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Original Article |

Progressive Mucosal Injury in Patients With Gastroesophageal Reflux Disease and Increasing Peripheral Blood Eosinophil Counts FREE

Farzaneh Banki, MD; Patrick Flanagan, MS; Joerg Zehetner, MD; Analisa Armstrong, MS; Jeffrey A. Hagen, MD; Amit Joshi, MD; Raina Sinha, MD; Daniel Oh, MD; Arzu Oezcelik, MD; Steven R. DeMeester, MD; Emmanuele Abate, MD; John C. Lipham, MD; Parakrama Chandrasoma, MD; Peter F. Crookes, MD; Tom R. DeMeester, MD
[+] Author Affiliations

Author Affiliations: University of Southern California, Los Angeles. Dr Banki is now with the Department of Cardiothoracic and Vascular Surgery, The University of Texas Medical School at Houston, Houston.


Arch Surg. 2010;145(4):363-366. doi:10.1001/archsurg.2010.44.
Text Size: A A A
Published online

Hypothesis  Peripheral blood eosinophil count increases with the degree of mucosal injury associated with gastroesophageal reflux disease (GERD).

Design  Retrospective review.

Setting  Single-institution tertiary hospital.

Patients  Two hundred ninety-five patients (215 men and 80 women; median age, 57 years [interquartile range (IQR), 46-66 years]). One hundred had GERD without intestinal metaplasia, 100 had GERD with intestinal metaplasia, 40 had GERD with dysplasia, and 55 had GERD with intramucosal carcinoma. Results of complete blood count with differential and serum chemistry studies were compared among the groups using a nonparametric test for trend.

Results  Patients with a higher degree of mucosal injury were older (P < .001). There were no differences between white blood count, percent neutrophil count, absolute neutrophil count, and hematocrit levels among the groups. Serum albumin level decreased as the degree of mucosal injury increased (P = .04) but lost significance when controlled for age (P = .53). Percent eosinophil counts were 2.0 (IQR, 1.3-2.8) in patients with GERD without intestinal metaplasia, 2.5 (IQR, 1.6-3.7) in GERD with intestinal metaplasia, 2.6 (IQR, 1.7-4.4) in GERD with dysplasia, and 2.7 (IQR, 1.5-4.3) in GERD with intramucosal carcinoma. This progressive increase in the percent eosinophil count was statistically significant (P = .006), remained significant after controlling for age (P = .04), and was also significant when measuring the absolute eosinophil count.

Conclusion  There is a progressive increase in the percent and absolute peripheral blood eosinophil count associated with progressive mucosal injury in patients with GERD.

Figures in this Article

The presence of intraepithelial eosinophils on esophageal biopsy was first noted to be a specific marker of esophagitis in children by Winter et al,1 who correlated the presence of eosinophils with abnormal esophageal acid exposure on pH monitoring. Additional studies have been published confirming the presence of eosinophils in the mucosa of patients with gastroesophageal reflux disease (GERD), but no studies have evaluated the significance of the peripheral blood eosinophil count in patients with GERD. The aim of our study was to evaluate alterations in the peripheral blood eosinophil count in patients with GERD and assess the association between the peripheral blood eosinophil count and the degree of mucosal injury.

The subjects of this study were chosen from a population of patients who were referred for evaluation and surgical treatment of GERD and its complications in the Thoracic and Foregut Division at the Department of Surgery of the University of Southern California. All patients underwent esophageal motility, pH study, and upper gastrointestinal endoscopy with biopsy. Laboratory studies included measurements of white blood cell count, neutrophil count, eosinophil count, albumin, and hematocrit.

Esophageal motility and pH studies were performed according to a standard protocol.2 The pH probe was placed 5 cm above the manometrically determined upper border of the lower esophageal sphincter. Upper gastrointestinal endoscopy was performed according to a protocol for biopsies of the gastric antrum and body, gastroesophageal junction, and distal esophagus.3 Patients were classified into 4 groups based on the degree of mucosal injury determined through biopsies taken from the gastroesophageal junction and distal esophagus.

