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Diagnostic Approach for Classic Compared With Localized Whipple Disease

Diagnostic Approach for Classic Compared With Localized Whipple Disease Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Open Forum Infectious Diseases MAJOR ARTICLE Diagnostic Approach for Classic Compared With Localized Whipple Disease 1 2 3,4 3,4 3 Nicholas R. Crews, Kelly A. Cawcutt, Bobbi S. Pritt, Robin Patel, and Abinash Virk 1 2 Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana; Divisions of Infectious Diseases and Pulmonary and Critical Care, University of Nebraska Medical Center, 3 4 Omaha, Nebraska; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; Division 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 local- ized 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 involve- ment. Small bowel tissue biopsy PAS stain/PCR was overwhelmingly positive (86%/92%) in CWD, yet seldom positive (12%/42%) in LWD (P < .001). Ae ff cted joint synovial fluid PCR was frequently positive in both CWD (100%, 3/3) and LWD (85%, 6/7). Conclusions. es Th e 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. Ae ff cted 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 diagnostic challenge due to its rarity and variable presentation, Tropheryma whipplei [1]. In 1949, Black-Schaer fir ff st described resulting in delayed or missed diagnosis [1, 11, 12]. the classic WD (CWD) histologic finding of Periodic acid-Schiff Fewer than 2000 WD cases have been reported in the literature (PAS)–positive macrophages within the intestinal mucosa and since WD was first described [13]. The majority were classified lymph nodes, which was later correlated with the presence of as CWD, in which nonspecific gastrointestinal manifestations T.  whipplei bacilli within the macrophage cytoplasm [2, 3]. predominate aer a p ft eriod of prodromal joint involvement and Subsequently, PAS staining of formalin-fixed paraffin-embed- constitutional symptoms [1, 11]. CWD frequently involves the ded (FFPE) small bowel (SB) tissue became the standard WD nervous system, with 10%–46% of patients developing neuro- diagnostic test and is commonly followed by amylase or dia- logic symptoms, and less commonly ae ff cts the endocardium, stase treatment (ie, PAS-D) to remove glycogen to aid in detec- uvea, lymphatic system, pulmonary parenchyma, and pleural tion of T. whipplei bacilli. Since the identification of T. whipplei cavities [13–15]. In contrast, localized WD (LWD) without clas- in 1992, polymerase chain reaction (PCR) assays targeting sic gastrointestinal involvement (including isolated T.  whipplei endocarditis, polyarticular inflammatory arthritis, or localized T. whipplei have been developed with excellent sensitivity [4–8]. neurologic infection) is becoming increasingly recognized, par- Additional methods include organism cell culture and immu- ticularly since the advent of T. whipplei PCR, which can be per- nohistochemical staining, although neither is practical or com- formed on a variety of tissues and body fluids [1, 16–20]. monly available [9, 10]. Despite these advances, WD remains a e r Th ole of PCR in the WD diagnostic paradigm remains unclear. Intestinal tissue PCR has been traditionally ordered Received 9 April 2018; editorial decision 29 May 2018; accepted 8 June 2018. as a confirmatory test aer ft PAS staining in CWD cases [11]. Correspondence: A. Virk, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (virka@mayo.edu). Some have recommended PCR in parallel to PAS staining Open Forum Infectious Diseases [8, 21]. Individualized diagnostic approaches for localized © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases T.  whipplei infection have not been fully investigated and thus Society of America. This is an Open Access article distributed under the terms of the Creative are likely underutilized. Recent series report SB PAS stain and 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 PCR positivity in only 39%–48% and 55%–93% of CWD cases medium, provided the original work is not altered or transformed in any way, and that the work without typical gastrointestinal symptoms, respectively [11, is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy136 16]. T.  whipplei synovial fluid PCR has been proposed as the Diagnostic Approach for Whipple Disease • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 firstline diagnostic test for seronegative arthritis [17, 22, 23]. involvement of the gastrointestinal system, joints, cardiopul- Cerebrospinal fluid (CSF) PCR has been recommended when monary system, lymphatic system, and/or CNS. LWD arthritis central nervous system (CNS) WD is suspected or in asymp- and CNS WD were defined as the presence of primarily joint tomatic patients, yet its role and usage in WD diagnosis are or CNS involvement, respectively, with or without prodromal unclear [11, 24, 25]. or constitutional symptoms, with minimal, if any, other organ We retrospectively investigated diagnostic approaches involvement, particularly gastrointestinal manifestations. and methodologies employed at our institution to diagnose Results were analyzed using descriptive statistics and likelihood WD from 1994 to 2016; 1994 was selected as the start date as ratio analysis to compare diagnostic test yield. Standard statis- T.  whipplei PCR has been oer ff ed routinely at our institution tical software (JMP, version 12, SAS Institute, Cary, NC) was since 1994. We aimed to assess the various testing yields and used for analysis. This study was approved by the Mayo Clinic diagnostic methods employed based on variations in clinical Institutional Review Board. manifestations, comparing classic with nonclassic cases. RESULTS METHODS Retrospective database searches yielded 35 cases of WD with We retrospectively collected all WD cases diagnosed at the 47 positive T.  whipplei PCR results, 16 positive PAS SB biopsy Mayo Clinic between 1994 (when T. whipplei PCR became avail- results, and 2 PAS-positive endocardial tissue biopsies consist- able at our institution) and January 1, 2016. The PCR method- ent with WD. Two cases (each with 1 single positive blood PCR) ologies used at our institution since 1994 have been previously were excluded from further analysis because neither patient described [26]. Microbiology laboratory databases were que- demonstrated WD symptoms, nor were they treated for WD. ried for positive T. whipplei PCR results performed at our insti- Thus, 33 WD cases were diagnosed at our institution from tution during the study period. Anatomic pathology databases 1994 to January 2016, with 2 being reported previously [27, 28]. were queried for the terms “Whipple disease” AND “positive” Eighteen patients (55%) had CWD, 9 (27%) had LWD arthritis, AND/OR “consistent.” These findings were confirmed against and 6 (18%) had localized CNS WD. a separate query of the same database for the terms “PAS” OR e co Th hort consisted of 28 (85%) males with a mean (SD) “PAS-D” AND “positive.” Duplicate results, testing ordered by age of 52 (13) years at the time of diagnosis. Table  1 reports providers external to our institution, and tests to confirm dis- patient characteristics and symptoms by disease manifestation. ease relapse were excluded. These queries were confirmed by Diagnosis was confirmed a median (range) of 4.6 (0.6–22.5) cross-checking against a query of WD cases in our electronic years aer p ft rodromal symptoms presented. Mean (IQ1, 3) time medical record (EMR). The EMR was reviewed to ascertain from initial presentation to our institution to diagnosis was WD symptoms, diagnosis, treatment, and response to therapy. 