Proton Pump Inhibitors and Corticosteroids as Synergistic Risk Factors for Candida Esophagitis

Introduction: Inhaled & systemic steroids are one of the well-documented risks factors for Candida esophagitis. However, the role of gastric acid suppression remains controversial. Methods: We conducted a retrospective case-control study of 420 patients consisting of 84 cases of Candida esophagitis and 336 matched controls. Our cohort was gathered from subjects evaluated from 2001 to 2012. The diagnosis of Candida esophagitis was based on endoscopic and/or histological criteria. Results: On univariate analysis, proton pump inhibitors were associated with higher risk (OR = 2.14; 95 % CI: 1.30 to 3.54); steroid use also increased the risk (OR = 3.55; 95% CI: 2.10 to 6.00). Furthermore, concurrent use of proton pump inhibitors & steroids substantially raised this risk (OR = 13.8; 95% CI 5.07 to 37.5), suggesting a synergistic effect. When adjusted for covariates (cancer, chemotherapy/radiation, antibiotic use, hypothyroidism, anemia, chronic liver disease & diabetes), anemia decreased the odds ratio for proton pump inhibitors to 1.67 (95% CI 1.02 to 2.75) and steroids to 1.69 (95% CI to 1.03 to 2.87). Hypothyroidism also substantially reduced the observed risk associated with steroid use. However, neither anemia nor hypothyroidism reduced the odds ratio for combined use of steroids and proton pump inhibitors. Conclusions: Our data suggests that patients who have been treated with steroids or proton pump inhibitors are at an increased risk for developing Candida esophagitis. Our data also suggests that steroids and proton pump inhibitors act synergistically to greatly increase the likelihood of Candida esophagitis.


INTRODUCTION
Esophageal candidiasis is known to occur in immuno-compromised patients, but has been less commonly reported in immuno-competent hosts. Esophageal candidiasis appears to occur when colonization of the esophagus is followed by subsequent invasion of the epithelial layer [1]. Colonization of the esophagus by Candida species is found in 20% of healthy adults [2][3][4][5]. A review by Ellepola et al. reported colonization with Candida species in 24-66% of patients using inhaled steroids [6]. It is one of the most common causes of infectious esophagitis [7][8][9]. Amongst Candida species, Candida albicans (C. albicans) is the most common & virulent causative organism, however, other species including C. tropicalis, C. krusei & C. stellatoidea have also been implicated [10].
There are multiple physiologic defense mechanisms that normally inhibit colonization. Such mechanisms include salivation, mechanical clearance of esophageal luminal contents, a mucosal barrier, an intact pH gradient including gastric acidity, and normal bacterial and fungal flora. Proton pump inhibitors (PPIs) alter the gastric pH. In the study by Karmeli et al. [11] the gastric pH in patients treated with omeprazole was found to be greater than 4.5, which may predispose to floral migration and colonization of the stomach by oral bacteria and yeasts. Additionally, PPIs also decrease salivary secretion and subsequent clearance of esophageal luminal contents.
In recent years, the use of PPIs has increased because of a number of contributing factors. Easy availability as an over the counter medication, generic formulation, low cost, increased incidence of dyspepsia, and gastroesophageal reflux disease (GERD), as well as the use of non-steroidal anti-inflammatory agents. PPIs are considered to be relatively safe and thus very commonly prescribed to treat conditions like gastritis, dyspepsia, GERD, duodenal ulcers, esophagitis and utilized in stress ulcer prophylaxis in hospitalized patients.
Recent studies have suggested an association of PPIs with CE [1,11,15,23]. This class of drugs produces hypochlorhydria, which alters the physiologic gastric and esophageal environment and skews the balance of normal flora. This altered environment predisposes to commensal colonization by oral bacteria and yeast. Histamine Type-2 antagonists (H2 blockers), and prior vagotomy may have similar implications [21,24]. Oropharyngeal candidiasis is a welldocumented side effect of inhaled steroids [4][5][6]22]. However limited data exists regarding the development of esophageal candidiasis in association with PPI use. The main aim of our study is to explore the association between the use of PPIs, corticosteroids and the risk of CE.

Subjects
We retrospectively identified 84 patients who were diagnosed with CE after undergoing upper endoscopy at our facilities between January 2001 and January 2012.The diagnosis of CE was made on the basis of endoscopy. These patients were further matched with 336 patients who underwent upper endoscopy but had no CE (controls) based upon age and gender. We excluded all known Human immunodeficiency Virus (HIV) infected patients from our study.

Protocol
The study was conducted at two academic Medical Centers in the north eastern United States. The protocol was approved by the Institutional Review Board of the Saint Joseph's Regional Medical Center in Paterson, New Jersey and Trinitas Regional Medical Center in Elizabeth New Jersey. The data gathered included patient demographics (age and sex), Human Immunodeficiency Virus (HIV) status, recent use of PPIs, H2 blockers, antibiotics, inhaled or systemic corticosteroids, history of diabetes mellitus, chronic liver disease, carcinoma, hypothyroidism, chemotherapy, radiation therapy, hypertension and anemia.

