Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy

et al. (2013) Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy. PLoS ONE 8(3): e58217. doi:10.1371/journal.pone.0058217 Factors Associated with Esophageal Candidiasis and Its Endoscopic Severity in the Era of Antiretroviral Therapy So Nishimura 0 Naoyoshi Nagata 0 Takuro Shimbo 0 Naoki Asayama 0 Junichi Akiyama 0 Norio Ohmagari 0 Hirohisa Yazaki 0 Shinichi Oka 0 Naomi Uemura 0 Genevie`ve Chene, Institut National de la Sante et de la Recherche Medicale, France 0 1 Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital , Chiba , Japan , 2 Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan, 3 Department of Clinical Research and Informatics, International Clinical Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan, 4 Department of Infectious Disease, National Center for Global Health and Medicine, Tokyo, Japan, 5 Division of AIDS Clinical Center (ACC), National Center for Global Health and Medicine , Tokyo , Japan Background: Candidia esophagitis (CE) is an AIDS-defining condition, usually occurring in individuals with low CD4 counts of ,200 cells/mL. Endoscopy is a valuable definitive diagnostic method for CE but may not be indicated for asymptomatic patients or for those with high CD4 counts or without oral candidiasis. This study assessed such patients to clarify the factors associated with CE and its severity on endoscopy in the highly active antiretroviral therapy (HAART) era. Methodology/ Principal Findings: A total of 733 HIV-infected patients who underwent upper gastrointestinal (GI) endoscopy were analyzed. Sexual behavior, CD4+ count, HIV-RNA viral load (VL), history of HAART, GI symptoms, GI diseases, and oral candidiasis were assessed. Endoscopic severity of CE was classified as mild (Kodsi's grade I/II) or severe (grade III/IV). Of the 733 subjects, 62 (8.46%) were diagnosed with CE (mild, n = 33; severe, n = 29). Of them, 56.5% (35/62) had no GI symptoms, 30.6% (19/62) had CD4 + $200 cells/mL, and 55.3% (21/38) had no oral candidiasis. Univariate analysis found lower CD4+ counts, higher HIV VL, and no history of HAART to be significantly associated with CE. With lower CD4+ counts and higher HIV VL, CE occurrence increased significantly (P,0.01 for trend in odds). Multivariate analysis showed low CD4+ counts and high HIV VL to be independently associated with CE. Of the severe CE patients, 55.2% (16/29) had no GI symptoms and 44.4% (8/18) had no oral candidiasis. Median CD4+ counts in severe cases were significantly lower than in mild cases (27 vs. 80; P = 0.04). Conclusions: Low CD4+ counts and high HIV VL were found to be factors associated with CE, and advanced immunosuppression was associated with the development of severity. Endoscopy is useful as it can detect CE, even severe CE, in patients without GI symptoms, those with high CD4 counts, and those without oral candidiasis. - Funding: This study was partly supported by Medicine for Ministry of Health, Labour and Welfare, Health and Labour Sciences Research Grants, Research on Clinical Trials Infrastructure Development and grants for research and development in National Center for Global Health and Medicine. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Candida esophagitis (CE) is the most common infectious disease of the esophagus [13] and the most common gastrointestinal (GI) opportunistic disorder among individuals infected with human immunodeficiency virus (HIV) [4,5]. The prevalence of CE among HIV patients with esophageal symptoms who have undergone endoscopy was approximately 42% prior to the introduction of highly active antiretroviral therapy (HAART) [6]. Although the rate of AIDS-related opportunistic infections has decreased dramatically since, CE remains one of the most common AIDS defining illnesses [46]. Only a limited number of studies have investigated the associated factors of CE, and no study has yet been conducted with a large population of patients. In the pre-HAART era, a low CD4+ cell count (,200 cells/mL) was identified as one such associated factor [1,3,5,7,8]. In the HAART era, esophageal symptoms such as odynophagia and dysphagia are associated factors, while a CD4+ cell count .200, an HIV viral load ,400, and the presence of gastric ulcers are considered protective factors for CE [6]. The prevailing view is that a presumptive diagnosis of CE can usually be made following the recent onset of typical symptoms [7] or the presence of oral candidiasis, and empiric antifungal therapy can then be started as a diagnostic trial [7,9 11]. Endoscopy is a highly valuable definitive method for CE as it enables tissue biopsy and pathological and cultural examinations of specimens in addition to the evaluation of gross appearance [7,8,10,12]. However, under these conditions, endoscopy may not be indicated for asymptomatic patients, or for those with high CD4 cell counts or without oral candidiasis. The gross appearance and severity of CE on endoscopy can vary from small white plaques or confluent, linear, and nodular elevated plaques to thick white plaque cover on esophageal mucosa which may cause circumferential narrowing of the esophageal lumen [7,8,10,12]. However, the clinical factors associated with CE severity remain to be identified. In Japan, screening endoscopy is frequently performed for the early detection of malignant or premalignant lesions, even for asymptomatic patients. In this study, we performed endoscopy for a large number of HIV-infected patients including those with no GI symptoms, high CD4 counts, or no oral candidiasis. Materials and Methods Objectives We conducted a cross-sectional study to identify clinical factors associated with the diagnosis of CE. We also assessed the association between the severity of CE and clinical factors. Participants Upper gastrointestinal endoscopy was performed in a cohort of 752 HIV-infected patients between 2003 and 2009 at the National Center for Global Health and Medicine (NCGM), a 900-bed hospital located in the Tokyo metropolitan area and the largest referral center for HIV/AIDS in Japan. Indications for endoscopy were: 1) gastrointestinal symptoms in symptomatic patients; and 2) fecal occult blood test results, abnormal findings on CT or annual health checkups, or laboratory abnormal findings of tumor markers or infections suspicious of colorectal cancer in asymptomatic patients. In Japan, screening endoscopy is frequently performed for the early detection of malignant or premalignant lesions, even as part of the examination for patients who are asymptomatic. We excluded patien (...truncated)