3 (3, 8.25) months, though diagnosis was delayed more than Additional data obtained included demographics, clinical 1 year aer p ft resentation in 5 cases. Table 2 displays initial and manifestations, medical specialty (initial and diagnosing), lab- confirmatory testing results for each case. Previous misdiagno- oratory, imaging, and WD diagnostic testing. Diagnostic meth- sis was common, including seronegative inflammatory arth- odology and test results were stratified by CWD, LWD arthritis, ritis (n  =  5), rheumatoid arthritis (n  =  2), sarcoidosis (n  =  2), and CNS WD. CWD was defined as systemic disease involve- adult Still disease (n  =  1), polymyalgia rheumatica (n  =  1), ment with prodromal symptoms in addition to multiple-organ chronic Lyme disease (n = 1), and chronic meningitis (n = 1). Table 1. Differences in Clinical Data for 33 WD Patients by Whipple Disease Type: Classic vs Localized Characteristics Classic WD (n = 18) Localized WD Arthritis (n = 9) Localized CNS WD (n = 6) Male, No. (%) 17 (94) 7 (78%) 4 (67) Mean age (SD), y 52 (13) 46 (15) 56 (9.3) Median time from initial symptoms to diagnosis (IQ1,3), y 5.4 (2.6, 6.8) 5.8 (1.4, 6.3) 2.7 (1.5, 3.5) Previously immunosuppressed, No. (%) 7 (39) 6 (67) 2 (33) General systemic involvement, No. (%) 18 (100) 4 (44) 5 (83) GI involvement, No. (%) 16 (89) 0 (0) 1 (16) Joint involvement, No. (%) 17 (94) 9 (100) 1 (16) Cardiac involvement, No. (%) 3 (17) 0 (0) 0 (0) CNS involvement, No. (%) 1 (11) 2 (22) 6 (100) Anemia, No. (%) 17 (94) 3 (33) 4 (67) Elevated inflammatory markers, No. (%) 15 (93) 4 (44) 1 (25) Fat soluble vitamin deficiencies, No. (%) 7 (58) 0 (0) 1 (33) Abbreviations: CNS, central nervous system; GI, gastrointestinal; WD, Whipple disease. 2 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Table 2. Diagnostic Approach With Initial and Confirmatory Diagnostic Test Results by Whipple Disease Type: Classic vs Localized Confirmator y Tests Small Bowel Synovial Case WD Type Initial Diagnostic Test Initial Test Result PAS/PCR Fluid PCR CSF PCR Blood PCR Other PCR 1 CNS WD SB PAS/PCR +/+ + 2 CWD SF PCR + +/+ - - - 3 CWD SB PAS/PCR +/+ + 4 CWD SB PAS/PCR +/+ + 5 CWD SB PAS/PCR +/+ + 6 CWD SB PAS/PCR +/+ + 7 CWD SB PAS + 8 LWD SB PAS + 9 CNS WD CSF PCR + -/+ - 10 CNS WD CSF PCR + -/- 11 LWD SF PCR + -/- - 12 CNS WD CSF PCR + -/- 13 LWD SF PCR + -/+ 14 LWD SF PCR + + 15 CWD SB PAS/PCR +/+ 16 LWD SB PAS/PCR -/+ - - 17 LWD Blood PCR + -/- + 18 CNS WD CSF PCR + -/- 19 CWD SB PAS/PCR +/+ 20 CNS WD SB PAS - + + 21 CWD SB PAS/PCR -/- + + 22 LWD SF PCR + -/- 23 CWD SB PAS/PCR -/+ + + 24 LWD SB PAS/PCR -/- + - - 25 CWD Endocardial biopsy PAS/PCR +/+ +/+ - 26 CWD SB PAS/PCR +/+ 27 CWD SF PCR + - 28 LWD SB PAS/PCR -/+ - - 29 CWD Endocardial biopsy PAS/PCR +/+ + 30 CWD SB PAS/PCR +/+ - - 31 CWD SB PAS + + 32 CWD SB PAS/PCR +/+ 33 CWD SF PCR + - - + indicates positive result. – indicates negative result. Blank space indicates test not performed. Abbreviations: CNS WD, localized T. whipplei central nervous system infection; CSF, cerebrospinal fluid; CWD, classic Whipple disease; LWD, localized T. whipplei arthritis; PAS, Periodic acid-Schiff; PCR, polymerase chain reaction; SB, small bowel; SF, synovial fluid.  Other PCR includes 2 vitreous aqueous humor fluid PCRs (1 negative and one positive), 1 lymph node tissue specimen PCR (positive), and 1 arterial thrombus surgical pathology speci- men PCR (positive). Furthermore, 43% of patients were prescribed immunosup- Additionally, 17 of 18 (94%) patients with CWD had prodro- pressive therapy for misdiagnosis treatment. Chronic therapy mal arthralgias for an average of 72  months before presenta- for T.  whipplei included 1 or more of the following: penicillin, tion, whereas 89% had nonspecific gastrointestinal symptoms, tetracycline, doxycycline, ceftriaxone, and trimethoprim/sul - including intermittent abdominal pain, chronic diarrhea, and/or famethoxazole. Patients were followed for a mean (SD) of 10.5 weight loss. Five patients with CWD had developed neurologic (7.3) years aer di ft agnosis, during which 4 patients had WD manifestations, including cognitive impairment, psychiatric relapse and 6 died, all of non-WD-related causes. changes, and/or movement abnormalities. Lymphadenopathy was present, clinically or on radiographic imaging, in 7 CWD Classic Whipple Disease cases. Additional manifestations among CWD patients included At the time of diagnosis, all patients with CWD reported sys- endocarditis (n  =  2), pericarditis (n  =  1), arterial thrombus temic symptoms including intermittent fevers, fatigue, chills, (n = 1), and fat-soluble vitamin deficiencies (n = 7). and/or night sweats, whereas elevated inflammatory markers e ini Th tial diagnostic test obtained was SB biopsy with PAS and anemia were found in 83% and 94% of cases, respectively. staining in 13 of 18 CWD cases with 11 (85%) positive results Diagnostic Approach for Whipple Disease • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Localized T. whipplei CNS Infection (Table  2); 7/12 (63%) of the biopsies were obtained from the Six patients with localized CNS WD presented with cognitive duodenum while rest were from the jejunum, stomach, mesen- deficits, psychiatric symptoms, movement abnormalities, and/ teric lymph nodes, lymph nodes, parietal pericardium, terminal or supranuclear ophthalmoplegia. Uveitis was present in 1 case ileum, or colon, with tissue obtained from multiple locations [28]. Only 1 patient had gastrointestinal symptoms (abdom- in some patients. Both negative results were in the setting of inal pain); none had diarrhea or weight loss. Systemic symp- antibiotics for more than 30 days before biopsy, prescribed for toms including fever, asthenia, fatigue, and chills were present presumed chronic Lyme disease and Pneumocystis jirovecii in 5 cases. Laboratory abnormalities included anemia (n  =  4), pneumonia prophylaxis for chronic immunosuppression for elevated inflammatory markers (n = 1), and vitamin B12 defi- presumed seronegative arthritis. Duodenal PCR was ordered in ciency (n  =  1). Residual neurologic deficits were noted in 3 parallel to PAS stain in 11 cases (10 were positive and 1 neg- cases after treatment, with 1 relapse. ative in a case with a negative PAS stain). The 2 patients with e ini Th tial diagnostic test was lumbar puncture for CSF PCR negative duodenal PAS stains were diagnosed by PCR (case 1: in 4 of 6 cases, with 4/4 positive (Table 2). Confirmation of diag- blood and lymph node tissue specimen; case 2: blood and arter- nosis was pursued in all 4 cases with SB PAS stain/PCR (1/4 ial thrombus). Additional diagnostic tests ordered in these 13 PCR and 0/4 PAS stain positive). SB biopsy was the initial diag- cases included 1 negative vitreous aqueous humor PCR and 9 nostic test in the other 2 CNS WD cases. In 1 case, duodenal blood PCRs (3 positive). CSF PCR was performed in 4 of the 5 PAS was nonreactive (PCR not performed), but blood and patients with neurologic manifestations (1 positive). vitreous aqueous humor fluid PCR were positive; CSF was not Five patients with CWD did not undergo SB sampling as the tested. In the second case, duodenal PAS/PCR were positive on initial diagnostic test. Two patients with endocarditis were diag- initial testing, and subsequently CSF PCR was positive. nosed with positive endocardial tissue PAS stain and PCR. One case was confirmed with blood PCR; the other case was con- Diagnostic Approach and Comparison of Results firmed with positive duodenal PAS stain, and PCR aer b ft lood The 33 WD patients initially presented to 11 different medical PCR was negative. The other 3 patients were diagnosed aer ft specialties: rheumatology (n = 8), neurology (n = 7), gastroen- undergoing arthrocentesis with positive synovial fluid PCR. terology (n = 5), hematology (n = 4), general medicine (n = 4), One of these 3 subsequently underwent confirmatory SB testing cardiology (n = 1), ophthalmology (n = 1), pulmonology (n = 1), with positive duodenal PAS stain and PCR. infectious disease (n = 1), and endocrinology (n = 1) (Figure 1). When initial presentation was to rheumatology, neurology, or Localized T. whipplei Arthritis gastroenterology, the diagnosis was made by that specialist in Nine patients with localized T.  whipplei arthritis reported 19 of 20 cases (Figure  2). In these 20 cases, consultation from arthralgias for a median (range) of 5.0 (1.0–22) years before a second specialist was requested in 8 cases (gastroenterology presentation to our institution. None reported gastrointestinal [n  =  3], rheumatology [n  =  2], infectious disease [n  =  2], and symptoms (abdominal pain, chronic diarrhea, or weight loss), neurology [n  =  1]). In the other 13 cases, consultation from a whereas 2 reported minor cognitive changes (memory loss). gastroenterologist or rheumatologist was requested in 11 cases. Four had intermittent systemic symptoms of fatigue, night Small bowel testing with PAS stain and/or PCR was ordered sweats, and/or asthenia. None reported weight loss or devel- as the initial WD test in 18 of 33 (55%) cases but ordered by oped vitamin deficiencies, but