Greub, Gilbert

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522 • CID 2010:51 (1 September) • EDITORIAL COMMENTARYE D I T O R I A L C O M M E N T A R YA New Piece Added to the Whipple Puzzle: Tropherymawhipplei Primary Infection with Bacteremia and CoughGilbert GreubInstitute of Microbiology and Service of Infectious Diseases, University of Lausanne and University Hospital Center, Lausanne, Switzerland(See the article by Fenollar et al, on pages 515–521.)In 1907, when the first case of Whippledisease was described by George Whipple,the clinical presentation of the disease, al-though not considered to be of infectiousorigin, already included cough and diar-rhea [1]. This index patient had a chronicform of the disease, coined here as late-onset Whipple disease. During the pastcentury, Whipple disease has been consid-ered to be a rare and chronic disease,mainly affecting white, middle-aged menand presenting mainly as diarrhea, weightloss, steatorrhea, arthralgia, lymphade-nopathy, anemia, and, to a lesser extent,neurologic impairments, ocular involve-ment, and/or endocarditis [2]. The visu-alization by electron microscopy of rodsin intestinal biopsy specimens suggestedthat Whipple disease was of microbial or-igin [3, 4], a hypothesis confirmed in the1990s by sequencing the 16S ribosomalRNA encoding gene of the causative bac-teria [5, 6], named Tropheryma whipplei[7].However, our understanding of the ep-Received 26 May 2010; accepted 27 May 2010; electronicallypublished 26 July 2010.Reprints or correspondence: Dr Gilbert Greub, InfectiousDiseases Service and Institute of Microbiology, University Hos-pital Center and University of Lausanne, Lausanne, Switzerland(gilbert.greub@chuv.ch).Clinical Infectious Diseases 2010; 51(5):522–524 2010 by the Infectious Diseases Society of America. Allrights reserved.1058-4838/2010/5105-0006$15.00DOI: 10.1086/655678idemiology, mode of transmission, path-ogenesis, and natural history of Whippledisease remained largely incomplete, beingimpaired by the few diagnostic tools avail-able. Indeed, the diagnosis still mainly re-lies on histologic analysis (periodic acid–Schiff–positive macrophages), polymerasechain reaction (PCR), and immunohis-tochemical analysis [2, 8, 9]. Cultureproved to be challenging because of theslow replication rate of the bacteria (gen-eration time of∼18 days) [10], and cultureis still currently performed only in a fewspecialized laboratories. Moreover, devel-opment of serologic tools has been com-plicated by the paradoxical lack of anti-body response in serum samples takenfrom patients with late-onset Whipple dis-ease, likely related to glycosylation of bac-terial antigens, which allows the bacteriato mask its own major antigens [11].The mode of transmission and the clin-ical presentation of acute T. whipplei pri-mary infection was partially uncovered re-cently. Fecal-oral transmission was sug-gested by the amplification of bacterialDNA from sewage and from feces of sewerworkers and by the higher prevalenceamong this occupationally exposed pop-ulation [12, 13]. Moreover, the coinciden-tal presence of the bacteria with other en-teric pathogens, such as Giardia lamblia[14], further supported the hypothesis ofa fecal-oral transmission. Although fecal-oral primary infection might be asymp-tomatic, Raoult et al [15] hypothesizedthat T. whipplei might cause gastroenter-itis. They thus studied prospectivelyFrench children with and without gastro-intestinal symptoms, convincingly dem-onstrating that T. whipplei may indeedrepresent an agent of gastroenteritis be-cause both increased immunoglobulin Mtiters and higher bacterial DNA load wereobserved among cases.The same group reported a high prev-alence (44%) of T. whipplei DNA in stoolsfrom healthy 2- to 10-year-old childrenliving in Ndiop and Dielmo, 2 rural vil-lages located in the south of Senegal [16].Suspecting an ongoing outbreak of acuteWhipple disease, Fennolar et al [17] un-dertook the study reported in this issueand identified 13 bacteremic cases amongfebrile patients living in these 2 villages.Interestingly, most cases were identifiedduring the dry season (December to Jan-uary) and among children (np10). How-ever, contrary to what has been expected,the bacteremia was not associated with di-arrhea (np1) but rather with cough (np10) and sleep disorders (np5). Thisstudy thus adds an important new pieceto the Whipple puzzle that makes it pos-sible to consider febrile bacteremia andcough as possible common clinical pre-sentations of acute T. whipplei infection.This new information completely changesEDITORIAL COMMENTARY • CID 2010:51 (1 September) • 523Figure 1. A new piece added to the puzzle describing the natural history of Whipple disease. A, Interhuman transmission likely takes place through fecal-oral contamination. However, infection might also possibly follow exposure to human saliva and/or aerosols or be associated with yet unknown environmentalor zoonotic risks. B, Primary infection might be asymptomatic but may also present as a febrile illness associated with cough and sleep disorders, as demonstratedby Fenollar et al. in this issue [17]. This additional piece added to the Whipple puzzle also supports previous reports that suggest a role of T. whipplei as anagent of pneumonia [18, 19]. Nevertheless, primary infection might also present as a common gastroenteritis [15] and some yet unknown additional syndromes.C, Only a limited number of patients will later develop focal or multifocal clinical manifestation of late-onset Whipple disease. Immunogenetic factors are likelyimportant in this rare pathological evolution [23]. Please note that the list of manifestations provided here is not exhaustive. Focal manifestations such asprodromal arthritis may precede classic multifocal Whipple disease for years. D and E, Most infected patients would either became asymptomatic carriers orcompletely recover from T. whipplei primary infection. Whether asymptomatic carriers are at risk to later develop clinical manifestations of focal or multifocallate-onset Whipple disease is yet unknown.the way we perceive the pathogenesis andnatural history of Whipple disease. Thus,in addition to the rare late-onset Whippledisease that includes both focal and mul-tifocal clinical manifestations, T. whippleialso causes an acute common illness, likelycorresponding to primary infection withbacteremia, cough, and/or gastroenteritis(Figure 1).The absence of T. whipplei DNA in allinvestigated water sources present inNdiop and Dielmo villages suggested hu-man-to-human transmission. Althoughprimary infection after oral-oral and/orfecal-oral transmission is suggested by thepresence of T. whipplei DNA in both sali-va and stools from healthy individuals(asymptomatic carriers), the clinical pre-sentation observed by Fenollar et al [17]among 10 of the 13 bacteremic patients(ie, fever and cough) might also possiblyreflect an airborne transmission. Thus,respiratory tract infection might be con-secutive to inhalation of infected droplets,whereas gastroenteritis might follow in-gestion of infectious particles.Recent evidence suggests a role of T.whipplei as an agent of pneumonia [18,19]. In 1 of these reports, T. whipplei wasidentified in 6 (3%) of 210 bronchoalveo-lar lavages tested [19]. Notably, 3 patientsexperienced aspiration pneumonia. Be-cause T. whipplei may be present in thesaliva of asymptomatic persons [20, 21],it has been proposed that this gram-pos-itive rod could contribute to aspirationpneumonia along with other bacteria pres-ent in the oropharyngeal microbiota [19].Conversely, the presence of T. whippleiDNA in the saliva of asymptomatic pa-tients complicates the interpretation ofDNA positivity in bronchoalveolar lavages(possible contamination of the respiratorysample with saliva). Moreover, in the workof Bousbia et al [19], T. whipplei was gen-erally not the only detected agent. In thatcontext, the documentation by Fenollar etal [17] of an association between T. whip-plei bacteremia and cough is importantbecause it further supports a role of T.whipplei as a possible agent of lower res-piratory tract infection.One of the main limitations of the workperformed by Fenollar et al [17] is theabsence of a control group among Sene-galese patients. Indeed, the negative resultsof the PCR performed on the French con-trols support an absence of PCR contam-ination but do not rule out horizontalcontamination of the samples during theearly phase of DNA extraction performedin Senegal.Despite this limitation, the study per-formed by Fenollar et al [17] represents apivotal work that opens new questionsthat