Diagnostic Approach for Classic Compared With Localized Whipple Disease

Open Forum Infectious Diseases MAJOR ARTICLE Diagnostic Approach for Classic Compared With Localized Whipple Disease Nicholas R. Crews,1 Kelly A. Cawcutt,2 Bobbi S. Pritt,3,4 Robin Patel,3,4 and Abinash Virk3 1 Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana; 2Divisions of Infectious Diseases and Pulmonary and Critical Care, University of Nebraska Medical Center, Omaha, Nebraska; 3Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; 4Division of Clinical Microbiology, Mayo Clinic, Rochester, Minnesota Background. Whipple disease (WD), a rare systemic infection caused by Tropheryma whipplei, can be a diagnostic challenge due to its variable presentation. The role of T. whipplei polymerase chain reaction (PCR) is unclear as small bowel biopsy with Periodic acid-Schiff (PAS) staining remains the diagnostic gold standard. Individualized diagnostic approaches based on variable clinical manifestations are underutilized. We investigated the methodologies employed at our institution to diagnose WD. Methods. We retrospectively collected all cases of WD diagnosed from 1994 to 2016. Microbiology laboratory and anatomic pathology databases were queried. Case characteristics and disease clinical phenotypes (classical, localized WD arthritis, and localized central nervous system [CNS] disease) were described. The diagnostic approach and testing yield were analyzed and reported. Results. Thirty-three cases of WD were diagnosed (18 classic WD [CWD], 9 localized WD arthritis [LWD], 6 CNS WD). Misdiagnosis and delay in diagnosis were frequent. Diagnostic approach and test yield differed by classical vs localized WD involvement. Small bowel tissue biopsy PAS stain/PCR was overwhelmingly positive (86%/92%) in CWD, yet seldom positive (12%/42%) in LWD (P < .001). Affected joint synovial fluid PCR was frequently positive in both CWD (100%, 3/3) and LWD (85%, 6/7). Conclusions. These results support the role of small bowel biopsy PAS stain/PCR in the diagnosis of CW, though this approach may be of limited utility in LWD or CNS WD without gastrointestinal symptoms. Affected joint synovial fluid or cerebrospinal fluid PCR was frequently positive in both CWD and LWD, supporting its diagnostic usefulness. Keywords. diagnostics; PAS; PCR; Tropheryma whipplei; Whipple disease. Whipple disease (WD) is a chronic infection caused by Tropheryma whipplei [1]. In 1949, Black-Schaffer first described the classic WD (CWD) histologic finding of Periodic acid-Schiff (PAS)–positive macrophages within the intestinal mucosa and lymph nodes, which was later correlated with the presence of T. whipplei bacilli within the macrophage cytoplasm [2, 3]. Subsequently, PAS staining of formalin-fixed paraffin-embedded (FFPE) small bowel (SB) tissue became the standard WD diagnostic test and is commonly followed by amylase or diastase treatment (ie, PAS-D) to remove glycogen to aid in detection of T. whipplei bacilli. Since the identification of T. whipplei in 1992, polymerase chain reaction (PCR) assays targeting T. whipplei have been developed with excellent sensitivity [4–8]. Additional methods include organism cell culture and immunohistochemical staining, although neither is practical or commonly available [9, 10]. Despite these advances, WD remains a Received 9 April 2018; editorial decision 29 May 2018; accepted 8 June 2018. Correspondence: A. Virk, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (). Open Forum Infectious Diseases® © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact DOI: 10.1093/ofid/ofy136 diagnostic challenge due to its rarity and variable presentation, resulting in delayed or missed diagnosis [1, 11, 12]. Fewer than 2000 WD cases have been reported in the literature since WD was first described [13]. The majority were classified as CWD, in which nonspecific gastrointestinal manifestations predominate after a period of prodromal joint involvement and constitutional symptoms [1, 11]. CWD frequently involves the nervous system, with 10%–46% of patients developing neurologic symptoms, and less commonly affects the endocardium, uvea, lymphatic system, pulmonary parenchyma, and pleural cavities [13–15]. In contrast, localized WD (LWD) without classic gastrointestinal involvement (including isolated T. whipplei endocarditis, polyarticular inflammatory arthritis, or localized neurologic infection) is becoming increasingly recognized, particularly since the advent of T. whipplei PCR, which can be performed on a variety of tissues and body fluids [1, 16–20]. The role of PCR in the WD diagnostic paradigm remains unclear. Intestinal tissue PCR has been traditionally ordered as a confirmatory test after PAS staining in CWD cases [11]. Some have recommended PCR in parallel to PAS staining [8, 21]. Individualized diagnostic approaches for localized T. whipplei infection have not been fully investigated and thus are likely underutilized. Recent series report SB PAS stain and PCR positivity in only 39%–48% and 55%–93% of CWD cases without typical gastrointestinal symptoms, respectively [11, 16]. T. whipplei synovial fluid PCR has been proposed as the Diagnostic Approach for Whipple Disease • OFID • 1 firstline diagnostic test for seronegative arthritis [17, 22, 23]. Cerebrospinal fluid (CSF) PCR has been recommended when central nervous system (CNS) WD is suspected or in asymptomatic patients, yet its role and usage in WD diagnosis are unclear [11, 24, 25]. We retrospectively investigated diagnostic approaches and methodologies employed at our institution to diagnose WD from 1994 to 2016; 1994 was selected as the start date as T. whipplei PCR has been offered routinely at our institution since 1994. We aimed to assess the various testing yields and diagnostic methods employed based on variations in clinical manifestations, comparing classic with nonclassic cases. involvement of the gastrointestinal system, joints, cardiopulmonary system, lymphatic system, and/or CNS. LWD arthritis and CNS WD were defined as the presence of primarily joint or CNS involvement, respectively, with or without prodromal or constitutional symptoms, with minimal, if any, other organ involvement, particularly gastrointestinal manifestations. Results were analyzed using descriptive statistics and likelihood ratio analysis to compare diagnostic test yield. Standard statistical software (JMP, version 12, SAS Institute, Cary, NC) was used for analysis. This study was approved (...truncated)