elevated inflammatory markers were present in 4. In 4 of the 9 LWD cases, the initial diagnostic test was syno- Infectious disease vial fluid PCR with 4/4 positive (Table 2). Small bowel PAS stain Endocrinology and PCR were ordered to confirm the initial result in 3 of these Pulmonology 4 cases (1/3 PCR and 0/3 PAS stain positive). Four patients Ophthalmology Cardiology underwent initial testing with SB PAS stain; PCR was ordered in General medicine parallel to PAS in 3 of 4 cases. Results were PAS (without PCR) Hematology positive in 1 case, negative PAS/positive PCR in 2 cases, and Neurology negative PCR/negative PAS in 1 case (diagnosis subsequently Rheumatology made with positive synovial fluid PCR). One patient initially Gastroenterology diagnosed with blood PCR was confirmed by positive syno- 02468 10 12 vial fluid PCR. CSF PCR was negative in the 2 patients report- Number of patiens ing cognitive deficits. Synovial fluid total nucleated cell count Diagnosing subspecialty Initial subspecialty ranged from 208 to 45 708 cells/mcL (median, 3016 cells/mcL), with the polymorphonuclear cell percentage ranging from 13% Figure  1. Proportion of medical subspecialties that initially evaluated and ulti- to 86% (median, 75%). mately diagnosed 33 patients with Whipple disease. 4 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Card Endo GI Hem ID IM Neuro Opht Pulm Rheum Consults requested by initial evaluating medical subspecialty Figure 2. Proportion of medical subspecialties consulted by initially evaluating subspecialty in 33 patients with Whipple disease. Abbreviations: Card, cardiology; Endo, endocrinology; GI, gastroenterology; Hem, hematology; ID, infectious diseases; IM, internal medicine; Neuro, neurology; Opht, ophthalmology; Pulm, pulmonology; Rheum, rheumatology. a gastroenterologist in 4 (22%) cases. When CSF or synovial 3/3) and localized T. whipplei arthritis (83%, 5/6; P = .35). CSF uid PCR wa fl s obtained as the initial WD test, these diagnostics PCR was positive in 100% (5/5) of CNS WD cases, whereas it were almost exclusively (10/11 cases) ordered by a neurologist was only positive in 25% (1/4) of CWD patients with neurologic or rheumatologist, respectively. Confirmatory testing with a symptoms (P  =  .009). CSF PCR was negative in patients with different method was pursued in 31 of the 33 cases with a 64% localized T.  whipplei arthritis with cognitive changes. Blood positive rate. PCR lacked sensitivity in CWD and LWD cases (CWD: 54%, 6/11, including 50%, 1/2, positivity in 2 cases of endocarditis; Differences in Diagnostic Test Results T. whipplei arthritis: 33%, 2/6; CNS WD: 50%, 1/2; P = .69). Table 3 reports diagnostic test yields for CWD, LWD, and CNS WD. Duodenal PAS stain was overwhelmingly positive (86%) DISCUSSION in the 18 CWD cases; however, it was rarely positive (13%) in We report 33 WD cases diagnosed at our institution from 1994 the 15 non-CWD cases with minimal, if any, gastrointestinal to 2016, which is to our knowledge the largest series of American manifestations (P < .001). Small bowel PCR was positive in 42% WD cases reported since the development of T.  whipplei PCR. (5/12) of localized WD cases without diarrhea compared with Eighteen patients (55%) were diagnosed with CWD, 9 (27%) 13% PAS stain reactivity (P = .018). Duodenal PAS stain reac- with localized WD arthritis, and 6 (18%) with localized CNS tivity was similar in LWD arthritis (12%, 1/8) and CNS WD WD. These results support the role of PAS stain and PCR of cases (17%, 1/6). Similarly, duodenal PCR positivity rates were duodenal tissue in the diagnosis of CWD. Although 5 patients comparable in LWD (42%, 3/7) and CNS WD cases (40%, 2/5). did not have histological findings on small-bowel biopsies or did Synovial fluid PCR testing was high yield, with positive not have a biopsy done at all, their symptoms and PCR positivity results in 89% (8/9) of patients with arthritis. Synovial fluid PCR from other sites were consistent with CWD. This is consistent positivity rates were comparable in patients with CWD (100%, Table 3. Diagnostic Test Yields Differ by Classic vs Localized Whipple Disease Classic WD (n = 18), No. Positive/ Localized WD Arthritis (n = 9), No. Localized CNS WD (n = 6), No. No. Tested (%) Positive/No. Tested (%) Positive/No. Tested (%) P Value a * Small bowel biopsy PAS stain 13/15 (86) 1/8 (12) 1/6 (17) <.001 Small bowel biopsy PCR 12/13 (92) 3/7 (42) 2/5 (40) .018 Synovial fluid PCR 3/3 (100) 6/7 (85) 0/0 (0) .35 Cerebrospinal fluid PCR 1/4 (25) 0/2 (0) 5/5 (100) .009 Blood PCR 7/12 (58) 2/6 (33) 1/2 (50) .69 Other PCR 4/5 (80) 0/0 (0) 1/1 (100) .52 Abbreviations: CNS, central nervous system; PAS, Periodic acid-Schiff; PCR, polymerase chain reaction; WD, Whipple disease. P value considered significant if <.05. Other PCR included 2 vitreous aqueous humor fluid PCRs (1 negative and 1 positive), 1 lymph node tissue specimen PCR (positive), and 1 arterial thrombus surgical pathology specimen PCR (positive). Diagnostic Approach for Whipple Disease • OFID • 5 Number of patients Rheum GI Neuro Rheum (none) ID Neuro Rheum (none) GI Rheum (none) GI ID (none) (none) (none) GI ID (none) Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 with findings in the largest series of CWD, which showed that synovial fluid or CSF fluid were ordered by a rheumatologist or in 91% of 191 cases of CWD, the duodenum had characteris- neurologist, respectively. With the increased awareness of the tic histological changes in SB biopsies [11]. However, the diag- diagnostic value of WD PCR testing, we expect an increase in nostic yield of SB PAS stain, and PCR to a lesser degree, was familiarity of synovial fluid– and CSF fluid–based T.  whipplei decreased in non-CWD cases without gastrointestinal involve- PCR testing. It is difficult to develop a 1-size-fits-all diagnos- ment. Diagnosis in non-CWD was most often made by positive tic scheme for WD; however, this study supports the use of PCR of blood, CSF, synovial fluid, or other tissue, suggesting extra-intestinal PCR testing and early referral to gastroenterol- that a combination of clinical suspicion for WD and sampling ogy, rheumatology, or neurology to mitigate delay in diagnosis. of potentially affected sites is helpful in diagnosis even in the Potential limitations exist in our study. Physician practices absence of SB PAS stain or PCR positivity. Affected joint syno- could have been influenced by progression in medical knowl- vial fluid PCR was frequently positive in both CWD and LWD. edge over 2 and a half decades, thus potentially aeff cting Blood PCR was poorly sensitive in all WD cases, irrespective diagnostic paradigms. Temporal trends of diagnostic meth- of classical or local disease involvement, including endocardi- odologies were not assessed but could be evaluated in future tis. There were 2 apparently false-positive blood PCR results in investigations. Although the PCR assay evolved from a conven- this study. Stool and saliva PCR were not performed at the Mayo tional PCR assay to a real-time PCR assay over the study period, Clinic as a routine clinical test during the study period. clinical performance characteristics did not change. Similarly, This cohort includes a significant proportion (45%) of cases PAS staining on FFPE tissue remained unchanged during this with LWD, which is greater than the proportion reported in time frame. European studies. Gunther et  al. reported only CWD cases, In conclusion, this study reports the test yield and diagnostic with few nonintestinal PCR tests, whereas Lagier and colleagues paradigms employed by physicians at our institution for WD reported 80% CWD cases and 20% isolated WD cases (mostly diagnosis over 22 years, during which WD PCR was routinely endocarditis) in their series [1, 11]. Endocarditis is the most available. Yield of SB PAS and PCR was low in patients with WD common LWD manifestation reported in European studies, without overt gastrointestinal symptoms. Synovial fluid or CSF though multiple series of localized T. whipplei arthritis have also PCR should be strongly considered during the initial diagnos- been reported recently [1, 16, 17, 29]. Fleming and colleagues tic investigation in patients presenting with localized symptoms described 29 WD cases diagnosed at our institution from 1954 consistent with localized T. whipplei arthritis or localized CNS to 1984 [12]. In their publication, 12 (43%) patients devel- WD, respectively. oped CNS involvement, nearly double the proportion in recent Acknowledgments European series [1, 11, 13]. The etiology of these differences is Author contributions. Nicholas R.  