The study groups consisted of patients with GERD without intestinal metaplasia, GERD with intestinal metaplasia, GERD with dysplasia (low-grade dysplasia and high-grade dysplasia), and GERD with intramucosal carcinoma. The presence of eosinophils in biopsy specimens from the gastroesophageal junction and distal esophagus was noted.

Blood samples were obtained from peripheral veins on the morning of the preoperative visit. Normal values for our laboratory were percent eosinophil count of 0.8 to 5.0, absolute eosinophil count of less than 200/μL, percent neutrophil count of 72.2 to 75.5, absolute neutrophil count of 1400 to 6500/μL, white blood cell count of 3800 to 10 800/μL, hematocrit level of 35.0% to 46.0%, and albumin level of 3.5 to 5.2 g/dL. To convert eosinophil, neutrophil, and white blood cell counts to ×109/L, multiply by 0.001.

Results of complete blood cell count with differential and serum chemistry studies were compared among the groups using a nonparametric test for trend. Preliminary statistical analysis indicated that there was an association between progressive mucosal injury and age. As a result, comparisons were adjusted for age when required by computing residuals from a simple linear regression model. The presence of intraepithelial eosinophils in patients with and without intestinal metaplasia was compared using the χ2 test. All statistical analyses were done using the Stata statistical software program. Statistical power calculations indicated that a sample size of 100 patients per group would be necessary to detect significant differences in peripheral blood eosinophil count in patients with GERD. The study was approved by the institutional board review at the University of Southern California.

The study population consisted of 295 patients: 215 men and 80 women, with a median age of 57 years (interquartile range [IQR], 46-66 years). One hundred patients with GERD and no intestinal metaplasia and 100 with GERD and intestinal metaplasia were randomly identified for inclusion. There were 40 patients with GERD and dysplasia and 55 with GERD and intramucosal carcinoma who met the inclusion criteria.

Demographic information and laboratory values in the 4 patient groups are shown in the Table. Patients with a higher degree of mucosal injury were older (P < .001). There were no differences between white blood count, percent neutrophil count, absolute neutrophil count, or hematocrit levels among the groups. Serum albumin decreased as the degree of mucosal injury increased (P = .04) but lost significance when controlled for age (P = .53). The absolute eosinophil count progressively increased with increase in mucosal injury (P = .01) and remained significant after controlling for age (P = .04). The percent eosinophil count in the 4 patient groups are shown in the Figure. The percent eosinophil count rose significantly with increase in mucosal injury (P = .006) and remained significant after controlling for age (P = .04).

Place holder to copy figure label and caption
Figure.

Association between percent eosinophil in the peripheral blood and the degree of mucosal injury in 4 patient groups. Dysplasia included low- and high-grade disease. Values are adjusted for age (P = .006, unadjusted for age; P = .04, adjusted for age). Error bars indicate interquartile range; GERD, gastroesophageal reflux disease; IM, intestinal metaplasia; IMC, intramucosal carcinoma.

Graphic Jump Location
Table Graphic Jump LocationTable. Comparison of Demographic Information and Laboratory Values in the 4 Study Groups With GERD Based on the Degree of Mucosal Injury

Intraepithelial eosinophils were present in the distal esophagus or the gastroesophageal junction in 35% of patients with GERD without intestinal metaplasia and 42% in GERD with intestinal metaplasia (P = .34). When dysplasia or intramucosal carcinoma were present, intraepithelial eosinophils on pathology specimens were not assessed. There was no difference in the frequency of asthma or asthma-like symptoms among the groups (13 of 100 [13%] patients with GERD without intramucosal carcinoma, 13 of 100 [13%] with GERD and intramucosal carcinoma, 4 of 40 [10%] with GERD and dysplasia, and 2 of 55 [3.6%] with GERD and intramucosal carcinoma; P = .34).

The current study shows that an increase in the peripheral blood eosinophil count occurs in progressive stages of GERD. This suggests that eosinophils may have a unique purpose in the pathophysiology of this disease. Despite remaining within the normal range, a gradual and independent increase in the absolute eosinophil count and percent eosinophil count was observed as the degree of mucosal injury increased. This finding may have several clinical implications, and understanding this observation requires an appreciation of the presence and function of eosinophils in normal tissues.

