signs (hiatal hernia, Schatzki’s ring, Barrett oesophagus, strictures, loss of vascular pattern, erosions or exudates) were recorded. The histological findings were grouped as normal: 0–5 eosinophils ⁄ high power field (e ⁄ hpf), indeterminate: 6–20 e ⁄ hpf, and EoE: ‡21 e ⁄ hpf. We chose these histological parameters as the study was designed prior to the publication of the AGA guidelines recommending ‡15 e ⁄ hpf for the diagnosis of EoE.1 The combined group of indeterminate eosinophilic infiltration and EoE was considered an abnormal eosinophilic infiltration. A pathologist (MK) experienced in gastrointestinal histology and unaware of the study aims reviewed the cases. The single field with the highest eosinophilic density was chosen to perform the eosinophilic count. Using a microscopic field with X400 power provides an area of examination of 0.20 mm3. A chart review was conducted to extract patient’s demographics and clinical history. In addition to chest pain, symptoms of GER such as heartburn and regurgitation, globus and proton pump inhibitor (PPI) use prior to endoscopy were noted. Any history of dysphagia and environmental or food allergies (dust, pollen, grass, food, etc.) and clinical history of asthma and rhinitis were also recorded. The prevalence of normal eosinophilic infiltration (0– 5 e ⁄ hpf), indeterminate eosinophilic infiltration (6–20 e ⁄ hpf) and EoE (‡21 e ⁄ hpf) was estimated along with exact binomial 95% confidence intervals (CIs). Patient demographics, clinical and endoscopic variables were compared between groups using Fisher exact test or Wilcoxon rank sum test. In examining diagnostic utility for abnormal eosinophilic infiltration, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated along with 95% CIs for individual demographic, clinical and endoscopic variables as well as for combination variables; only variables that were significantly different between normal and abnormal patients were considered for diagnostic evaluation. P-values £0.05 were considered statistically significant and no adjustments for multiple testing were made in these exploratory analyses. All statistical analyses were performed using S-Plus (version 8.0.1; Insightful 1195

S. R. Achem et al. Corporation, Seattle, WA, USA). The study was approved by the Mayo Clinic IRB.

RESULTS During the study period, 223 patients were referred for upper endoscopy for NCCP. Of these patients, 52 were excluded (biopsies were not available in 23, 6 of whom were on anticoagulants, and 29 patients had dysphagia as the main indication for the endoscopy). The remaining 171 patients with chest pain, as the dominant complaint, were included in the final analysis. An abnormal eosinophilic infiltrate was noted in 24 patients (14%, 95% CI: 9–20%). Eleven patients (6%, 95% CI: 3–11%) with abnormal infiltrate had EoE (‡21 e ⁄ hpf), where individual counts were, in increasing order, 26, 32, 37, 66, 105, 125, 125, 130, 140, 150 and 220 e ⁄ hpf (median: 125 e ⁄ hpf). Thirteen patients (8%, 95% CI: 4– 13%) had indeterminate counts (6–20 e ⁄ hpf), with a median count of 15 (min = 7, max = 18). Of note, 16 of 112 patients (14%, 95% CI: 8–22%) still had abnormal eosinophilic infiltration despite taking double-dose PPI medication, whereas 8 of 59 patients (14%, 95% CI: 6– 25%) not taking PPIs had abnormal eosinophilic infiltration. When defining EoE based on AGA guidelines of ‡15 e ⁄ hpf, overall 20 patients had EoE (12%, 95% CI: 7– 17%); 13 (12%, 95% CI: 6–19%) of those taking double dose PPI medication had EoE, whereas seven (12%, 95% CI: 5–23%) of those not taking PPIs had EoE based on current AGA guidelines. Table 1 shows a comparison of patient demographic, clinical and endoscopic information between normal patients and patients with abnormal eosinophilic infiltration. Male gender was much more common in patients with abnormal eosinophilic infiltration in comparison with normal patients (71% vs. 34%, P = 0.001), as were a history of allergies (29% vs. 12%, P = 0.050), rings on endoscopy (54% vs. 22%, P = 0.002), furrows on endoscopy (21% vs. 1%, P < 0.001) and any abnormal EoE finding on endoscopy (67% vs. 32%, P = 0.001). In addition to chest pain, three patients complained of dysphagia among patients with abnormal oesophageal infiltration: one in the group with ‡21 e ⁄ hpf and two in the intermediate group with 6–20 e ⁄ hpf. Eleven patients had dysphagia in those with 0–5 e ⁄ hpf. There were no other statistically significant differences in demographic, clinical and endoscopy information between normal patients and patients with abnormal eosinophilic infiltration. The ability of the six aforementioned demographic, clinical and endoscopic variables that differed between 1196

Table 1 | Comparison of patient demographic, clinical and endoscopic information between normal patients (0–5 e ⁄ hpf) and patients with abnormal eosinophilic infiltration (‡6 e ⁄ hpf)

Normal (n = 147)

Variable

Abnormal eosinophilic infiltration (n = 24) P-value

Demographic information Age*

59 (25, 86) 55 (21, 81)

0.30

Gender (Male)

50 (34)

17 (71)

0.001

PPI use

96 (65)

16 (67)

1.00

History of GER

79 (54)

17 (71)

0.13

History of allergies

17 (12)

7 (29)

0.050

Clinical information

Asthma

7 (5)

0 (0)

0.60

26 (18)

10 (42)

0.013

2 (1)

1 (4)

0.37

32 (22)

13 (54)

0.002

2 (1)

5 (21)