Crews contributed to study con- unclear but could be due to referral bias or geographic variance, cept and design; acquisition of data; analysis and interpretation of data; and possibly related to varying bacterium strains. Geographic vari- drae ft d the manuscript. Kelly A. Cawcutt contributed to study concept and design; acquisition of data; analysis and interpretation of data. Bobbi S. Pritt ance has recently been reported [16]. contributed to acquisition of data and critical revision of the manuscript In our cohort, SB PAS stain and PCR were positive in 14% and for important intellectual content. Robin Patel contributed to acquisition of 42%, respectively, of LWD cases without weight loss or chronic data and critical revision of the manuscript for important intellectual con- diarrhea. These results are congruent with previous studies tent. Abinash Virk contributed to study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript demonstrating increased sensitivity of duodenal PCR compared for important intellectual content; study supervision. with PAS staining [11, 16, 30]. Lagier and colleagues recently Financial support. None. reported 24 cases of LWD in which duodenal tissue PAS stain and Potential conifl cts of interest. Bobbi Pritt, MD, Nicholas R.  Crews, MD, Kelly A.  Cawcutt, MD: none. Abinash Virk, MD: inventor for travel PCR were positive, 0% (0/22) and 6.7% (1/15), respectively [1]. health and wellness, LLC. Robin Patel, MD: Dr. Patel has participated in Localized T.  whipplei arthritis and localized CNS WD are research studies supported by CD Diagnostics, BioFire, Curetis, Merck, most commonly diagnosed by synovial fluid and CSF PCR, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, Allergan, and The Medicines Company; and is a consultant to Curetis and Specific respectively, as shown in our cohort and others [1, 16, 17]. Technologies. She receives editor’s stipends from the Infectious Diseases es Th e findings support the role of nonintestinal PCR testing as a Society of America and American Society for Microbiology (ASM). preferred initial diagnostic investigation in cases of non-CWD. Dr. Patel also receives travel reimbursement from ASM and honoraria from Due to the rarity and variable presentation of WD, misdi- the National Board of Medical Examiners, Up-to-Date, and the Infectious Diseases Board Review Course. Dr. Patel has a patent on Bordetella pertus- agnosis and delay in correct diagnosis is commonplace, and sis/parapertussis PCR issued, a patent on a device/method for sonication patients may be referred to multiple different medical sub- with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-bi- specialties before diagnosis. The 33 WD patients presented ofilm substance issued. to 11 different specialties. Most patients initially presented to References a gastroenterologist, rheumatologist, or neurologist. Small 1. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma whipplei: clinical bowel–based testing was ordered commonly by all specialists, presentation of 142 patients with infections diagnosed or confirmed in a reference regardless of subspecialty; however, nearly all PCR tests of center. Medicine 2010; 89:337–45. 6 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 2. Black-Schaffer B. The tinctoral demonstration of a glycoprotein in Whipple’s dis- 16. Lehmann P, Ehrenstein B, Hartung W, et al. PCR analysis is superior to histology ease. Proc Soc Exp Biol Med 1949; 72:225–7. for diagnosis of Whipple’s disease mimicking seronegative rheumatic diseases. 3. Silva MT, Macedo PM, Moura Nunes JF. Ultrastructure of bacilli and the bacillary Scand J Rheumatol 2017; 46:138–42. origin of the macrophagic inclusions in Whipple’s disease. J Gen Microbiol 1985; 17. Puéchal X. Whipple’s arthritis. Joint Bone Spine 2016; 83:631–5. 131:1001–13. 18. Tábuas-Pereira M, Vicente M, Coelho F, Santana I. Prosopagnosia as the present- 4. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncul- ing symptom of Whipple disease. Cogn Behav Neurol 2016; 29:100–6. tured bacillus of Whipple’s disease. N Engl J Med 1992; 327:293–301. 19. Misbah SA, Ozols B, Franks A, Mapstone N. Whipple’s disease without malab- 5. Moter A, Schmiedel D, Petrich A, et al. Validation of an rpoB gene PCR assay for sorption: new atypical features. QJM 1997; 90:765–72. detection of Tropheryma whipplei: 10  years’ experience in a National Reference 20. Escher R, Roth S, Droz S, et al. Endocarditis due to Tropheryma whipplei: rapid Laboratory. J Clin Microbiol 2013; 51:3858–61. detection, limited genetic diversity, and long-term clinical outcome in a local 6. Maibach RC, Altwegg M. Cloning and sequencing an unknown gene of experience. Clin Microbiol Infect 2010; 16(8):1213–22. Tropheryma whipplei and development of two LightCycler PCR assays. Diagn 21. Fenollar F, Laouira S, Lepidi H, et al. Value of Tropheryma whipplei quantitative Microbiol Infect Dis 2003; 46:181–7. polymerase chain reaction assay for the diagnosis of Whipple disease: useful- 7. Maibach RC, Dutly F, Altwegg M. Detection of Tropheryma whipplei DNA in ness of saliva and stool specimens for first-line screening. Clin Infect Dis 2008; feces by PCR using a target capture method. J Clin Microbiol 2002; 40:2466–71. 47:659–67. 8. Fenollar F, Puéchal X, Raoult D. Whipple’s disease. N Engl J Med 2007; 356:55–66. 22. Lange U, Teichmann J. Whipple arthritis: diagnosis by molecular analysis of syn- 9. Baisden BL, Lepidi H, Raoult D, et  al. Diagnosis of Whipple disease by immu- ovial fluid–current status of diagnosis and therapy. Rheumatology (Oxford) 2003; nohistochemical analysis: a sensitive and specific method for the detection of 42:473–80. Tropheryma whipplei (the Whipple bacillus) in paraffin-embedded tissue. Am J 23. Rezk A, Gunnerson AC, Komar M. A disease that is often missed without gastro- Clin Pathol 2002; 118:742–8. intestinal symptoms. Gastroenterology 2016; 150:1096–7. 10. Fenollar F, Birg ML, Gauduchon V, Raoult D. Culture of Tropheryma whipplei 24. El-Abassi R, Soliman MY, Williams F, England JD. Whipple’s disease. J Neurol Sci from human samples: a 3-year experience (1999 to 2002). J Clin Microbiol 2003; 2017; 377:197–206. 41(8):3816–22. 25. Panegyres PK. Diagnosis and management of Whipple’s disease of the brain. Pract 11. Günther U, Moos V, Offenmüller G, et  al. Gastrointestinal diagnosis of clas- Neurol 2008; 8:311–7. sical Whipple disease: clinical, endoscopic, and histopathologic features in 191 26. Sloan LM, Rosenblatt JE, Cockerill FR 3rd. Detection of Tropheryma whipplei patients. Medicine (Baltimore) 2015; 94:e714. DNA in clinical specimens by LightCycler real-time PCR. J Clin Microbiol 2005; 12. Fleming JL, Wiesner RH, Shorter RG. Whipple’s disease: clinical, biochemical, 43:3516–8. and histopathologic features and assessment of treatment in 29 patients. Mayo 27. Brinkman CL, Vergidis P, Uhl JR, et al. PCR-electrospray ionization mass spec- Clin Proc 1988; 63:539–51. trometry for direct detection of pathogens and antimicrobial resistance from heart 13. Ojeda E, Cosme A, Lapaza J, et  al. Whipple’s disease in Spain: a clinical review valves in patients with infective endocarditis. J Clin Microbiol 2013; 51:2040–6. of 91 patients diagnosed between 1947 and 2001. Rev Esp Enferm Dig 2010; 28. Razonable RR, Pulido JS, Deziel PJ, et  al. Chorioretinitis and vitreitis due to 102(2):108–23. Tropheryma whipplei after transplantation: case report and review. Transpl Infect 14. Urbanski G, Rivereau P, Artru L, et al. Whipple disease revealed by lung involve- Dis 2008; 10:413–8. ment: a case report and literature review. Chest 2012; 141:1595–8. 29. Fenollar F, Célard M, Lagier JC, et al. Tropheryma whipplei endocarditis. Emerg 15. Stojan G, Melia MT, Khandhar SJ, et  al. Constrictive pleuropericarditis: a Infect Dis 2013; 19:1721–30. dominant clinical manifestation in Whipple’s disease. BMC Infect Dis 2013; 30. Flemmer MC, Flenner RW. Toward a new understanding of Whipple’s disease. 13:579. Curr Gastroenterol Rep 2000; 2:299–304. 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Diagnostic Approach for Classic Compared With Localized Whipple Disease

