Diagnostic Approach and Testing of Whippleʼs Disease

Abstract

Introduction: Whipple's disease (WD) is a rare systemic infection caused by Tropheryma whipplei that remains a diagnostic challenge due to its non-specific symptoms and variable presentation. The diagnostic role of T. whipplei polymerase chain reaction (PCR) is unclear as small bowel biopsy with periodic acid-Schiff (PAS) staining remains diagnostic gold standard. Individualized diagnostic approaches based on disease clinical phenotype have not yet been evaluated. We retrospectively investigated the methodology employed at our institution to diagnose WD. Methods: We retrospectively collected all cases of WD diagnosed at our institution since the development of PCR in 1992. Microbiology laboratory and anatomic pathology databases were queried for all positive results of PCR and PAS, respectively, for all specimen sources. The cohort of positive results was cross-checked against query of WD cases in our medical record. Each case with at least one positive laboratory result was reviewed and confirmed with clinical correlation of WD symptoms and WD treatment response. Two cases with a single PCR without WD symptoms or treatment for WD were excluded. Case characteristics and disease clinical phenotype (classical (CWD), localized arthralgia predominant without GI involvement (LWD), and CNS predominant) were reported. Results were analyzed using descriptive statistics and likelihood ratio analysis to compare diagnostic test yield. Results: Thirty-three cases of WD were diagnosed from 1992 to present (18 CWD, 8 LWD, 7 CNS predominant WD). Patients were 85% male with a mean (SD) age of 52 (13) years. Symptoms preceded diagnosis on average of 61 months, furthermore 43% of patients had been misdiagnosed with immunosuppressive therapy initiated. Table 1 shows symptom proportions. Diagnostic approach and test yield differed by disease clinical phenotype (Table 2). PAS stain/PCR of small bowel biopsy were overwhelmingly positive (86%/92%) in CWD, yet seldom positive (0%/42%) in LWD (p < 0.001). Affected joint synovial fluid PCR was positive frequently in both CWD and LWD.Table 1: Proportion of Symptoms and Laboratory Findings differ by Whipple's Disease Clinical Phenotype.Table 2: Diagnostic Approach and Test Yield differ by Whipple's Disease Clinical Phenotype.Conclusion: These results support the role of small bowel biopsy PAS stain and PCR in the diagnosis of CWD. However, the diagnostic yield of small bowel biopsy PAS stain and PCR significantly decreased in WD without GI symptoms. PCR of other sources such as synovial fluid or cerebrospinal fluid was helpful in diagnosis of WD without GI symptoms.