Eosinophils reside mainly in tissue. It is estimated that for every 1 eosinophil in the peripheral blood, there are 100 eosinophils in the tissue.4 Eosinophil infiltration of the tissue usually occurs independently of other blood leukocytes.5 Eosinophils are normally seen in the gastrointestinal tract, spleen, and lymphatic and thymic tissues. The most predominant population of eosinophils is in the gastrointestinal tract,6 where they are located in the lamina propria of the stomach, small intestine, cecum, and colon.7 In contrast to the other segments of the gastrointestinal tract, eosinophils are uncommon in the esophageal mucosa, and their presence is a marker of pathology,7 such as of reflux esophagitis, parasitic infections, systemic eosinophilic conditions,8 and eosinophilic esophagitis.9

Accumulation of eosinophils in the tissue occurs in several other diseases not related to the esophagus,10 such as bronchial asthma.11 In this condition, the peripheral blood eosinophilia is shown to be correlated with the degree of bronchial hyperactivity.12

One of the first studies to suggest that there is an association between GERD and the eosinophil infiltration of the esophagus was written by Winter et al1 in 1982. They reported that the presence of intraepithelial eosinophils in children correlated with increased esophageal acid exposure on pH monitoring. This association was further supported by Lee13 in 1985, who showed that eosinophil infiltration may indicate prolonged or severe GERD. The report of excessive intraepithelial eosinophilia by Attwood et al14 in 1993 introduced the possibility that esophageal eosinophilia may not solely be a reflux phenomenon. They introduced the concept of eosinophilic esophagitis as a separate entity manifested by the symptom of dysphagia rather than heartburn.

The exact mechanism of esophageal infiltration by eosinophils is unknown but is likely due to diverse stimuli that recruit eosinophils from the peripheral circulation into inflammatory foci, where they modulate the immune responses and regulate vascular permeability. These stimuli include nonspecific tissue injury, infections, allograft, allergens, and tumors.15 Recent studies have suggested several potential mechanisms whereby GERD is a stimulus for the recruitment of the eosinophils into the esophageal mucosa. In one study, vascular endothelial cells were shown to express adhesion molecules like vascular cell adhesion molecule–1 that are recognized by ligands on the eosinophil cell surface.16 In another study, increased acid exposure was shown to induce the expression of vascular cell adhesion molecule–1 in cultures of human esophageal microvascular endothelial cells.17 Acid exposure has also been shown in animal studies to increase esophageal blood flow, thereby enhancing the delivery of eosinophils to the esophageal epithelium.18 In human esophageal mucosa, acid exposure has been shown to release a platelet-activating factor, which has the capacity to attract and activate eosinophils.19 Furthermore, esophageal acid exposure has been shown to induce the esophageal epithelium to release chemokines that attract eosinophils.20 Two recently described chemokines, eotaxin-1 and eotaxin-2, are reported to be relatively specific for eosinophils.21,22 Eosinophil infiltration of tissue frequently occurs independently of other blood leukocytes, suggesting that a specific mechanism exists for the extravasation of eosinophils into the tissues.

The maturation of eosinophils in the bone marrow and their release into the blood is dependent on cytokines, including IL-5 (interleukin 5),23 IL-2,24 and granulocyte macrophage and colony-stimulating factors.25,26 Of these factors, IL-5 is known as an eosinophil-differentiation factor and appears to be directly and specifically involved in eosinopoiesis23 and their release into the peripheral circulation.27

The elevation of eosinophil counts in the blood of patients with intramucosal carcinoma in our study corresponds to previous reports in which both peripheral blood and tissue eosinophil count are known to be elevated in other neoplasms. Iwasaki et al,28 in a prospective study of 647 patients with gastric carcinoma, found that 157 (24%) patients showed eosinophil infiltration in the resected tumor. They identified a chemotactic factor (eosinophil chemotactic factor) in the tumor extracts with the capacity for marked eosinophil chemotaxis. In their study, the degree of eosinophil infiltration into tumors correlated well with the blood eosinophil count. Similarly, in colonic carcinoma, eosinophil infiltration of the tumor specimen has been reported.29 In carcinoma of the lung, an eosinopoiesis factor has been isolated from tumor extracts as well as tumor cells from patients with lung cancer. In these patients, peripheral blood eosinophilia and tumor eosinophil infiltration are known to secrete an eosinopoietic polypeptide that stimulates bone marrow production of eosinophils followed by a rise in the peripheral blood eosinophil count.30