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Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Open Forum Infectious Diseases MAJOR ARTICLE Diagnostic Approach for Classic Compared With Localized Whipple Disease 1 2 3,4 3,4 3 Nicholas R. Crews, Kelly A. Cawcutt, Bobbi S. Pritt, Robin Patel, and Abinash Virk 1 2 Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana; Divisions of Infectious Diseases and Pulmonary and Critical Care, University of Nebraska Medical Center, 3 4 Omaha, Nebraska; Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota; Division 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 local- ized 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 involve- ment. Small bowel tissue biopsy PAS stain/PCR was overwhelmingly positive (86%/92%) in CWD, yet seldom positive (12%/42%) in LWD (P < .001). Ae ff cted joint synovial fluid PCR was frequently positive in both CWD (100%, 3/3) and LWD (85%, 6/7). Conclusions. es Th e 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. Ae ff cted 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 diagnostic challenge due to its rarity and variable presentation, Tropheryma whipplei [1]. In 1949, Black-Schaer fir ff st described resulting in delayed or missed diagnosis [1, 11, 12]. the classic WD (CWD) histologic finding of Periodic acid-Schiff Fewer than 2000 WD cases have been reported in the literature (PAS)–positive macrophages within the intestinal mucosa and since WD was first described [13]. The majority were classified lymph nodes, which was later correlated with the presence of as CWD, in which nonspecific gastrointestinal manifestations T.  whipplei bacilli within the macrophage cytoplasm [2, 3]. predominate aer a p ft eriod of prodromal joint involvement and Subsequently, PAS staining of formalin-fixed paraffin-embed- constitutional symptoms [1, 11]. CWD frequently involves the ded (FFPE) small bowel (SB) tissue became the standard WD nervous system, with 10%–46% of patients developing neuro- diagnostic test and is commonly followed by amylase or dia- logic symptoms, and less commonly ae ff cts the endocardium, stase treatment (ie, PAS-D) to remove glycogen to aid in detec- uvea, lymphatic system, pulmonary parenchyma, and pleural tion of T. whipplei bacilli. Since the identification of T. whipplei cavities [13–15]. In contrast, localized WD (LWD) without clas- in 1992, polymerase chain reaction (PCR) assays targeting sic gastrointestinal involvement (including isolated T.  whipplei endocarditis, polyarticular inflammatory arthritis, or localized T. whipplei have been developed with excellent sensitivity [4–8]. neurologic infection) is becoming increasingly recognized, par- Additional methods include organism cell culture and immu- ticularly since the advent of T. whipplei PCR, which can be per- nohistochemical staining, although neither is practical or com- formed on a variety of tissues and body fluids [1, 16–20]. monly available [9, 10]. Despite these advances, WD remains a e r Th ole of PCR in the WD diagnostic paradigm remains unclear. Intestinal tissue PCR has been traditionally ordered Received 9 April 2018; editorial decision 29 May 2018; accepted 8 June 2018. as a confirmatory test aer ft PAS staining in CWD cases [11]. Correspondence: A. Virk, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (virka@mayo.edu). Some have recommended PCR in parallel to PAS staining Open Forum Infectious Diseases [8, 21]. Individualized diagnostic approaches for localized © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases T.  whipplei infection have not been fully investigated and thus Society of America. This is an Open Access article distributed under the terms of the Creative are likely underutilized. Recent series report SB PAS stain and 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 PCR positivity in only 39%–48% and 55%–93% of CWD cases medium, provided the original work is not altered or transformed in any way, and that the work without typical gastrointestinal symptoms, respectively [11, is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy136 16]. T.  whipplei synovial fluid PCR has been proposed as the Diagnostic Approach for Whipple Disease • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 firstline diagnostic test for seronegative arthritis [17, 22, 23]. involvement of the gastrointestinal system, joints, cardiopul- Cerebrospinal fluid (CSF) PCR has been recommended when monary system, lymphatic system, and/or CNS. LWD arthritis central nervous system (CNS) WD is suspected or in asymp- and CNS WD were defined as the presence of primarily joint tomatic patients, yet its role and usage in WD diagnosis are or CNS involvement, respectively, with or without prodromal unclear [11, 24, 25]. or constitutional symptoms, with minimal, if any, other organ We retrospectively investigated diagnostic approaches involvement, particularly gastrointestinal manifestations. and methodologies employed at our institution to diagnose Results were analyzed using descriptive statistics and likelihood WD from 1994 to 2016; 1994 was selected as the start date as ratio analysis to compare diagnostic test yield. Standard statis- T.  whipplei PCR has been oer ff ed routinely at our institution tical software (JMP, version 12, SAS Institute, Cary, NC) was since 1994. We aimed to assess the various testing yields and used for analysis. This study was approved by the Mayo Clinic diagnostic methods employed based on variations in clinical Institutional Review Board. manifestations, comparing classic with nonclassic cases. RESULTS METHODS Retrospective database searches yielded 35 cases of WD with We retrospectively collected all WD cases diagnosed at the 47 positive T.  whipplei PCR results, 16 positive PAS SB biopsy Mayo Clinic between 1994 (when T. whipplei PCR became avail- results, and 2 PAS-positive endocardial tissue biopsies consist- able at our institution) and January 1, 2016. The PCR method- ent with WD. Two cases (each with 1 single positive blood PCR) ologies used at our institution since 1994 have been previously were excluded from further analysis because neither patient described [26]. Microbiology laboratory databases were que- demonstrated WD symptoms, nor were they treated for WD. ried for positive T. whipplei PCR results performed at our insti- Thus, 33 WD cases were diagnosed at our institution from tution during the study period. Anatomic pathology databases 1994 to January 2016, with 2 being reported previously [27, 28]. were queried for the terms “Whipple disease” AND “positive” Eighteen patients (55%) had CWD, 9 (27%) had LWD arthritis, AND/OR “consistent.” These findings were confirmed against and 6 (18%) had localized CNS WD. a separate query of the same database for the terms “PAS” OR e co Th hort consisted of 28 (85%) males with a mean (SD) “PAS-D” AND “positive.” Duplicate results, testing ordered by age of 52 (13) years at the time of diagnosis. Table  1 reports providers external to our institution, and tests to confirm dis- patient characteristics and symptoms by disease manifestation. ease relapse were excluded. These queries were confirmed by Diagnosis was confirmed a median (range) of 4.6 (0.6–22.5) cross-checking against a query of WD cases in our electronic years aer p ft rodromal symptoms presented. Mean (IQ1, 3) time medical record (EMR). The EMR was reviewed to ascertain from initial presentation to our institution to diagnosis was WD symptoms, diagnosis, treatment, and response to therapy. 3 (3, 8.25) months, though diagnosis was delayed more than Additional data obtained included demographics, clinical 1 year aer p ft resentation in 5 cases. Table 2 displays initial and manifestations, medical specialty (initial and diagnosing), lab- confirmatory testing results for each case. Previous misdiagno- oratory, imaging, and WD diagnostic testing. Diagnostic meth- sis was common, including seronegative inflammatory arth- odology and test results were stratified by CWD, LWD arthritis, ritis (n  =  5), rheumatoid arthritis (n  =  2), sarcoidosis (n  =  2), and CNS WD. CWD was defined as systemic disease involve- adult Still disease (n  =  1), polymyalgia rheumatica (n  =  1), ment with prodromal symptoms in addition to multiple-organ chronic Lyme disease (n = 1), and chronic meningitis (n = 1). Table 1. Differences in Clinical Data for 33 WD Patients by Whipple Disease Type: Classic vs Localized Characteristics Classic WD (n = 18) Localized WD Arthritis (n = 9) Localized CNS WD (n = 6) Male, No. (%) 17 (94) 7 (78%) 4 (67) Mean age (SD), y 52 (13) 46 (15) 56 (9.3) Median time from initial symptoms to diagnosis (IQ1,3), y 5.4 (2.6, 6.8) 5.8 (1.4, 6.3) 2.7 (1.5, 3.5) Previously immunosuppressed, No. (%) 7 (39) 6 (67) 2 (33) General systemic involvement, No. (%) 18 (100) 4 (44) 5 (83) GI involvement, No. (%) 16 (89) 0 (0) 1 (16) Joint involvement, No. (%) 17 (94) 9 (100) 1 (16) Cardiac involvement, No. (%) 3 (17) 0 (0) 0 (0) CNS involvement, No. (%) 1 (11) 2 (22) 6 (100) Anemia, No. (%) 17 (94) 3 (33) 4 (67) Elevated inflammatory markers, No. (%) 15 (93) 4 (44) 1 (25) Fat soluble vitamin deficiencies, No. (%) 7 (58) 0 (0) 1 (33) Abbreviations: CNS, central nervous system; GI, gastrointestinal; WD, Whipple disease. 