Research Article
19 January 2023

Contribution of PCR to Differential Diagnosis between Patients with Whipple Disease and Tropheryma whipplei Carriers


Differentiation between Whipple disease (WD) patients and patients carrying Tropheryma whipplei but suffering from disease other than WD (“carriers”) remains complex. We aimed to evaluate T. whipplei PCR among patients with WD and carriers in a large cohort at our referral clinical microbiology laboratory. This is an observational retrospective cohort study, including all patients between 2008 and 2020 with at least one positive result for T. whipplei using the real-time PCR RealCycler TRWH-UX kit. A total of 233 patients were included: 197 were considered carriers, and 36 had WD. Among the WD patients, 32 underwent biopsies, of which 18 (56%) had a positive periodic acid-Schiff (PAS) staining. Among the 27 duodenal biopsy specimens, 13 (48%) were PAS positive. PCR results before antibiotic treatment were positive in both feces and saliva in 16/21 WD (76%) patients and 68/197 (35%) carriers (P < 0.001). Duodenal biopsy specimens yielded positive PCR in 20/22 (91%) WD patients and 27/72 (38%) carriers (P < 0.001). The cycle threshold (CT) value detected in duodenal biopsy specimens from WD patients was significantly lower than that of carriers (P < 0.001), regardless of the PAS staining results. For a diagnosis of WD, duodenal PCR sensitivity and specificity at a CT value below 30 were 52.4% and >99.9%, respectively. The high specificity of duodenal PCR with low CT values may help confirming the diagnosis of WD, especially in patients with negative PAS results in digestive biopsy specimens, who represent half of all patients. A low PCR CT value from a duodenal biopsy specimen provides valuable guidance, especially in patients with PAS-negative results.


Tropheryma whipplei infection remains a difficult diagnosis based on clinical, pathological, and microbiological results (1, 2). In patients with classic Whipple disease (WD), duodeno-jejunal biopsy specimens provide evidence of infiltration of the mucosa by foamy macrophages stained with periodic acid-Schiff (PAS) (1, 3). The amplification of a T. whipplei-specific gene by PCR from digestive tract specimens confirms the diagnosis. Patients with arthritis, central nervous system involvement, uveitis, endocarditis, or spondylodiscitis may have no digestive symptoms, and histological analyses of specimens from the proximal intestine may be negative (3). In some of these patients with localized WD, digestive tract specimens are PCR positive for T. whipplei (3, 4).
Asymptomatic carriage of the bacteria has been described in the general population at rates of up to 10% according to the level of exposure (5). Therefore, the interpretation of a positive PCR for T. whipplei in saliva or feces in a patient with nonspecific symptoms becomes challenging to differentiate patients with localized WD from carriers (3).
As PCR tests for T. whipplei on saliva and stool samples are now included among the initial diagnostic tests for WD diagnosis (3), the number of samples analyzed has increased during the last 10 years in many laboratories where the PCR assays have been implemented (6). PCR of feces and saliva seemed to be a useful test to identify patients hosting the bacteria (7), but interpretation of a positive result is still difficult (8). Furthermore, PCR positivity in duodenal samples has also been reported in healthy carriers (9), making the interpretation of microbiological results even more complex.
Hence, the objective of the present study was to compare microbiological results between patients with WD and T. whipplei carriers.


Study design and definitions.