This study provides data confirming that eosinophils may have a particular role in patients with GERD and introduces the concept that an increase in the peripheral blood eosinophil count correlates with the degree of mucosal injury. The exact etiology of the increase in the eosinophil count and their selective infiltration in patients with GERD remains unknown. It is hypothesized that the degree of increase is related to the degree of acid- and bile-induced injury at the intraepithelial level. The intraepithelial injury initiates a cascade of inflammatory response mediated by cytokines such as IL-5, which attracts the eosinophils to the injured epithelium and causes the release of eosinopoietic factor to stimulate bone marrow production of eosinophils, resulting in a rise of the peripheral blood eosinophil count.

Our study is limited by its retrospective design, lack of a control group composed of healthy individuals, and the inability to assess the effect of acid-suppression therapy in these patients. It would be interesting to measure the peripheral blood eosinophil count in patients with squamous cell carcinoma of the esophagus, which is not associated with GERD. It would also be clinically pertinent to measure the peripheral blood eosinophil count in patients with GERD before and after medical therapy or antireflux surgery and in patients with esophageal adenocarcinoma before and after esophagectomy in a prospective fashion. In addition, we did not investigate the degree of intraepithelial eosinophils in patients with dysplasia and intramucosal carcinoma. Furthermore, it is known that the eosinophil count has a diurnal variation,31 with the lowest count in the morning and the highest count in the evening. This time-related variation did not affect our results, as the blood samples were drawn during the day. We also did not collect information about food allergies, which made it difficult to control for this factor.

Despite these limitations, this study is the first to focus on the significance of peripheral blood eosinophil count in patients with GERD and shows that an independent increase in peripheral eosinophil count was associated with the progression in the sequence of mucosal injury from GERD to metaplasia to dysplasia to intramucosal carcinoma. Our study further indicates that GERD is a chronic disease with a progressive degree of inflammation reflected by an increasing peripheral blood eosinophil count with each epithelial change. The microscopic resolution of this inflammatory process should be an integral part of the treatment of patients with GERD, and effective therapy should prevent the progression of the mucosal changes associated with the inflammation.

Correspondence: Farzaneh Banki, MD, 11914 Astoria Blvd, Medical Plaza 1, Ste 260, Houston, TX 77089 (farzaneh.banki@uth.tmc.edu).

Accepted for Publication: May 21, 2009.

Author Contributions:Study concept and design: Banki and Lipham. Acquisition of data: Banki, Flanagan, Zehetner, Armstrong, Sinha, Oh, Oezcelik, Abate, and Lipham. Analysis and interpretation of data: Banki, Hagen, Joshi, S. DeMeester, Lipham, Chandrasoma, Crookes, and T. DeMeester. Drafting of the manuscript: Banki, Flanagan, Zehetner, Armstrong, Sinha, Oh, Oezcelik, Abate, and Chandrasoma. Critical revision of the manuscript for important intellectual content: Banki, Hagen, Joshi, S. DeMeester, Lipham, Crookes, and T. DeMeester. Statistical analysis: Joshi. Obtained funding: T. DeMeester. Administrative, technical, and material support: Joshi, Chandrasoma, and T. DeMeester. Study supervision: Banki, Hagen, and Lipham. Institutional review board approval: Zehetner.

Financial Disclosure: None reported.

Previous Presentation: This study was presented at the 80th Annual Meeting of the Pacific Coast Surgical Association; February 14, 2009; San Francisco, California.