2 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Table 2. Diagnostic Approach With Initial and Confirmatory Diagnostic Test Results by Whipple Disease Type: Classic vs Localized Confirmator y Tests Small Bowel Synovial Case WD Type Initial Diagnostic Test Initial Test Result PAS/PCR Fluid PCR CSF PCR Blood PCR Other PCR 1 CNS WD SB PAS/PCR +/+ + 2 CWD SF PCR + +/+ - - - 3 CWD SB PAS/PCR +/+ + 4 CWD SB PAS/PCR +/+ + 5 CWD SB PAS/PCR +/+ + 6 CWD SB PAS/PCR +/+ + 7 CWD SB PAS + 8 LWD SB PAS + 9 CNS WD CSF PCR + -/+ - 10 CNS WD CSF PCR + -/- 11 LWD SF PCR + -/- - 12 CNS WD CSF PCR + -/- 13 LWD SF PCR + -/+ 14 LWD SF PCR + + 15 CWD SB PAS/PCR +/+ 16 LWD SB PAS/PCR -/+ - - 17 LWD Blood PCR + -/- + 18 CNS WD CSF PCR + -/- 19 CWD SB PAS/PCR +/+ 20 CNS WD SB PAS - + + 21 CWD SB PAS/PCR -/- + + 22 LWD SF PCR + -/- 23 CWD SB PAS/PCR -/+ + + 24 LWD SB PAS/PCR -/- + - - 25 CWD Endocardial biopsy PAS/PCR +/+ +/+ - 26 CWD SB PAS/PCR +/+ 27 CWD SF PCR + - 28 LWD SB PAS/PCR -/+ - - 29 CWD Endocardial biopsy PAS/PCR +/+ + 30 CWD SB PAS/PCR +/+ - - 31 CWD SB PAS + + 32 CWD SB PAS/PCR +/+ 33 CWD SF PCR + - - + indicates positive result. – indicates negative result. Blank space indicates test not performed. Abbreviations: CNS WD, localized T. whipplei central nervous system infection; CSF, cerebrospinal fluid; CWD, classic Whipple disease; LWD, localized T. whipplei arthritis; PAS, Periodic acid-Schiff; PCR, polymerase chain reaction; SB, small bowel; SF, synovial fluid.  Other PCR includes 2 vitreous aqueous humor fluid PCRs (1 negative and one positive), 1 lymph node tissue specimen PCR (positive), and 1 arterial thrombus surgical pathology speci- men PCR (positive). Furthermore, 43% of patients were prescribed immunosup- Additionally, 17 of 18 (94%) patients with CWD had prodro- pressive therapy for misdiagnosis treatment. Chronic therapy mal arthralgias for an average of 72  months before presenta- for T.  whipplei included 1 or more of the following: penicillin, tion, whereas 89% had nonspecific gastrointestinal symptoms, tetracycline, doxycycline, ceftriaxone, and trimethoprim/sul - including intermittent abdominal pain, chronic diarrhea, and/or famethoxazole. Patients were followed for a mean (SD) of 10.5 weight loss. Five patients with CWD had developed neurologic (7.3) years aer di ft agnosis, during which 4 patients had WD manifestations, including cognitive impairment, psychiatric relapse and 6 died, all of non-WD-related causes. changes, and/or movement abnormalities. Lymphadenopathy was present, clinically or on radiographic imaging, in 7 CWD Classic Whipple Disease cases. Additional manifestations among CWD patients included At the time of diagnosis, all patients with CWD reported sys- endocarditis (n  =  2), pericarditis (n  =  1), arterial thrombus temic symptoms including intermittent fevers, fatigue, chills, (n = 1), and fat-soluble vitamin deficiencies (n = 7). and/or night sweats, whereas elevated inflammatory markers e ini Th tial diagnostic test obtained was SB biopsy with PAS and anemia were found in 83% and 94% of cases, respectively. staining in 13 of 18 CWD cases with 11 (85%) positive results Diagnostic Approach for Whipple Disease • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Localized T. whipplei CNS Infection (Table  2); 7/12 (63%) of the biopsies were obtained from the Six patients with localized CNS WD presented with cognitive duodenum while rest were from the jejunum, stomach, mesen- deficits, psychiatric symptoms, movement abnormalities, and/ teric lymph nodes, lymph nodes, parietal pericardium, terminal or supranuclear ophthalmoplegia. Uveitis was present in 1 case ileum, or colon, with tissue obtained from multiple locations [28]. Only 1 patient had gastrointestinal symptoms (abdom- in some patients. Both negative results were in the setting of inal pain); none had diarrhea or weight loss. Systemic symp- antibiotics for more than 30 days before biopsy, prescribed for toms including fever, asthenia, fatigue, and chills were present presumed chronic Lyme disease and Pneumocystis jirovecii in 5 cases. Laboratory abnormalities included anemia (n  =  4), pneumonia prophylaxis for chronic immunosuppression for elevated inflammatory markers (n = 1), and vitamin B12 defi- presumed seronegative arthritis. Duodenal PCR was ordered in ciency (n  =  1). Residual neurologic deficits were noted in 3 parallel to PAS stain in 11 cases (10 were positive and 1 neg- cases after treatment, with 1 relapse. ative in a case with a negative PAS stain). The 2 patients with e ini Th tial diagnostic test was lumbar puncture for CSF PCR negative duodenal PAS stains were diagnosed by PCR (case 1: in 4 of 6 cases, with 4/4 positive (Table 2). Confirmation of diag- blood and lymph node tissue specimen; case 2: blood and arter- nosis was pursued in all 4 cases with SB PAS stain/PCR (1/4 ial thrombus). Additional diagnostic tests ordered in these 13 PCR and 0/4 PAS stain positive). SB biopsy was the initial diag- cases included 1 negative vitreous aqueous humor PCR and 9 nostic test in the other 2 CNS WD cases. In 1 case, duodenal blood PCRs (3 positive). CSF PCR was performed in 4 of the 5 PAS was nonreactive (PCR not performed), but blood and patients with neurologic manifestations (1 positive). vitreous aqueous humor fluid PCR were positive; CSF was not Five patients with CWD did not undergo SB sampling as the tested. In the second case, duodenal PAS/PCR were positive on initial diagnostic test. Two patients with endocarditis were diag- initial testing, and subsequently CSF PCR was positive. nosed with positive endocardial tissue PAS stain and PCR. One case was confirmed with blood PCR; the other case was con- Diagnostic Approach and Comparison of Results firmed with positive duodenal PAS stain, and PCR aer b ft lood The 33 WD patients initially presented to 11 different medical PCR was negative. The other 3 patients were diagnosed aer ft specialties: rheumatology (n = 8), neurology (n = 7), gastroen- undergoing arthrocentesis with positive synovial fluid PCR. terology (n = 5), hematology (n = 4), general medicine (n = 4), One of these 3 subsequently underwent confirmatory SB testing cardiology (n = 1), ophthalmology (n = 1), pulmonology (n = 1), with positive duodenal PAS stain and PCR. infectious disease (n = 1), and endocrinology (n = 1) (Figure 1). When initial presentation was to rheumatology, neurology, or Localized T. whipplei Arthritis gastroenterology, the diagnosis was made by that specialist in Nine patients with localized T.  whipplei arthritis reported 19 of 20 cases (Figure  2). In these 20 cases, consultation from arthralgias for a median (range) of 5.0 (1.0–22) years before a second specialist was requested in 8 cases (gastroenterology presentation to our institution. None reported gastrointestinal [n  =  3], rheumatology [n  =  2], infectious disease [n  =  2], and symptoms (abdominal pain, chronic diarrhea, or weight loss), neurology [n  =  1]). In the other 13 cases, consultation from a whereas 2 reported minor cognitive changes (memory loss). gastroenterologist or rheumatologist was requested in 11 cases. Four had intermittent systemic symptoms of fatigue, night Small bowel testing with PAS stain and/or PCR was ordered sweats, and/or asthenia. None reported weight loss or devel- as the initial WD test in 18 of 33 (55%) cases but ordered by oped vitamin deficiencies, but elevated inflammatory markers were present in 4. In 4 of the 9 LWD cases, the initial diagnostic test was syno- Infectious disease vial fluid PCR with 4/4 positive (Table 2). Small bowel PAS stain Endocrinology and PCR were ordered to confirm the initial result in 3 of these Pulmonology 4 cases (1/3 PCR and 0/3 PAS stain positive). Four patients Ophthalmology Cardiology underwent initial testing with SB PAS stain; PCR was ordered in General medicine parallel to PAS in 3 of 4 cases. Results were PAS (without PCR) Hematology positive in 1 case, negative PAS/positive PCR in 2 cases, and Neurology negative PCR/negative PAS in 1 case (diagnosis subsequently Rheumatology made with positive synovial fluid PCR). One patient initially Gastroenterology diagnosed with blood PCR was confirmed by positive syno- 02468 10 12 vial fluid PCR. CSF PCR was negative in the 2 patients report- Number of patiens ing cognitive deficits. Synovial fluid total nucleated cell count Diagnosing subspecialty Initial subspecialty ranged from 208 to 45 708 cells/mcL (median, 3016 cells/mcL), with the polymorphonuclear cell percentage ranging from 13% Figure  1. Proportion of medical subspecialties that initially evaluated and ulti- to 86% (median, 75%). mately diagnosed 33 patients with Whipple disease. 