This observational retrospective case-control study was conducted at the Clinical Microbiology Laboratory of the Necker Hospital in Paris, France, which centralizes the Whipple PCR tests from over 10 Parisian university hospitals. A cohort was constituted with all patients who presented signs and symptoms that initially suggested a diagnosis of WD and for whom at least one T. whipplei-positive PCR result was found between January 2008 and July 2020. Medical records were reviewed for collection of relevant clinical data concerning age, sex, final diagnosis, age at diagnosis, signs and symptoms, date of first symptoms and diagnosis, treatment, dates of the institution and ending of treatment, pathological results, number of PCR tests requested, and the cycle threshold (CT) value. Only patients with PCR performed on samples before antibiotic treatment were included. Patients with no available clinical history, with a follow-up of less than 6 months, or who died within 6 months were excluded. This study was conducted in compliance with the Helsinki Declaration and approved by Cochin University Hospital Ethics Committee (AAA-2022-08021).
Patients were classified according to the final diagnosis between WD cases and T. whipplei carriers for test performance analysis. WD cases had to fulfil the following criteria (10): (i) the clinical criteria consistent with a diagnosis of WD include unintentional weight loss, unexplained arthritis, chronic fever, chronic diarrhea, or endocarditis (3), (ii) the molecular criteria include at least one positive PCR on feces or saliva or at least one positive PCR for T. whipplei in sterile tissues (blood, cerebrospinal fluid [CSF], lymph node, synovial fluid), and (iii) the histological criteria include a positive PAS staining for the identification of the intracellular pathogen recovered from a biopsy specimen (1, 3). When the PAS staining was negative, the diagnosis of localized WD was made in patients fulfilling the above clinical and molecular criteria, who additionally had a complete and rapid symptom resolution after initiation of antibiotic treatment. Carriers were defined as patients fulfilling the same clinical criteria with at least one positive PCR test for T. whipplei from feces or saliva but not from sterile tissue and having negative biopsy specimen PAS staining.

PCR assays.

All samples were analyzed using the real-time PCR RealCycler TRWH-UX kit (Progenie Molecular) following the manufacturer’s recommendations. Briefly, the samples were extracted by the automated EMAG system (bioMérieux, Marcy l’Etoile, France) and then amplified with the CFX196 thermocycler, with primers targeting the repeated regions of the WiSP family proteins (11). The sensitivity reported by the manufacturer is 10 copies/µL. The absence of PCR inhibitors was monitored by the concomitant amplification of an internal control in each reaction. In addition to the qualitative PCR result (positive versus negative), the PCR CT was recorded. The CT value corresponds to the lowest number of PCR cycles required to reach the positivity threshold in a positive sample, thus rendering PCR into a semiquantitative test, for which CT values are inversely related to the bacterial load in the sample. In addition, for all duodenal biopsy specimens, an rpoB PCR followed by sequencing of the 650-bp amplified product was performed on patients and carriers (12).

Statistical analysis.

All analyses were performed using the RStudio 3.6.1 software. Data are displayed using descriptive statistics: total numbers and percentages were used for categorical variables and mean ± standard deviation (SD) for continuous variables. Categorical variables were compared between WD patients and carriers using the chi-square test, while continuous variables were compared using Student's t test. Statistical significance was defined as a P value of <0.05.
The PCRs’ performance, including their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated on the basis of the case-control comparison (WD versus carriage), using as a “gold standard” the combined diagnostic criteria described above.


Clinical characteristics.

Three hundred fifty-five patients had at least one positive PCR sample for T. whipplei during the past 13 years. Seventy-six patients were excluded because of insufficient clinical data and 46 because no samples were available before introduction of an antibiotic therapy. Overall, 233 patients were included in this cohort: 36 with WD and 197 carriers (Fig. 1). Seventy percent of the WD patients were men with a mean age at the symptoms’ onset of 49 ± 13 years. Compared to carriers, WD patients had significantly more frequent arthralgia/arthritis, unintentional weight loss, adenopathies, and unexplained chronic fever. Among carriers, unexplained arthralgia/arthritis, chronic diarrhea, or ophthalmic symptoms (uveitis) were the leading symptoms justifying a T. whipplei PCR test (Table 1).
FIG 1 Flow chart of the study population with patient characteristic numbers and PAS and PCR results from the different biopsy specimens included.
TABLE 1 Clinical characteristics of the study population
Clinical characteristicResult fora:P valueb
Total (n = 233)WD patients (n = 36)T. whipplei carriers (n = 197)
Men, no. (%)120 (51)25 (70)94 (48)0.016
Age at onset of symptoms, yr4549 ± 1344 ± 180.113
Age at diagnosis, yrNA56 ± 12NANA
Clinical manifestations, no. (%)    
 Arthralgia/arthritis159 (68)30 (83)129 (65)0.034
 Chronic diarrhea67 (29)14 (39)53 (27)0.144
 Neurologic41 (18)8 (22)33 (17)0.428
 Cardiac13 (6)9 (25)4 (2)<0.001
 Unintentional wt loss66 (28)24 (67)42 (21)<0.001
 Unexplained fever46 (20)15 (42)30 (15)<0.001
 Adenopathy40 (17)16 (44)24 (12)<0.001
 Ophthalmologic32 (14)3 (8)29 (15)0.306
Continuous variables are expressed as means ± SD. WD, Whipple disease; NA, not applicable.
Boldface for significant P values and for different categories.