Winter  HSMadara  JLStafford  RJGrand  RJQuinlan  JEGoldman  H Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982;83 (4) 818- 823
PubMed
Banki  FMason  RJHagen  JA  et al.  The crura and crura-sphincter pressure dynamics in patients with isolated upright and isolated supine reflux. Am Surg 2001;67 (12) 1150- 1156
PubMed
Chandrasoma  PTDT GERD: Reflux to Esophageal Adenocarcinoma.  San Diego, CA: Elsevier Academic Press; 2006:421-423
Mansur  ATGoktay  FYasar  SP Peripheral blood eosinophilia in association with generalized pustular and erythrodermic psoriasis. J Eur Acad Dermatol Venereol 2008;22 (4) 451- 455
PubMed Link to Article
Sanderson  CJ Interleukin-5, eosinophils, and disease. Blood 1992;79 (12) 3101- 3109
PubMed
Mishra  AHogan  SPLee  JJFoster  PSRothenberg  ME Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 1999;103 (12) 1719- 1727
PubMed Link to Article
Gonsalves  N Eosinophilic esophagitis: history, nomenclature, and diagnostic guidelines. Gastrointest Endosc Clin N Am 2008;18 (1) 1- 9, vii
PubMed Link to Article
Dahms  BB Reflux esophagitis: sequelae and differential diagnosis in infants and children including eosinophilic esophagitis. Pediatr Dev Pathol 2004;7 (1) 5- 16
PubMed Link to Article
Bohm  MRichter  JE Treatment of eosinophilic esophagitis: overview, current limitations, and future direction. Am J Gastroenterol 2008;103 (10) 2635- 2644, quiz 2645
PubMed Link to Article
Weller  PF The immunobiology of eosinophils. N Engl J Med 1991;324 (16) 1110- 1118
PubMed Link to Article
Frigas  EGleich  GJ The eosinophil and the pathophysiology of asthma. J Allergy Clin Immunol 1986;77 (4) 527- 537
PubMed Link to Article
Gleich  GJ The eosinophil and bronchial asthma: current understanding. J Allergy Clin Immunol 1990;85 (2) 422- 436
PubMed Link to Article
Lee  RG Marked eosinophilia in esophageal mucosal biopsies. Am J Surg Pathol 1985;9 (7) 475- 479
PubMed Link to Article
Attwood  SESmyrk  TCDemeester  TRJones  JB Esophageal eosinophilia with dysphagia: a distinct clinicopathologic syndrome. Dig Dis Sci 1993;38 (1) 109- 116
PubMed Link to Article
Rothenberg  MEHogan  SP The eosinophil. Annu Rev Immunol 2006;24147- 174
PubMed Link to Article
Barthel  SRAnnis  DSMosher  DFJohansson  MW Differential engagement of modules 1 and 4 of vascular cell adhesion molecule-1 (CD106) by integrins alpha4beta1 (CD49d/29) and alphaMbeta2 (CD11b/18) of eosinophils. J Biol Chem 2006;281 (43) 32175- 32187
PubMed Link to Article
Rafiee  PTheriot  MENelson  VM  et al.  Human esophageal microvascular endothelial cells respond to acidic pH stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27. Am J Physiol Cell Physiol 2006;291 (5) C931- C945
PubMed Link to Article
Hollwarth  MESmith  MKvietys  PRGranger  DN Esophageal blood flow in the cat: normal distribution and effects of acid perfusion. Gastroenterology 1986;90 (3) 622- 627
PubMed
Cheng  LCao  WBehar  JFiocchi  CBiancani  PHarnett  KM Acid-induced release of platelet-activating factor by human esophageal mucosa induces inflammatory mediators in circular smooth muscle. J Pharmacol Exp Ther 2006;319 (1) 117- 126
PubMed Link to Article
Schnyder  BLugli  SFeng  N  et al.  Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain. Blood 1996;87 (10) 4286- 4295
PubMed
Jose  PJGriffiths-Johnson  DACollins  PD  et al.  Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med 1994;179 (3) 881- 887
PubMed Link to Article
Forssmann  UUguccioni  MLoetscher  P  et al.  Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med 1997;185 (12) 2171- 2176
PubMed Link to Article
Clutterbuck  EJHirst  EMSanderson  CJ Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood 1989;73 (6) 1504- 1512
PubMed
Forni  GGiovarelli  MSantoni  AModesti  AForni  M Tumour inhibition by interleukin-2 at the tumour/host interface. Biochim Biophys Acta 1986;865 (3) 307- 327
PubMed
Vadas  MAVarigos  GNicola  N  et al.  Eosinophil activation by colony-stimulating factor in man: metabolic effects and analysis by flow cytometry. Blood 1983;61 (6) 1232- 1241
PubMed
Metcalf  DParker  JChester  HMKincade  PW Formation of eosinophilic-like granulocytic colonies by mouse bone marrow cells in vitro. J Cell Physiol 1974;84 (2) 275- 289
PubMed Link to Article
Collins  PDMarleau  SGriffiths-Johnson  DAJose  PJWilliams  TJ Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med 1995;182 (4) 1169- 1174
PubMed Link to Article
Iwasaki  KTorisu  MFujimura  T Malignant tumor and eosinophils, I: prognostic significance in gastric cancer. Cancer 1986;58 (6) 1321- 1327
PubMed Link to Article
Pretlow  TPKeith  EFCryar  AK  et al.  Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res 1983;43 (6) 2997- 3000
PubMed
Slungaard  AAscensao  JZanjani  EJacob  HS Pulmonary carcinoma with eosinophilia. Demonstration of a tumor-derived eosinophilopoietic factor. N Engl J Med 1983;309 (13) 778- 781
PubMed Link to Article
Wardlaw  AJKA Eosinophils and their disorders. In: Beutler  E, Lichman  MA, Coller  BS, Kipps  TJ, eds. Williams Hematology. New York, NY: McGraw Hill; 2001:785