4 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 Card Endo GI Hem ID IM Neuro Opht Pulm Rheum Consults requested by initial evaluating medical subspecialty Figure 2. Proportion of medical subspecialties consulted by initially evaluating subspecialty in 33 patients with Whipple disease. Abbreviations: Card, cardiology; Endo, endocrinology; GI, gastroenterology; Hem, hematology; ID, infectious diseases; IM, internal medicine; Neuro, neurology; Opht, ophthalmology; Pulm, pulmonology; Rheum, rheumatology. a gastroenterologist in 4 (22%) cases. When CSF or synovial 3/3) and localized T. whipplei arthritis (83%, 5/6; P = .35). CSF uid PCR wa fl s obtained as the initial WD test, these diagnostics PCR was positive in 100% (5/5) of CNS WD cases, whereas it were almost exclusively (10/11 cases) ordered by a neurologist was only positive in 25% (1/4) of CWD patients with neurologic or rheumatologist, respectively. Confirmatory testing with a symptoms (P  =  .009). CSF PCR was negative in patients with different method was pursued in 31 of the 33 cases with a 64% localized T.  whipplei arthritis with cognitive changes. Blood positive rate. PCR lacked sensitivity in CWD and LWD cases (CWD: 54%, 6/11, including 50%, 1/2, positivity in 2 cases of endocarditis; Differences in Diagnostic Test Results T. whipplei arthritis: 33%, 2/6; CNS WD: 50%, 1/2; P = .69). Table 3 reports diagnostic test yields for CWD, LWD, and CNS WD. Duodenal PAS stain was overwhelmingly positive (86%) DISCUSSION in the 18 CWD cases; however, it was rarely positive (13%) in We report 33 WD cases diagnosed at our institution from 1994 the 15 non-CWD cases with minimal, if any, gastrointestinal to 2016, which is to our knowledge the largest series of American manifestations (P < .001). Small bowel PCR was positive in 42% WD cases reported since the development of T.  whipplei PCR. (5/12) of localized WD cases without diarrhea compared with Eighteen patients (55%) were diagnosed with CWD, 9 (27%) 13% PAS stain reactivity (P = .018). Duodenal PAS stain reac- with localized WD arthritis, and 6 (18%) with localized CNS tivity was similar in LWD arthritis (12%, 1/8) and CNS WD WD. These results support the role of PAS stain and PCR of cases (17%, 1/6). Similarly, duodenal PCR positivity rates were duodenal tissue in the diagnosis of CWD. Although 5 patients comparable in LWD (42%, 3/7) and CNS WD cases (40%, 2/5). did not have histological findings on small-bowel biopsies or did Synovial fluid PCR testing was high yield, with positive not have a biopsy done at all, their symptoms and PCR positivity results in 89% (8/9) of patients with arthritis. Synovial fluid PCR from other sites were consistent with CWD. This is consistent positivity rates were comparable in patients with CWD (100%, Table 3. Diagnostic Test Yields Differ by Classic vs Localized Whipple Disease Classic WD (n = 18), No. Positive/ Localized WD Arthritis (n = 9), No. Localized CNS WD (n = 6), No. No. Tested (%) Positive/No. Tested (%) Positive/No. Tested (%) P Value a * Small bowel biopsy PAS stain 13/15 (86) 1/8 (12) 1/6 (17) <.001 Small bowel biopsy PCR 12/13 (92) 3/7 (42) 2/5 (40) .018 Synovial fluid PCR 3/3 (100) 6/7 (85) 0/0 (0) .35 Cerebrospinal fluid PCR 1/4 (25) 0/2 (0) 5/5 (100) .009 Blood PCR 7/12 (58) 2/6 (33) 1/2 (50) .69 Other PCR 4/5 (80) 0/0 (0) 1/1 (100) .52 Abbreviations: CNS, central nervous system; PAS, Periodic acid-Schiff; PCR, polymerase chain reaction; WD, Whipple disease. P value considered significant if <.05. Other PCR included 2 vitreous aqueous humor fluid PCRs (1 negative and 1 positive), 1 lymph node tissue specimen PCR (positive), and 1 arterial thrombus surgical pathology specimen PCR (positive). Diagnostic Approach for Whipple Disease • OFID • 5 Number of patients Rheum GI Neuro Rheum (none) ID Neuro Rheum (none) GI Rheum (none) GI ID (none) (none) (none) GI ID (none) Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 with findings in the largest series of CWD, which showed that synovial fluid or CSF fluid were ordered by a rheumatologist or in 91% of 191 cases of CWD, the duodenum had characteris- neurologist, respectively. With the increased awareness of the tic histological changes in SB biopsies [11]. However, the diag- diagnostic value of WD PCR testing, we expect an increase in nostic yield of SB PAS stain, and PCR to a lesser degree, was familiarity of synovial fluid– and CSF fluid–based T.  whipplei decreased in non-CWD cases without gastrointestinal involve- PCR testing. It is difficult to develop a 1-size-fits-all diagnos- ment. Diagnosis in non-CWD was most often made by positive tic scheme for WD; however, this study supports the use of PCR of blood, CSF, synovial fluid, or other tissue, suggesting extra-intestinal PCR testing and early referral to gastroenterol- that a combination of clinical suspicion for WD and sampling ogy, rheumatology, or neurology to mitigate delay in diagnosis. of potentially affected sites is helpful in diagnosis even in the Potential limitations exist in our study. Physician practices absence of SB PAS stain or PCR positivity. Affected joint syno- could have been influenced by progression in medical knowl- vial fluid PCR was frequently positive in both CWD and LWD. edge over 2 and a half decades, thus potentially aeff cting Blood PCR was poorly sensitive in all WD cases, irrespective diagnostic paradigms. Temporal trends of diagnostic meth- of classical or local disease involvement, including endocardi- odologies were not assessed but could be evaluated in future tis. There were 2 apparently false-positive blood PCR results in investigations. Although the PCR assay evolved from a conven- this study. Stool and saliva PCR were not performed at the Mayo tional PCR assay to a real-time PCR assay over the study period, Clinic as a routine clinical test during the study period. clinical performance characteristics did not change. Similarly, This cohort includes a significant proportion (45%) of cases PAS staining on FFPE tissue remained unchanged during this with LWD, which is greater than the proportion reported in time frame. European studies. Gunther et  al. reported only CWD cases, In conclusion, this study reports the test yield and diagnostic with few nonintestinal PCR tests, whereas Lagier and colleagues paradigms employed by physicians at our institution for WD reported 80% CWD cases and 20% isolated WD cases (mostly diagnosis over 22 years, during which WD PCR was routinely endocarditis) in their series [1, 11]. Endocarditis is the most available. Yield of SB PAS and PCR was low in patients with WD common LWD manifestation reported in European studies, without overt gastrointestinal symptoms. Synovial fluid or CSF though multiple series of localized T. whipplei arthritis have also PCR should be strongly considered during the initial diagnos- been reported recently [1, 16, 17, 29]. Fleming and colleagues tic investigation in patients presenting with localized symptoms described 29 WD cases diagnosed at our institution from 1954 consistent with localized T. whipplei arthritis or localized CNS to 1984 [12]. In their publication, 12 (43%) patients devel- WD, respectively. oped CNS involvement, nearly double the proportion in recent Acknowledgments European series [1, 11, 13]. The etiology of these differences is Author contributions. Nicholas R.  