Gastrointestinal diagnosis of classical Whipple disease: clinical, endoscopic, and histopathologic features in 191 patients

Abstract

Classic Whipple disease (CWD) is a systemic infection caused by Tropheryma whipplei. Different diagnostic tools have been developed over the last decades: periodic acid-Schiff (PAS) staining, T whipplei-specific polymerase chain reaction (PCR), and T whipplei-specific immunohistochemistry (IHC). Despite all these advances, CWD is still difficult to diagnose because of a variety of clinical symptoms and possibly a long time span between first unspecific symptoms and the full-blown clinical picture of the disease. Herein, we report an observational cohort study summarizing epidemiologic data, clinical manifestations, and diagnostic parameters of 191 patients with CWD collected at our institution. Gastrointestinal manifestations are the most characteristic symptoms of CWD affecting 76% of the cohort. Although the small bowel was macroscopically conspicuous in only 27% of cases, 173 (91%) patients presented with characteristic histological changes in small bowel biopsies (in 2 patients, these changes were only seen within the ileum). However, 18 patients displayed normal small bowel histology without typical PAS staining. In 9 of these patients, alternative test were positive from their duodenal specimens (ie, T whipplei-specific PCR and/or IHC). Thus, in 182 patients (95%) a diagnostic hint toward CWD was obtained from small bowel biopsies. Only 9 patients (5%) were diagnosed solely based on positive T whipplei-specific PCR and/or IHC of extraintestinal fluids (eg, cerebrospinal fluid, synovial fluid) or extraintestinal tissue (eg, lymph node, synovial tissue), respectively. Thus, despite efforts to diagnose CWD from alternative specimens, gastroscopy with duodenal biopsy and subsequent histological and molecular-biological examination is the most reliable diagnostic tool for CWD.

FIGURE 1

Details of the described cohort of suspected and excluded cases and 191 patients with CWD. CNS = central nervous system, CWD = classic Whipple disease, IHC = immunohistochemistry, PAS = periodic acid-Schiff, PCR = polymerase chain reaction.

FIGURE 2

Macroscopic appearance of the duodenum at diagnostic endoscopy. (A) Characteristic but rare macroscopic appearance of the duodenal mucosa of a heavily affected case with clumsy and dilated villi with ecstatic lymph vessels that are extensively infiltrated with macrophages. (B) Discrete macroscopic appearance with whitened villus tips. (C) Duodenal mucosa with signs of a duodenitis. (D) Reddened crinkle tips as the only macroscopic abnormality. (E) Reddened and swollen appearance of the villi. (F) Aphthous ulcerations as hint of gastrointestinal affection.

FIGURE 3

Histopathological appearance of the duodenal mucosa of CWD patients following PAS staining (A, C, E, G) or Tropheryma whipplei-specific IHC (B, D, F, H). (A) Classical histopathological appearance of the duodenal mucosa of untreated CWD with flattened and clumsy villi, lymphangiectasia, and numerous PAS-positive macrophages of type 1 that can be visualized more intensively and specifically with (B) T whipplei-specific IHC. (C) Atypical PAS staining of only the submucosa (faint PAS-positive cells in the inset that can be specified with (D) IHC. (E) Villus lamina propria with negative PAS staining with few (F) T whipplei-containing cells visualized by IHC (marked by black arrows and with a close-up in the inset). (G) PAS-negative duodenal submucosa containing positive cells following (H) T whipplei-specific IHC. CWD = classic Whipple disease, IHC = immunohistochemistry, PAS = periodic acid-Schiff.

FIGURE 4

Three-stage schema for the diagnosis of CWD. First-line diagnosis should be performed for all cases suspected to suffer from Whipple disease. Even in the absence of gastrointestinal symptoms, the second step only when diagnosis from the small intestine is doubtful, and the third step for all patients with the assured diagnosis of Whipple disease. ^∗A possible antimicrobial pretreatment, also for other causes than Whipple disease, should be checked carefully in cases with PAS-positive cells of types 2 to 4 or only a positive IHC. ^∗∗PAS-positive cells of type 1 in the presence of the typical clinical picture of CWD that are evaluated by an experienced pathologist assure the diagnosis, PCR or IHC should be added whenever possible. ^∗∗∗For patients with gastrointestinal symptoms, negative histological results are very rare, so further diagnostic steps are only recommended for patients with additional extraintestinal symptoms. CWD = classic Whipple disease, IHC = immunohistochemistry, PAS = periodic acid-Schiff, PCR = polymerase chain reaction.