Whipple Syndrome Definition
In our first two patients, the diagnosis was made mainly by biopsy of the small intestine. Specific PCR for T. whipplei from saliva and stool samples was considered a first-line non-invasive detection of ODS with high specificity when both samples are positive, but low sensitivity in localized WEDs requiring biopsy of affected tissues . In most cases, the small intestine is involved, but WD-related lesions can be minimal with false-negative results, especially if gastrointestinal symptoms are absent. Therefore, frequently repeated biopsies are required for diagnosis . To ensure the diagnosis of WD in these cases, two different diagnostic methods such as biopsy with PAS staining and PCR for T-specific 16S rRNA. whipplei should be used: WD is likely an underdiagnosed condition because T. whipplei bacteria can be found in asymptomatic carriers , and PCR tests can detect 16S T. whipplei rRNA in healthy volunteers .
The prevalence of the disease is higher in middle-aged men of European descent . In one study with healthy blood donors, one in 174 blood samples (0.6%) had a positive PCR for T. whipplei , and in another study of 620 healthy people, PCR was positive in 0.6% of saliva samples and 1.5% of stool samples . Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore). 2010;89(5):337–45. The disease is considered extremely rare, with an incidence (number of new cases per year) of one case per million people. The patients are predominantly male (86% in a survey of U.S.
patients), although in some countries the rate of women diagnosed with Whipple`s disease has increased in recent years. It occurs mainly in people of Caucasian ethnicity, suggesting a genetic predisposition in this population.  T. Whipplei appears to be an environmental organism commonly present in the gastrointestinal tract but remaining asymptomatic.  Several lines of evidence suggest that a defect – inherited or acquired – in immunity is necessary for it to become pathogenic.  The possible immunological defect may be specific to T. whipplei because the disease is not associated with a significantly increased risk of other infections.  The disease is usually diagnosed in middle age (median 49 years). Studies conducted in Germany have shown that age at diagnosis has increased since the 1960s.  In June 2015, the patient was referred for a second opinion.
A new upper endoscopy was performed with biopsy of the duodenum. In histology, infiltration of polymorphic nuclear granulocytes into the lamina propria has been observed at the same time as mild cryptitis. The PAS staining was negative with no aberrant macrophages or other WD-consistent results. PCR for T. whipplei was positive. They will likely recommend a procedure called upper GI endoscopy — a flexible tube with a camera at the end allows your doctor to take a closer look at the stomach lining and take a sample to be tested for T. whipplei. You will be given medication to help you relax during the procedure.
WD has a poor prognosis if left untreated. It is important to treat with antibiotics that cross the blood-brain barrier, as T. whipplei is often present in cerebrospinal fluid . CNS-free WED is first treated with intravenous ceftriaxone 2 g once daily or meropenem (three doses of 1 g/day) for 2 weeks, followed by maintenance therapy with oral TMP-SMX 160 mg/800 mg twice daily for 1 year . Treatment of WD with endocarditis is penicillin G (2 million IU IV every 4 hours) or ceftriaxone (2 g IV once daily) for 4 weeks, followed by TMP-SMX 160 mg/800 mg twice daily for 1 year. CNS involvement is treated with ceftriaxone (2 g IV once daily) or penicillin G (4 million IU IV every 4 hours) for 2 weeks, followed by TMP-SMX 160 mg/800 mg twice daily for 1 year. Alternative therapies for intolerance are meropenem (1 g IV every 8 hours) for 2 weeks, followed by doxycycline (200 mg daily) in combination with hydroxychloroquine (600 mg daily) for 1 year . The patient was readmitted and a colonoscopy was performed, which showed signs of relatively recent bleeding and diffuse mucosal edema. No obvious sources of bleeding or signs of IBD were found. In the distal ileum, a diffusely swollen mucosa with abundant white villi was observed (Fig.
1, 2), which raised the suspicion of WD. In the histology of ileum biopsies, a positive to mild to moderate Schiff periodic cell infiltrate (SBP) was present in the lamina propria with an abundance of histiocytes; Therefore, an image compatible with WD (Fig. 3). PCR for the 16S rRNA gene of T. Whipplei from the ileum was positive. Upper endoscopy revealed acute duodenitis with abundant tight fibrin (Fig. 4). Duodenal biopsies showed results similar to those of the ileum, i.e.
PAS-positive histiocytes with diastase-resistant granulated cytoplasm diagnosis for WD (Fig. 5) and positive PCR for the 16S rRNA gene of T. whipplei. Microscopy of an extirpated paraaortic lymph node was consistent with WD. Other PCR analyses for the 16S rRNA gene of T. whipplei were positive in serum but negative in cerebrospinal fluid (CSF). Transthoracic echocardiography (TTE) showed no signs of endocarditis or other abnormalities. Between 20% and 40% of people with Tropheryma whipplei infection have neurological problems. If Whipple`s disease affects the nervous system, you may have: Diagnosis is made by biopsy, usually by duodenal endoscopy, which shows PAS-positive macrophages in the lamina propria that contain non-acidic gram-positive bacilli.  [a] Immunohistochemical staining for antibodies against T. Whipplei has been used to detect the organism in a variety of tissues, and a polymerase chain reaction test is also available, which can be confirmed when performed on blood, vitreous fluid, synovial fluid, heart valves or cerebrospinal fluid.
 PCR of saliva, gastric or intestinal fluid, and stool samples is very sensitive, but not specific enough, suggesting that healthy individuals may harbor the causative bacteria even without the manifestation of Whipple`s disease, but that a negative PCR most likely indicates a healthy individual.  Diagnostic electron microscopy shows coccobacillary bodies representing the T-Whipplei organism. This is diagnostic because a polymerase chain reaction (PCR) positive for T-whipplei is present in the affected tissue. [7, 8, 9] Marth T. Systematic review: Whipple`s disease (Tropheryma whipplei infection) and its unmasking by tumour necrosis factor inhibitors. Food Pharmacol Ther. 2015;41(8):709–24. T. whipplei culture is time-consuming, possibly false negative, and is therefore not used in clinical routine. In addition, serology is not useful for diagnosis, as patients with WD and up to 70% of healthy individuals may develop a humoral immune response specific to T. whipplei .
The diagnosis of WD is therefore histopathological with the detection of PAS-positive inclusions in the histiocytes/macrophages of the lamina propria from biopsies of the mucosa of the small intestine, but also from other tissues such as synovial fluid, lymph nodes, cerebrospinal fluid and heart valves . Direct visualization of live or dead bacteria is possible with electron microscopy [3, 25], but is not available in many centers and is rarely needed today when RNA16 tests are available. Treatment with anti-TNF inhibitors can reverse these “characteristic” histopathological findings , as seen in patient two, where a first upper endoscopy failed diagnosis, highlighting the importance of including PCR tests on bioptic material in all cases of suspected WD.