Figures

Place holder to copy figure label and caption
Figure.

Association between percent eosinophil in the peripheral blood and the degree of mucosal injury in 4 patient groups. Dysplasia included low- and high-grade disease. Values are adjusted for age (P = .006, unadjusted for age; P = .04, adjusted for age). Error bars indicate interquartile range; GERD, gastroesophageal reflux disease; IM, intestinal metaplasia; IMC, intramucosal carcinoma.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Comparison of Demographic Information and Laboratory Values in the 4 Study Groups With GERD Based on the Degree of Mucosal Injury

References

Winter  HSMadara  JLStafford  RJGrand  RJQuinlan  JEGoldman  H Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis. Gastroenterology 1982;83 (4) 818- 823
PubMed
Banki  FMason  RJHagen  JA  et al.  The crura and crura-sphincter pressure dynamics in patients with isolated upright and isolated supine reflux. Am Surg 2001;67 (12) 1150- 1156
PubMed
Chandrasoma  PTDT GERD: Reflux to Esophageal Adenocarcinoma.  San Diego, CA: Elsevier Academic Press; 2006:421-423
Mansur  ATGoktay  FYasar  SP Peripheral blood eosinophilia in association with generalized pustular and erythrodermic psoriasis. J Eur Acad Dermatol Venereol 2008;22 (4) 451- 455
PubMed Link to Article
Sanderson  CJ Interleukin-5, eosinophils, and disease. Blood 1992;79 (12) 3101- 3109
PubMed
Mishra  AHogan  SPLee  JJFoster  PSRothenberg  ME Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 1999;103 (12) 1719- 1727
PubMed Link to Article
Gonsalves  N Eosinophilic esophagitis: history, nomenclature, and diagnostic guidelines. Gastrointest Endosc Clin N Am 2008;18 (1) 1- 9, vii
PubMed Link to Article
Dahms  BB Reflux esophagitis: sequelae and differential diagnosis in infants and children including eosinophilic esophagitis. Pediatr Dev Pathol 2004;7 (1) 5- 16
PubMed Link to Article
Bohm  MRichter  JE Treatment of eosinophilic esophagitis: overview, current limitations, and future direction. Am J Gastroenterol 2008;103 (10) 2635- 2644, quiz 2645
PubMed Link to Article
Weller  PF The immunobiology of eosinophils. N Engl J Med 1991;324 (16) 1110- 1118
PubMed Link to Article
Frigas  EGleich  GJ The eosinophil and the pathophysiology of asthma. J Allergy Clin Immunol 1986;77 (4) 527- 537
PubMed Link to Article
Gleich  GJ The eosinophil and bronchial asthma: current understanding. J Allergy Clin Immunol 1990;85 (2) 422- 436
PubMed Link to Article
Lee  RG Marked eosinophilia in esophageal mucosal biopsies. Am J Surg Pathol 1985;9 (7) 475- 479
PubMed Link to Article
Attwood  SESmyrk  TCDemeester  TRJones  JB Esophageal eosinophilia with dysphagia: a distinct clinicopathologic syndrome. Dig Dis Sci 1993;38 (1) 109- 116
PubMed Link to Article
Rothenberg  MEHogan  SP The eosinophil. Annu Rev Immunol 2006;24147- 174
PubMed Link to Article