Among the 36 WD patients, 32 underwent biopsies, including 27 duodenal biopsies. Half of these biopsy specimens (14/27) were negative in PAS staining despite diagnosis of WD (Fig. 1). Other positive PAS stainings were found either on lymph nodes (4/4) or on vitrectomy (1/1) specimens. Half of WD patients had a localized disease with no evidence of macrophage infiltration demonstrated in biopsy specimens. Four patients refused digestive endoscopy; they were considered as having WD according to clinical criteria consistent with a diagnosis of WD and with complete resolution of signs and symptoms after antibiotic treatment in association with a positive PCR in a deep sample (CSF, lymph node [n = 1 each] or blood [n = 2]).


All WD patients received specific antibiotic treatment following, in most cases, the French treatment recommendations (1) based on the combination of doxycycline at 200 mg/day and hydroxychloroquine at 600 mg/day (n = 32/36 [86%]), sometimes associated with trimethoprim-sulfamethoxazole (TMP/SMT) (n = 13/36 [40%]). Five WD patients additionally received sulfadiazine due to neurological involvement. With antibiotic treatment, complete resolution of symptoms was observed in all patients within 4 weeks except for those with neurologic presentation. Twenty-one patients are still under lifelong antibiotic therapy.
Thirty-three carriers received an antibiotic treatment without any clinical success (lack of symptomatic resolution).

PCR analyses.

