Elsevier

Journal of Infection

Volume 69, Issue 2, August 2014, Pages 103-112
Journal of Infection

Review
Tropheryma whipplei and Whipple's disease

https://doi.org/10.1016/j.jinf.2014.05.008Get rights and content

Highlights

  • Whipple's disease (WD) is rare but Tropheryma whipplei commonly infects humans.

  • Asymptomatic carriage of T. whipplei, mainly in feces, is observed.

  • Chronic infections include disseminated WD and localized infections, such as endocarditis.

  • T. whipplei is associated with acute infections: gastroenteritis, pneumonia, and bacteremia.

  • T. whipplei seems to be an opportunistic bacterium.

Summary

Since its identification, information concerning Tropheryma whipplei, the causative agent of Whipple's disease (WD), has increased. Although T. whipplei is commonly infecting humans, WD is rare. The bacterium is most likely transmitted among humans via the oro-oral and the feco-oral routes. Infections result in chronic conditions such as asymptomatic carriage, disseminated Whipple's disease, which is usually preceded by arthralgias, and localized infections, such as endocarditis or encephalitis. T. whipplei is associated with acute infections including gastroenteritis, pneumonia, and/or bacteremia. Screening, based on the combined analyses of saliva and stool specimens using specific quantitative PCR, is useful if WD is suspected. Doxycycline and hydroxychloroquine for 12 months is the best treatment for WD; it should be followed by life-long treatment with doxycycline, as potentially fatal relapses can occur. T. whipplei seems to be an opportunistic bacterium that causes chronic infections in susceptible patients with as yet unknown predisposing factors.

Introduction

Tropheryma whipplei was identified in the 1990s following the molecular sequencing of an unknown 16S rRNA sequence in the small-bowel biopsies of patients with Whipple's disease (WD).1 This disease, described in 1907, was first considered to be a metabolic disorder.2 In 2000, when the first T. whipplei cell cultures were established, WD was thought to result from an uncommon bacterium that caused a rare chronic infection.3, 4 The availability of T. whipplei cultures resulted in the full genome sequencing of the bacterium and the development of molecular tools for the diagnosis and treatment of WD.3, 5, 6, 7, 8, 9 This resulted in the discovery that, although WD is rare, T. whipplei is a common bacterium in humans.10, 11, 12, 13

T. whipplei can be involved in chronic, localized infections without systemic involvement and asymptomatic carriage (Fig. 1).13, 14 This bacterium has been also detected in acute infections such as pneumonia, gastroenteritis, and bacteremia, which may be T. whipplei “primary infections” that occur upon first contact with the bacterium (Fig. 1).10, 15, 16 Secondary acute infections, such as aspiration pneumonia, could also be observed in people previously infected with the bacterium.15, 16

T. whipplei carriage is endemic in sewer workers and is hyperendemic in rural Senegal (Africa), as well as in families of patients and carriers.10, 11, 12, 13, 17 Some genotypes of T. whipplei have been associated with limited strain outbreaks of gastroenteritis (France)10 and bacteremia (Senegal) (personal data). The seroprevalence in adult populations ranges from 50 to 70%, depending on the geographical location.11, 13, 18 The higher prevalence of T. whipplei in certain populations is not associated with a higher prevalence of WD, suggesting that only people with as yet unknown predisposing factors will develop WD.

Section snippets

Bacteriology

The ability to culture T. whipplei has resulted in the establishment of strains from small-bowel biopsies, heart valves, blood, cerebrospinal fluid (CSF), lymph node biopsies, skeletal muscular biopsies, synovial fluids, skin biopsies, saliva, feces, and broncho-alveolar liquid (BAL).17 Genome analysis has enabled the development of tools for diagnosis and genotyping; for the development of axenic culture media; and for the detection of antibiotic resistance, indicating the natural resistance