Statistical Methods
Descriptive statistics for interval data (age) were evaluated for fit-to normality by the D'Agostino-Pearson omnibus normality test and found to not fit a normal distribution. Thus, age is expressed as median and interquartile range (IQR) and ages for cases and controls were compared by a nonparametric test (Mann-Whitney). Categorical data were described as counts and percents and were evaluated for group-wise differences by Fisher's exact test for all univariate comparisons. As the study was conducted retrospectively, the effect size measurement used was the odds ratio (OR) and 95% CI. Multivariable analysis of exposures and outcomes were made using a binary logistic regression (BLR) mode, l which included as covariates any baseline characteristic deemed to be a potential confounder using p≤0.25 as the criterion for inclusion. This approach was used to estimate adjusted OR and 95% CI, as well as significant interaction between covariates and primary exposures. Rejection of the null hypothesis was based on a two-sided p-value ≤ 0.05 or exclusion of unity from the 95% 95% CI of the OR. Calculations were made using Prism® v. 5.04 (GraphPad Corp. San Diego, CA) and SPSS v. 21 (IBM Corp. Armonk, NY).

Characteristics of Cases and Controls
The baseline characteristics of cases and controls are given in Table 1. Few patients who were included in the study used H2 blockers, were recently post-operative or had evidence of rheumatologic disease. Thus, these characteristics could not be expected to demonstrate significant differences. Hypertensive subjects represented 55.9% of cases and 50.5% of controls; this difference was neither statistically significant nor within our criterion for inclusion in the BLR model. All other characteristics were, therefore, considered as potential confounders and included in the model.

PPIs and Corticosteroids as Risk Factors
The OR and 95% CI for the univariate analysis and adjusted OR are shown in Fig. 1. Upon performing univariate analysis, PPIs were associated with a higher risk of CE (OR = 2.14; 95% CI: 1.30 to 3.54); steroid use also  Fig. 1A, top panel), steroid use as primary exposure (Fig. 1B, middle panel) and combined use of PPI and steroids vs. use of neither (Fig. 1C, bottom  Hypothyroidism also substantially reduced the observed risk associated with steroid use. However, neither anemia nor hypothyroidism reduced the odds ratio for combined use of steroids and PPI. This OR was not affected to any extent by the presence of cancer, diabetes, antibiotic use or chemotherapy or radiation therapy. There was a slight, but insignificant increase in the OR adjusted for anemia and a similarly insignificant decrease in the OR adjusted for hypothyroidism. Chronic liver disease increased the odds of CE by 38%; however, despite this apparently large effect on the OR for combined use of PPI and steroids, the interaction term was not statistically significant, most likely due to the extremely large confidence interval. In this retrospective case control study involving eighty-four non-HIV/AIDS patients with CE, we found that previously recognized risk factors like steroid therapy, diabetes (type I and II), carcinoma, chemotherapy/radiation, hypothyroidism, antibiotics and chronic liver disease did correlate with the development of esophageal candidiasis. However, the most prominent finding was the synergistic risk of PPIs and steroid use with the prevalence of CE.
There is scant published evidence reporting the relationship between esophageal candidiasis and PPIs [1,11,15,23]. The relationship of inhaled and/or intravenous steroid and esophageal candidiasis is better documented in the literature [4,5,6,22]. Fidan et al. [4] reported a 42.9% frequency of esophageal candidiasis in a 21person cohort compared to a 0.2% rate in their control group. Kanda et al. [22] (n=49) reported a 37% prevalence of esophageal candidiasis in patients using inhaled fluticasone propionate compared to 0.3% of controls. To our knowledge this is the only case control study so far, analyzing the association of PPIs and steroids use with CE. Our study has certain limitations. It is a retrospective study and it does not specify duration of exposure to PPIs. Finally, it does not stratify for active comorbidities, which may increase the risk of CE. Moreover, as is the case with any case-control study, controls with active exposure to risk factors preclude a true association with risk. The observation that anemia and hypothyroidism both have the effect of decreasing the adjusted OR for PPI and steroids. One should consider the possibility that these are merely secondary effects of therapeutic approaches to these comorbidities rather than effects directly attributable to the specific comorbidity. We did not examine that prospect and suggest that a larger, prospective cohort study, stratifying covariates by duration/intensity as well as additional exposures attendant to these covariates, might provide additional insight into this issue.

CONCLUSION
Our data suggests that patients who have been treated with steroids or proton pump inhibitors are at an increased risk for developing Candida esophagitis. Our data also suggests that steroids and proton pump inhibitors act synergistically to greatly increase the likelihood of Candida esophagitis. So on the basis of this finding we recommend that PPIs be used judiciously, only in clinical conditions where they are indicated and have been proven efficacious. Also physicians should re-evaluate patients at each clinical encounter for the possibility of PPI and/or corticosteroid therapy discontinuation.

CONSENT
It is not applicable (This is a retrospective study).

ETHICAL APPROVAL
All authors hereby declare that all experiments have been examined and approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.