Barthel  SRAnnis  DSMosher  DFJohansson  MW Differential engagement of modules 1 and 4 of vascular cell adhesion molecule-1 (CD106) by integrins alpha4beta1 (CD49d/29) and alphaMbeta2 (CD11b/18) of eosinophils. J Biol Chem 2006;281 (43) 32175- 32187
PubMed Link to Article
Rafiee  PTheriot  MENelson  VM  et al.  Human esophageal microvascular endothelial cells respond to acidic pH stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27. Am J Physiol Cell Physiol 2006;291 (5) C931- C945
PubMed Link to Article
Hollwarth  MESmith  MKvietys  PRGranger  DN Esophageal blood flow in the cat: normal distribution and effects of acid perfusion. Gastroenterology 1986;90 (3) 622- 627
PubMed
Cheng  LCao  WBehar  JFiocchi  CBiancani  PHarnett  KM Acid-induced release of platelet-activating factor by human esophageal mucosa induces inflammatory mediators in circular smooth muscle. J Pharmacol Exp Ther 2006;319 (1) 117- 126
PubMed Link to Article
Schnyder  BLugli  SFeng  N  et al.  Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gamma chain. Blood 1996;87 (10) 4286- 4295
PubMed
Jose  PJGriffiths-Johnson  DACollins  PD  et al.  Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med 1994;179 (3) 881- 887
PubMed Link to Article
Forssmann  UUguccioni  MLoetscher  P  et al.  Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J Exp Med 1997;185 (12) 2171- 2176
PubMed Link to Article
Clutterbuck  EJHirst  EMSanderson  CJ Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF. Blood 1989;73 (6) 1504- 1512
PubMed
Forni  GGiovarelli  MSantoni  AModesti  AForni  M Tumour inhibition by interleukin-2 at the tumour/host interface. Biochim Biophys Acta 1986;865 (3) 307- 327
PubMed
Vadas  MAVarigos  GNicola  N  et al.  Eosinophil activation by colony-stimulating factor in man: metabolic effects and analysis by flow cytometry. Blood 1983;61 (6) 1232- 1241
PubMed
Metcalf  DParker  JChester  HMKincade  PW Formation of eosinophilic-like granulocytic colonies by mouse bone marrow cells in vitro. J Cell Physiol 1974;84 (2) 275- 289
PubMed Link to Article
Collins  PDMarleau  SGriffiths-Johnson  DAJose  PJWilliams  TJ Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med 1995;182 (4) 1169- 1174
PubMed Link to Article
Iwasaki  KTorisu  MFujimura  T Malignant tumor and eosinophils, I: prognostic significance in gastric cancer. Cancer 1986;58 (6) 1321- 1327
PubMed Link to Article
Pretlow  TPKeith  EFCryar  AK  et al.  Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res 1983;43 (6) 2997- 3000
PubMed
Slungaard  AAscensao  JZanjani  EJacob  HS Pulmonary carcinoma with eosinophilia. Demonstration of a tumor-derived eosinophilopoietic factor. N Engl J Med 1983;309 (13) 778- 781
PubMed Link to Article
Wardlaw  AJKA Eosinophils and their disorders. In: Beutler  E, Lichman  MA, Coller  BS, Kipps  TJ, eds. Williams Hematology. New York, NY: McGraw Hill; 2001:785

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
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