Reservoir, transmission, and epidemiology

WD patients and chronic carriers are the sources of T. whipplei among humans, but the bacterial load in the feces of carriers is lower than the load in WD patients.3, 6, 11, 12, 13 Contact with either feces or saliva is a plausible route for the transmission of T. whipplei, as the bacterium can be grown from both fecal and saliva samples.17 The prevalence of the carriage depends on age, exposure, and geographical area.11, 12, 13 Prevalence is higher among populations with poor personal hygiene,

Acute infections

T. whipplei has been detected in several acute infections. The different levels of causal evidence for its pathogenic role are summarized in Table 1.10, 15, 16 The percentage of symptomatic people at the time of primary infection is unknown as the infection spectrum is as yet unknown. Further studies will allow for the better determination of the effects and impacts of T. whipplei presence in these acute infections.

Chronic disseminated disease or classic WD

The typical patient is a Caucasian male (73–87%), approximately 50 year-old, who initially complains of intermittent arthralgias (73–80%) and suffers from chronic digestive troubles with diarrhea (72–81%) and/or weight loss (79–93%).3, 14, 28 The diagnosis is now commonly made after the appearance of new clinical manifestations such as weight loss, digestive troubles or fever when patients are treated for a rheumatologic disease with immunosuppressive therapy such as corticosteroids and tumor

Chronic localized infection

Many chronic localized infections located in the viscera without histological intestinal and systemic involvement have been described.14 Several differences exist between classic WD and chronic localized infection. Classic WD is a systemic disease; T. whipplei can be detected in the intestinal digestive tract but also in most of the organs, including the brain, heart, eyes, skin (even when no lesion is present), circulating monocytes, saliva, feces, and CSF (even in the absence of neurologic

Pathophysiology

A putative pathway of T. whipplei infections corresponding to our current speculations is shown on Fig. 3. Several findings suggest a genetic predisposition for WD: (i) most of the reported patients are Caucasian,14, 42, 43, 44 (ii) six familial-proven cases of this rare disease have been reported,3, 42, 45 (iii) a strong geographical specificity for this disease is observed,17, 34 and (iv) a higher frequency of the HLA alleles DRB*13 and DQB1*06 in patients with classic WD has been noted.43

Diagnosis

T. whipplei can be detected in various tissues, such as small-bowel biopsies and body fluids.48 The interpretation of molecular assays must be based on rigorous criteria.3, 6, 48 The quality of the extracted DNA from a sample must be checked by testing a human gene.48 Positive and negative controls are required in each assay.48 The accurate identification of T. whipplei must be confirmed using sequencing or specific probes.48 A case should be defined by 2 positive results in assays targeting 2

Treatment and follow-up

WD is a life-long disease with failures, relapses, and reinfections caused by different T. whipplei strains in patients who have been apparently cured.7, 42, 46, 50, 51, 52, 53, 54, 55 Relapses can occur as late as 20 years after the initial diagnosis and may occur in other organs than those previously involved.51

Until recently, treatment was empirical, with anecdotal reports from different countries.46, 50, 51, 53 Currently, we are in an era when antibiotic susceptibility testing must guide

Controversies

There are several discrepancies in the literature. For the treatment of classic WD, a difference is observed in the numbers of patients who relapse and fail following treatment with trimethoprim-sulfamethoxazole, with a contrast between the good results observed among German patients and the poor results observed in French patients.35, 46, 50, 53, 59 When investigating the clinical signs of endocarditis, discrepancies were observed for arthralgias, with a low frequency reported in a German

Conclusions

T. whipplei was first thought to be an uncommon bacterium that caused a rare disease. Subsequently, it has been shown to be a common bacterium that can cause asymptomatic carriage, a systemic generalized infection (WD), chronic localized infections, and various acute infections. With regard to WD, T. whipplei seems to be an opportunistic bacterium that causes chronic infections that are linked to an as yet unknown specific immunosuppression.

Funding source

This study was supported by the Programme Hospitalier de Recherche Clinique 2009 and the Foundation Mediterranée Infection.

Acknowledgments

We thank Laetitia Rouli for Supplementary Table 1 and Naima Ait-Gacem for her technical help.

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