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Diagnosis and Monitoring of Whipple Disease by Polymerase Chain Reaction

Nizar N. Ramzan, MD; Edward Loftus Jr., MD; Lawrence J. Burgart, MD; Michele Rooney, MD; Kenneth P. Batts, MD; Russell H. Wiesner, MD; David N. Fredricks, MD; David A. Relman, MD; and David H. Persing, MD, PhD
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For author affiliations and current author addresses, see end of text. Grant Support: In part by GI Basic Research Training grant DK07198 (Dr. Ramzan), public health service grants AI32403 and AI45253 from the National Institutes of Health (Dr. Persing), Centers for Disease Control Cooperative Agreement U50-CCU-510343, the Lucille P. Markey Charitable Trust (Dr. Relman), and National Institutes of Health grant K11 AI01360 (Dr. Fredricks). Acknowledgment: The authors thank Dr. Peter Wollan for statistical assistance. Requests for Reprints: David H. Persing, MD, PhD, Molecular Microbiology Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. Current Author Addresses: Drs. Ramzan, Loftus, Batts, Burgart, Wiesner, and Persing: Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;126(7):520-527. doi:10.7326/0003-4819-126-7-199704010-00004
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Background: Whipple disease is a chronic, multisystem disorder associated with infection with Tropheryma whippelii, an organism that has not yet been grown on artificial media. In some cases, the diagnosis of Whipple disease is uncertain if it is based on histology alone. Although antibiotic regimens of various durations have been used, the disease recurs in about one third of cases. No test for cure is available.

Objective: To develop a test that is more sensitive and specific than histologic examination to diagnose Whipple disease and monitor the effects of antibiotic therapy.

Design: Retrospective, laboratory-based evaluations of stored tissue specimens.

Patients: 30 patients with clinically diagnosed, histologically confirmed Whipple disease and 8 patients in whom Whipple disease was clinically suspected but who did not have definitive histologic evidence.

Measurements: Pretreatment and post-treatment biopsy specimens of the small bowel and lymph node were tested by polymerase chain reaction for the presence of T. whippelii DNA.

Results: Results on PCR were positive in 29 of the 30 specimens from patients with histologically confirmed disease (sensitivity, 96.6%; specificity, 100%) and in 7 of the 8 specimens from patients in whom disease was clinically suspected. Small-bowel biopsy specimens were obtained after treatment from 17 patients (median duration of follow-up, 119 months); specimens from 12 of these patients had positive results on PCR. When these cases were correlated with therapeutic outcome, it was found that 7 of the 12 patients had clinical relapse during subsequent follow-up or had never responded to treatment (positive predictive value, 58% [95% CI, 28% to 85%]). In contrast, none of the 5 patients whose post-treatment biopsy specimens had negative results on PCR had relapse (negative predictive value, 100% [CI, 48% to 100%]; P = 0.044). No correlation was found between post-treatment histology and clinical outcome (P > 0.2).

Conclusions: Polymerase chain reaction is highly sensitive and specific when used to confirm the diagnosis of Whipple disease, to identify inconclusive and suspicious cases, and to monitor response to therapy. A negative result on PCR may predict a low likelihood of clinical relapse; a positive test result that remains positive despite therapy may be associated with a poor clinical outcome. Histopathologic evaluation of post-treatment specimens does not predict clinical cure or relapse.





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