(i) Feces and saliva. Twenty-one WD patients for whom PCRs on both feces and saliva was performed were compared to 197 carriers with available PCR results from both feces and saliva specimens (see Fig. S1 in the supplemental material). As presented in Table 2, PCR results from feces and saliva were more frequently positive in WD patients (16/21 [76%]) than carriers (68/197 [35%]) (P < 0.001). On the other hand, carriers had significantly more frequently isolated positive feces PCR results than WD patients. There was no overall difference in PCR CT values between WD patients and carriers (Table 2), even in patients with positive results from feces and saliva (P = 0.056).
TABLE 2 Comparison of PCR results and CT values in feces, saliva, blood, CSF, synovial fluid, urine, digestive, and lymph node biopsy specimens in WD patients and carriersa
PCR result and CTNo. (%) forb:P value
WD patientsCarriers
Feces+ and saliva+16/21 (76)68/197 (35)<0.001
CT for feces32.1 ± 5.034.3 ± 3.80.056
CT for saliva31.4 ± 5.832.7 ± 5.70.391
Feces+ and saliva3/21 (14)87/197 (44)0.008
CT for feces34.7 ± 3.136.1 ± 3.10.443
Feces and saliva+2/21 (10)42/197 (21)0.200
CT for saliva33.2 ± 5.234.9 ± 3.50.800
Feces and saliva00 
Global feces32.6 ± 4.733.3 ± 3.60.441
Global saliva31.8 ± 5.533.6 ± 5.00.165
Blood+12/23 (52)1/129 (<1)<0.001
CT for blood33.2 ± 5.937.1 
CSF+9/19 (47)0/34 (0)0.005
CT for CSF33.2 ± 4.3NA 
Synovial fluid+1/1 (100)0/17 (0)<0.001
CT for synovial fluid34.8NA 
Urine+1/4 (25)2/44 (5)0.106
CT for urine31.939.2 
Digestive biopsy+20/22 (91)27/72 (38)<0.001
CT for digestive biopsy26.3 ± 8.336.9 ± 2.7<0.001
Lymph node+4/4 (100)0/2NA
CT for lymph nodes22.8 ± 3.7NA 
Continuous variables are expressed as means ± SD. Categorical variables are expressed as ratios (no. of positive results)/(total no. of tests performed) followed by percentage of positivity in parentheses. WD, Whipple disease; CSF, cerebrospinal fluid; CT, cycle threshold; NA, not applicable.
Boldface for significant P values and for different categories.
(ii) Other samples. The distributions of positive PCR results from blood, CSF, synovial fluids, urine, digestive biopsy specimens, and lymph nodes are shown in Table 2. Blood PCR results were positive in 12 among 23 WD patients. Three of them had endocarditis, and the others had no relevant clinical characteristics compared to those with negative blood PCR (data not shown). On the other hand, one patient among 129 carriers had a positive blood sample. The latter result was finally considered a false positive (contamination) because an alternative diagnosis of HLA B27-positive spondyloarthritis was retained in this patient. In addition, blood PCR results were confirmed to be negative by the National Reference Center in Marseille (France).
Most (20/22) of the WD patients who underwent a PCR test on a duodenal biopsy specimen had a positive result compared to carriers (27/72) (91% versus 38%; P < 0.001) (Table 2). The two negative duodenal biopsies were diagnosed as WD because of a positive synovial fluid sample for one of them and because of complete symptom resolution under antibiotic treatment in both cases. The characteristics of the positive PCR subpopulation are presented in Table S1. The CT value detected in duodenal biopsies of WD patients was significantly lower (P < 0.001) than CT values from carriers, and values over or below 30 have a high discriminant power. Results according to the duodenal biopsy CT value are shown on Fig. 2. For all WiSP PCRs with a CT value below 30, rpoB gene sequencing was positive, in contrast to WiSP PCRs with a CT value of over 30, for which rpoB gene sequencing remained negative (data not shown).
FIG 2 Comparison of duodenal biopsy PCR CT values before treatment between WD patients and carriers. The horizontal black lines represent the median of each group. ***, P < 0.001. WD, Whipple disease; PAS, periodic acid-Schiff stain.
There was no difference in the CT values among WD patients according to the PAS staining results, with mean CT values of 24.5 ± 9.6 and 27.5 ± 7.5 in the case of positivity or negativity of PAS staining (P = 0.669), respectively.
Clinical and biological characteristics of carriers were also investigated according to the duodenal PCR results (Table S2). Among this population of carriers, those with a positive duodenal PCR test had statistically lower CT values in the stool specimens (P = 0.003).

Duodenal biopsy specimen PCR sensitivity and specificity.

In Fig. 3A, the receiver operating characteristic (ROC) curve obtained for the duodenal biopsy PCR CT value shows a sensitivity of 55.0% (95% confidence interval [CI] = 34.2 to 74.2) and a specificity of >99.9% (95% CI = 87.5 to 100) at a CT cutoff value of 30. The area under the concentration-time curve (AUC) was 0.911 (95% CI = 0.829 to 0.993). Considering a CT cutoff value of 30, the PPV and NPV for a diagnosis of WD were >99.9% and 75.0%, respectively (Fig. 3B).
FIG 3 (A) ROC curve of the duodenal biopsy CT values; (B) contingency table used to perform sensitivity, specificity, PPV, and NPV calculations at a CT cutoff of 30.