need to be addressed in the near fu-ture. The prevalence of T. whipplei bac-teremia and associated clinical manifes-tations needs to be defined thoroughly in524 • CID 2010:51 (1 September) • EDITORIAL COMMENTARYvarious populations (children, adults, andimmunocompromised individuals) fromdifferent geographical areas. The preva-lence of T. whipplei pneumonia [19] andgastroenteritis [15] also needs to be stud-ied in different settings. These studies mayhelp to identify the reservoir and mode oftransmission of T. whipplei. Although hu-man-to-human transmission is likely, en-vironmental (food, water, and soil) and/or zoonotic risks should also be searchedfor.The documentation of T. whipplei bac-teremia also raises important treatment is-sues. Apparently, all 13 bacteremic patientsevolved favorably even though most ofthem were left untreated [17]. Neverthe-less, we may wonder whether such bac-teremia needs to be treated (1) to furtherimprove short-term outcome, (2) to re-duce transmission, (3) to avoid asymp-tomatic carriage, and/or (4) to preventlate-onset T. whipplei infection in some ofthese patients. The latter question will onlybe solved by starting a prospective ran-domized cohort study of any patientsidentified in similar outbreaks of acute in-fection. Randomization for treatment ver-sus absence of treatment includes an im-portant ethical issue given the unknownrisk of development of severe difficult-to-treat late-onset Whipple disease, suchas encephalitis or endocarditis. The un-treated group will be pivotal to define thenatural history of Whipple disease and toidentify factors associated with the rare de-velopment of late-onset Whipple disease.Given the absence of correlation of T.whipplei genotypes with clinical presen-tation [22], host factors are likely to playa major role. Some immunogenetic factorshave recently been identified [23], andthese hosts factors may explain why sucha common primary infection with bacte-remia, pneumonia, and/or gastroenteritisonly rarely causes focal or multifocal late-onset Whipple disease. Genetic factorsmay also potentially explain why late-on-set Whipple disease has been reportedmore frequently among white, male in-dividuals. In addition to genetic factors,the apparent discrepancy between the rel-atively high prevalence of acute T. whippleiinfection in Africa and the near absenceof classic Whipple disease among Africanresidents might also be partially explainedby the lower rate of recognition of late-onset Whipple disease.In conclusion, the landmark article byFenollar and colleagues published in thisissue of Clinical Infectious Diseases shouldbe added to the list of major contributionsto the understanding of Whipple diseasebecause it provides the first evidence of T.whipplei–associated bacteremia and rep-resents a missing piece of the primary-infection Whipple puzzle.AcknowledgmentsFinancial support. G.G. is supported by theLeenards Foundation through a career award en-titled “Bourse Leenards pour la rele`ve acade´miqueen me´decine clinique a` Lausanne.”Potential conflict of interests. G.G.: no con-flicts.References1. Whipple GH. A hiterto undescribed diseasecharacteized anatomically by deposits of fatand fatty acids in the intestinal and mesentericlymphatic tissues. John Hopkins Hosp Bull1907; 18:381–392.2. Schneider T, Moos V, Loddenkemper C,Marth T, Fenollar F, Raoult D. Whipple’s dis-ease: new aspects of pathogenesis and treat-ment. Lancet Infect Dis 2008; 8:179–190.3. Cohen AS, EM; Holt, PR; Isselbacher, KJ. Ul-trastructural abnormalities in Whipple’s dis-ease. Proc Soc Exp Biol Med 1960; 105:411–414.4. Cohen AS. An electron microscopic study ofthe structure of the small intestine in Whip-ple’s disease. J Ultrastruct Res 1964; 10:124–144.5. Wilson KH, Blitchington R, Frothingham R,Wilson JA. Phylogeny of the Whipple’s-dis-ease-associated bacterium. Lancet 1991; 338:474–475.6. Relman DA, Schmidt TM, MacDermott RP,Falkow S. Identification of the unculturedbacillus of Whipple’s disease. N Engl J Med1992; 327:293–301.7. La Scola B, Fenollar F, Fournier PE, Alt-wegg M, Mallet MN, Raoult D. 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A New Piece Added to the Whipple Puzzle: Tropheryma whipplei Primary Infection with Bacteremia and Cough

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