Crews contributed to study con- unclear but could be due to referral bias or geographic variance, cept and design; acquisition of data; analysis and interpretation of data; and possibly related to varying bacterium strains. Geographic vari- drae ft d the manuscript. Kelly A. Cawcutt contributed to study concept and design; acquisition of data; analysis and interpretation of data. Bobbi S. Pritt ance has recently been reported [16]. contributed to acquisition of data and critical revision of the manuscript In our cohort, SB PAS stain and PCR were positive in 14% and for important intellectual content. Robin Patel contributed to acquisition of 42%, respectively, of LWD cases without weight loss or chronic data and critical revision of the manuscript for important intellectual con- diarrhea. These results are congruent with previous studies tent. Abinash Virk contributed to study concept and design; acquisition of data; analysis and interpretation of data; critical revision of the manuscript demonstrating increased sensitivity of duodenal PCR compared for important intellectual content; study supervision. with PAS staining [11, 16, 30]. Lagier and colleagues recently Financial support. None. reported 24 cases of LWD in which duodenal tissue PAS stain and Potential conifl cts of interest. Bobbi Pritt, MD, Nicholas R.  Crews, MD, Kelly A.  Cawcutt, MD: none. Abinash Virk, MD: inventor for travel PCR were positive, 0% (0/22) and 6.7% (1/15), respectively [1]. health and wellness, LLC. Robin Patel, MD: Dr. Patel has participated in Localized T.  whipplei arthritis and localized CNS WD are research studies supported by CD Diagnostics, BioFire, Curetis, Merck, most commonly diagnosed by synovial fluid and CSF PCR, Hutchison Biofilm Medical Solutions, Accelerate Diagnostics, Allergan, and The Medicines Company; and is a consultant to Curetis and Specific respectively, as shown in our cohort and others [1, 16, 17]. Technologies. She receives editor’s stipends from the Infectious Diseases es Th e findings support the role of nonintestinal PCR testing as a Society of America and American Society for Microbiology (ASM). preferred initial diagnostic investigation in cases of non-CWD. Dr. Patel also receives travel reimbursement from ASM and honoraria from Due to the rarity and variable presentation of WD, misdi- the National Board of Medical Examiners, Up-to-Date, and the Infectious Diseases Board Review Course. Dr. Patel has a patent on Bordetella pertus- agnosis and delay in correct diagnosis is commonplace, and sis/parapertussis PCR issued, a patent on a device/method for sonication patients may be referred to multiple different medical sub- with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-bi- specialties before diagnosis. The 33 WD patients presented ofilm substance issued. to 11 different specialties. Most patients initially presented to References a gastroenterologist, rheumatologist, or neurologist. Small 1. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma whipplei: clinical bowel–based testing was ordered commonly by all specialists, presentation of 142 patients with infections diagnosed or confirmed in a reference regardless of subspecialty; however, nearly all PCR tests of center. Medicine 2010; 89:337–45. 6 • OFID • Crews et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/7/ofy136/5036561 by guest on 16 October 2019 2. Black-Schaffer B. The tinctoral demonstration of a glycoprotein in Whipple’s dis- 16. Lehmann P, Ehrenstein B, Hartung W, et al. PCR analysis is superior to histology ease. Proc Soc Exp Biol Med 1949; 72:225–7. for diagnosis of Whipple’s disease mimicking seronegative rheumatic diseases. 3. Silva MT, Macedo PM, Moura Nunes JF. Ultrastructure of bacilli and the bacillary Scand J Rheumatol 2017; 46:138–42. origin of the macrophagic inclusions in Whipple’s disease. J Gen Microbiol 1985; 17. Puéchal X. Whipple’s arthritis. Joint Bone Spine 2016; 83:631–5. 131:1001–13. 18. Tábuas-Pereira M, Vicente M, Coelho F, Santana I. Prosopagnosia as the present- 4. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncul- ing symptom of Whipple disease. Cogn Behav Neurol 2016; 29:100–6. tured bacillus of Whipple’s disease. N Engl J Med 1992; 327:293–301. 19. Misbah SA, Ozols B, Franks A, Mapstone N. Whipple’s disease without malab- 5. Moter A, Schmiedel D, Petrich A, et al. Validation of an rpoB gene PCR assay for sorption: new atypical features. QJM 1997; 90:765–72. detection of Tropheryma whipplei: 10  years’ experience in a National Reference 20. Escher R, Roth S, Droz S, et al. Endocarditis due to Tropheryma whipplei: rapid Laboratory. J Clin Microbiol 2013; 51:3858–61. detection, limited genetic diversity, and long-term clinical outcome in a local 6. Maibach RC, Altwegg M. Cloning and sequencing an unknown gene of experience. Clin Microbiol Infect 2010; 16(8):1213–22. Tropheryma whipplei and development of two LightCycler PCR assays. Diagn 21. Fenollar F, Laouira S, Lepidi H, et al. Value of Tropheryma whipplei quantitative Microbiol Infect Dis 2003; 46:181–7. polymerase chain reaction assay for the diagnosis of Whipple disease: useful- 7. Maibach RC, Dutly F, Altwegg M. Detection of Tropheryma whipplei DNA in ness of saliva and stool specimens for first-line screening. Clin Infect Dis 2008; feces by PCR using a target capture method. J Clin Microbiol 2002; 40:2466–71. 47:659–67. 8. Fenollar F, Puéchal X, Raoult D. Whipple’s disease. N Engl J Med 2007; 356:55–66. 22. Lange U, Teichmann J. Whipple arthritis: diagnosis by molecular analysis of syn- 9. Baisden BL, Lepidi H, Raoult D, et  al. Diagnosis of Whipple disease by immu- ovial fluid–current status of diagnosis and therapy. Rheumatology (Oxford) 2003; nohistochemical analysis: a sensitive and specific method for the detection of 42:473–80. Tropheryma whipplei (the Whipple bacillus) in paraffin-embedded tissue. Am J 23. Rezk A, Gunnerson AC, Komar M. A disease that is often missed without gastro- Clin Pathol 2002; 118:742–8. intestinal symptoms. Gastroenterology 2016; 150:1096–7. 10. Fenollar F, Birg ML, Gauduchon V, Raoult D. Culture of Tropheryma whipplei 24. El-Abassi R, Soliman MY, Williams F, England JD. Whipple’s disease. J Neurol Sci from human samples: a 3-year experience (1999 to 2002). J Clin Microbiol 2003; 2017; 377:197–206. 41(8):3816–22. 25. Panegyres PK. Diagnosis and management of Whipple’s disease of the brain. Pract 11. Günther U, Moos V, Offenmüller G, et  al. Gastrointestinal diagnosis of clas- Neurol 2008; 8:311–7. sical Whipple disease: clinical, endoscopic, and histopathologic features in 191 26. Sloan LM, Rosenblatt JE, Cockerill FR 3rd. Detection of Tropheryma whipplei patients. Medicine (Baltimore) 2015; 94:e714. DNA in clinical specimens by LightCycler real-time PCR. J Clin Microbiol 2005; 12. Fleming JL, Wiesner RH, Shorter RG. Whipple’s disease: clinical, biochemical, 43:3516–8. and histopathologic features and assessment of treatment in 29 patients. Mayo 27. Brinkman CL, Vergidis P, Uhl JR, et al. PCR-electrospray ionization mass spec- Clin Proc 1988; 63:539–51. trometry for direct detection of pathogens and antimicrobial resistance from heart 13. Ojeda E, Cosme A, Lapaza J, et  al. Whipple’s disease in Spain: a clinical review valves in patients with infective endocarditis. J Clin Microbiol 2013; 51:2040–6. of 91 patients diagnosed between 1947 and 2001. Rev Esp Enferm Dig 2010; 28. Razonable RR, Pulido JS, Deziel PJ, et  al. Chorioretinitis and vitreitis due to 102(2):108–23. Tropheryma whipplei after transplantation: case report and review. Transpl Infect 14. Urbanski G, Rivereau P, Artru L, et al. Whipple disease revealed by lung involve- Dis 2008; 10:413–8. ment: a case report and literature review. Chest 2012; 141:1595–8. 29. Fenollar F, Célard M, Lagier JC, et al. Tropheryma whipplei endocarditis. Emerg 15. Stojan G, Melia MT, Khandhar SJ, et  al. Constrictive pleuropericarditis: a Infect Dis 2013; 19:1721–30. dominant clinical manifestation in Whipple’s disease. BMC Infect Dis 2013; 30. Flemmer MC, Flenner RW. Toward a new understanding of Whipple’s disease. 13:579. Curr Gastroenterol Rep 2000; 2:299–304. Diagnostic Approach for Whipple Disease • OFID • 7

Journal

Open Forum Infectious Diseases – Oxford University Press

Published: Jul 1, 2018

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