In this large observational study, T. whipplei PCR results targeting WiSP regions were positive in both feces and saliva specimens in 76% of WD patients and 35% of carriers. PCR performed on digestive biopsy specimens was positive for 38% of carriers, thus limiting its diagnostic performance. However, the CT value detected in WD duodenal biopsy specimens was significantly lower than the one of carriers, with more than 99.9% specificity at a CT value of ≤30, regardless of the PAS staining results, indicating that duodenal biopsy specimens with a CT value of ≤30 yielded the most interesting and highest diagnostic performance, especially in patients with negative PAS staining.
We found that a CT value of ≤30 using WiSP PCR yielded T. whipplei sequences in 100% of cases using rpoB primers. This suggests that biopsy specimens with a WiSP PCR CT value of >30 have too small an amount of T. whipplei DNA, which does not allow for interpretable sequence results. However, the absence of such sequences should raise the question of a false positivity of this PCR when CT values are high. This hypothesis does not seem to be relevant as nine patients with a definite diagnosis of WD (clinical and pathological diagnosis) had biopsy specimens with PCR CT values of >30. It seems therefore that the most likely hypothesis is a lower sensitivity of the rpoB gene sequencing than real-time PCR.
The WD patients and carriers described in the present study are consistent with previous reports regarding the sex distribution, age, and time between symptoms’ onset and WD diagnosis (13). Nowadays, Whipple disease remains difficult to diagnose, as the clinical expression is wide and often nonspecific. Furthermore, PAS-positive staining remains negative in almost half of the cases, as found in our cohort, although it is a reliable marker of the disease (14). Therefore, PCR has become the main diagnostic support for clinicians.
To our knowledge, this is the first time that a low duodenal biopsy specimen CT value is reported to have an excellent specificity for the diagnosis of WD. CT values of duodenal samples were significantly lower in WD patients than in carriers. This finding was not influenced by the results of the PAS staining but was found similarly in both patients with positive PAS staining and those without. The difference remains also significant in patients with localized WD with negative PAS staining and for whom diagnosis remains the most challenging. Consistent with our finding, Grasman et al. also observed that all WD CT values on duodenal biopsy specimens were lower than those of controls, although the difference did not reach significance due to their limited sample size (9). Here, we were able to confirm the significant association of this low CT value with a diagnosis of WD in a large cohort of WD patients and carriers. A low PCR CT value is directly related to a high bacterial load. WD patients have been reported to have lower duodenal CT values than carriers (5, 7, 15), suggesting an association between bacterial load and pathogenicity. This result can thus help to better classify the disease, especially in patients with PAS-negative results. Duodenal PCR results should be integrated in the strategy as other studies have showed that patients with positive or negative PAS staining of a duodenal biopsy sample showed similar clinical features, responses to antibiotics, and outcome of patients diagnosed as classical WD (16).
Additionally, our analysis showed no statistical differences of CT values in stool and saliva samples between WD patients and carriers. Nevertheless, among the patients who underwent duodenal biopsies, WD patients had lower CT values in the stools than the carriers. This trend was also observed when comparing carriers with positive and negative duodenal PCR results. Therefore, patients with positive duodenal biopsy specimens tend to have a higher excreted bacterial load in the lumen than patients with negative ones. This suggests that higher bacterial tissue replication could be associated with a higher excretion, which emphasize the role of quantitative PCR results.
A positive PCR result in both feces and saliva was associated with lower sensitivity, specificity, and PPV than were reported in previous studies (6, 7). However, the discrepancies may be explained by the limited number of carriers in those previous studies (n = 14 and n = 7, respectively) and by a different selection of our controls, who all presented symptoms that suggested initially to clinicians the hypothesis of WD diagnosis. Moreover, positive stools and saliva showed a statistical difference between WD patients and carriers. They are included in the initial diagnostic of WD because of their ease of sampling and because they allow early detection and elimination of WD diagnosis. The results obtained here confirm the interest in this diagnostic strategy.
Interestingly, we found that 22% of the WD patients had neurologic symptoms in line with previous descriptions (17, 18). Importantly, nine cerebrospinal fluid (CSF) PCR results were positive in the WD group, four of them without neurological symptoms, underlining the need to screen for neurologic involvement by performing a PCR on CSF, which is part of the recommendations before treatment (3).
We also found positive PCR results in blood in half of the WD patients, which shows a lack of sensibility of this analysis to detect WD as has already been reported (7, 19). PCR testing from lymph nodes (20), synovial fluid (21), and urine (22) should also be kept in mind when facing a suspicion of WD, as we found here, despite the rare reported cases.
The possibility of pathogenicity of T. whipplei by other means than direct infection within the duodenal mucosae or other tissues might also be possible and should be investigated in the future. Puéchal et al. evoked this hypothesis for some arthritis that could result as an immunoreactive process as observed in Lyme or other reactive arthritis (23). In other words, it may be recalled that although a positive PCR in duodenal biopsy or tissues is required before lasting use of antibiotics, a negative PCR in duodenal mucosae may not rule out a contribution of T. whipplei to the symptoms observed.
The main strength of this study is its large sample size, including more than 12 years of Whipple diagnosis in Paris and a control group, including patients for whom the diagnosis of WD was initially considered. The WD group is also similar to what has already been described in terms of demographic and clinical characteristics. In addition, analysis of different types of samples’ PCR results allowed us to assess their diagnostic value and to show statistically significant PCR results at a CT value below 30 for duodenal digestive biopsies.
Nevertheless, this study has some limitations. First, the risk of false-positive results exists, as illustrated by the positive PCR result in one blood sample in the carrier group. The negative controls added in all PCR series help to prevent their occurrence. Second, this study has an intrinsic limitation due its retrospective design. Some patients could not be included because of missing data, recall bias, unclear diagnosis, or loss of follow-up. Third, a low sensitivity of 52.4% was associated with digestive biopsy PCR results at the CT value cutoff of 30, showing it cannot be used to discriminate WD patients on the basis of digestive biopsy values. This result may also be influenced by biopsy sampling (size and/or localization of sampling), as it is difficult to standardize the amount of biopsy specimen used for PCR. Nevertheless, all biopsy specimens sent to our laboratory have similar sizes—around 4 mm in diameter. However, we are aware that variability in the quality of the biopsy specimens may exist, depending on techniques, materials used or operator performing the endoscopy. This may limit the results of the interpretation of the CT cutoff, so a standardization based on biopsy mass or total DNA amount should be considered in the future. A low CT (below 30 with our technique) in WD patients should then be confirmed by a quantitative PCR, whatever the qualitative technique first used. It must be recalled that T. whipplei can be found in other locations of the digestive tract, such as the colonic (9) or stomach (24) mucosae, and this has not been investigated in this study.
Finally, in our cohort, the few PCRs found positive in urine did not help to establish the diagnosis.
In conclusion, this study, which analyzed the diagnostic values of T. whipplei PCRs on different samples, confirmed that their interpretation may still be difficult to differentiate WD patients from carriers. However, a low duodenal PCR CT value had excellent specificity and positive predictive value, regardless of PAS staining results, and thus may be helpful for diagnosing WD in patients with negative PAS digestive biopsy results. High duodenal CT values need confirmatory testing to differentiate between WD versus colonization. Further prospective studies should be performed to confirm these data.


We declare no conflict of interest.
X.P. and A.F. contributed to the conception and design of the study. G.Q. and I.M. contributed to sample processing. S.M. acquired, analyzed, and interpreted the data. S.M., X.P., A.J., and A.F. drafted the article, and all authors approved the final version.

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Information & Contributors


Published In

cover image Journal of Clinical Microbiology
Journal of Clinical Microbiology
Volume 61Number 222 February 2023
eLocator: e01457-22
Editor: Erin McElvania, NorthShore University HealthSystem
PubMed: 36656022


Received: 6 October 2022
Returned for modification: 21 November 2022
Accepted: 5 December 2022
Published online: 19 January 2023


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  1. Tropheryma whipplei
  2. Whipple
  3. PCR
  4. carriers
  5. duodenal biopsy



Department of Clinical Microbiology, AP-HP Centre Université de Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
Xavier Puéchal
National Referral Center for Rare Systemic Autoimmune Diseases, AP-HP Centre Université de Paris Cité, Hôpital Cochin, Paris, France
Gilles Quesne
Department of Clinical Microbiology, AP-HP Centre Université de Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
Isabelle Marques
Department of Clinical Microbiology, AP-HP Centre Université de Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
Anne Jamet
Department of Clinical Microbiology, AP-HP Centre Université de Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Paris, France
Agnès Ferroni
Department of Clinical Microbiology, AP-HP Centre Université de Paris Cité, Hôpital Necker-Enfants Malades, Paris, France


Erin McElvania
NorthShore University HealthSystem


The authors declare no conflict of interest.

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