Whipple's disease is a rare systemic infectious disease caused by the actinobacterium Tropheryma whipplei. Spondylodiscitis is an extremely rare manifestation of the infection and has previously been described in only three case reports. We present a 55-year-old man with persistent lumbago and signs of systemic illness, but without any gastrointestinal symptoms or arthralgia. The signal response in the lumbar spine in magnetic resonance tomography, both native and after intravenous gadolinium administration, was compatible with spondylodiscitis at the L4/L5 level. Culture of a specimen obtained by radiographically guided disc puncture and repeated blood cultures remained sterile. Tropheryma whipplei was detected by PCR amplification in material obtained from the disc specimen, from a biopsy of the terminal ileum and from the stool. The histology of duodenum, terminal ileum, colon and disc material was normal and, in particular, showed no PAS-positive inclusions in macrophages. Long-term antibiotic treatment with sulphamethoxazole and trimethoprim was successful, with marked improvement of the low back pain and normalisation of the systemic inflammatory signs. The possibility of Whipple's disease must be suspected in the case of a ‘culture-negative' spondylodiscitis even if there are no gastrointestinal symptoms and no arthralgia presen

Altwegg, M.

Gubler, J.

Maibach, R.

Morf, M.

Weber, U.

RERO DOC Digital Library

CASE REPORTU. Weber Æ M. H. Morf Æ J. G. H. Gubler Æ M. AltweggR. C. MaibachSpondylodiscitis as the first manifestation of Whipple’s disease–a removal worker with chronic low back painReceived: 24 January 2003 / Accepted: 15 May 2003 / Published online: 2 October 2003 Clinical Rheumatology 2003Abstract Whipples disease is a rare systemic infectiousdisease caused by the actinobacterium Tropherymawhipplei. Spondylodiscitis is an extremely rare manifes-tation of the infection and has previously been describedin only three case reports. We present a 55-year-old manwith persistent lumbago and signs of systemic illness, butwithout any gastrointestinal symptoms or arthralgia.The signal response in the lumbar spine in magneticresonance tomography, both native and after intrave-nous gadolinium administration, was compatible withspondylodiscitis at the L4/L5 level. Culture of a speci-men obtained by radiographically guided disc punctureand repeated blood cultures remained sterile. Trophe-ryma whipplei was detected by PCR ampliﬁcation inmaterial obtained from the disc specimen, from a biopsyof the terminal ileum and from the stool. The histologyof duodenum, terminal ileum, colon and disc materialwas normal and, in particular, showed no PAS-positiveinclusions in macrophages. Long-term antibiotic treat-ment with sulphamethoxazole and trimethoprim wassuccessful, with marked improvement of the low backpain and normalisation of the systemic inﬂammatorysigns. The possibility of Whipples disease must be sus-pected in the case of a culture-negative spondylodiscitiseven if there are no gastrointestinal symptoms and noarthralgia present.Keywords Low back pain Æ Spondylodiscitis ÆWhipples diseaseAbbreviations PAS Periodic acid–Schiff Æ PCR Poly-merase chain reaction Æ PSA Prostate-speciﬁc antigen ÆEDTA Ethylene diamine tetra-acetic acidIntroductionWhipples disease, ﬁrst described in 1907, is a systemicinfectious disease caused by Tropheryma whipplei. Themain clinical symptoms are diarrhoea, weight loss andarthralgia, with cardiac or central nervous manifestationsbeing indicative of a poor prognosis [1, 2, 3]. The clinicalsuspicion is usually conﬁrmedby the detection of diastase-resistant, non-acid fast PAS (periodic acid–Schiﬀ stain)-positive inclusions in macrophages of the small intestinalmucosa, or the electronmicroscopic imaging of the typicaltrilamellar cell membrane of the pathogen. Culture of theorganism has recently been described but is not availablefor routine diagnosis [4, 5].Molecular genetic detection bymeans of broad-spectrum PCR (polymerase chain reac-tion) ampliﬁcation of the bacterial 16S ribosomal RNAgene and subsequent identiﬁcation by sequencing of theamplicon or by species-speciﬁc PCR is gaining increasingdiagnostic relevance [2, 6, 7, 8, 9].We report a case of culture-negative spondylodiscitisas the ﬁrst manifestation of Whipples disease in whichthe pathogen was ﬁnally detected by broad-spectrumPCR with DNA isolated from disc puncture biopsymaterial.Case reportA 55-year-old removal worker was hospitalised forlumbago that had been refractory to physiotherapy andanalgesic medication for a year, with the appearance ofClin Rheumatol (2003) 22: 443–446DOI 10.1007/s10067-003-0786-2U. Weber (&)Physical Medicine and Rheumatology,Balgrist University Hospital,Forchstrasse 340, 8008 Zu¨rich, SwitzerlandE-mail: ulrich.weber@balgrist.chFax: +41-1-3863509M. H. MorfDepartment of Rheumatology and Rehabilitation,Triemli City Hospital, Zu¨rich, SwitzerlandJ. G. H. GublerDepartment of Medicine,Triemli City Hospital, Zu¨rich, SwitzerlandM. Altwegg Æ R. C. MaibachInstitute of Medical Microbiology,University of Zu¨rich, Zu¨rich, Switzerlandlower lumbar pain at night over the past 4 months.Systemic manifestations included loss of appetite, anunintentional loss of 4 kg in weight over 4 months, andoccasional night sweats. Arthralgia and gastrointestinalsymptoms such as diarrhoea or increased stool fre-quency were completely absent. The most prominentclinical features were lower lumbar percussion pain andthe reduction of lumbar spinal mobility by two-thirds.The neurological ﬁndings and peripheral joint statuswere normal. The patient was afebrile.The initial laboratory tests gave the following results:ESR 52 mm/h, CRP 50 mg/l (reference range up to10 mg/l), leucocytes 8.5·109/l with 48.5% stabnuclear;haemoglobin 14.9 g/dl, platelets 506·109/l; four bloodcultures without microbial growth; immune ﬁxation ofserum and urine as well as PSA normal; HIV serologynegative.Magnetic resonance tomography of the lumbar spinerevealed a sacralisation of the ﬁfth lumbar vertebra aswell as a considerable reduction in the height of the L4/L5 intervertebral space, with erosive alterations of theadjacent vertebral end plates (as previously documentedby plain radiographs). With T2 weighting the signal wasincreased centrally in the L4/L5 disc and there was L4and L5 vertebral body oedema, with marked enhance-ment after gadolinium administration. Streakyenhancement, more marked on the left, was also foundin the paravertebral space, but without evidence of aparavertebral or epidural abscess (Figs 1a–1c and 2a andb). A conventional chest X-ray and an abdominal CTscan were normal.We performed an invasive exploration by radio-graphically guided disc puncture biopsy because ofpersistent low back pain over 1 year with signs of sys-temic disease and the development of lumbar pain alsoat night and on percussion, together with elevatedinﬂammatory parameters and a marked left shift in the diﬀerential blood count, as well as a magnetic resonancetomography scan suggesting L4/L5 spondylodiscitiswith an absence of microbial growth in four blood cul-tures.Culture of the disc puncture biopsy material,including cultivation for Mycobacterium tuberculosis,revealed no microbial growth. Oesophageogastroduo-denoscopy was normal, as was coloileoscopy, apart froma small ulcer on the ileocaecal valve. Histologically, thedisc puncture biopsy material showed partially necrotic,partially degeneratively altered ﬁbrous cartilage in pla-Fig. 1 Magnetic resonance tomography of the lumbar spine, bothnative and after intravenous gadolinium. a MRI of lumbar spine,sagittal, T1 weighting; b MRI of lumbar spine, sagittal, T2weighting; c MRI of lumbar spine, sagittal, fat-suppressed andafter i.v. gadolinium. Lumbar L4/L5 disc reduced in height, withcentral T2 hyperintense signal. Erosive alterations of L4 bottomplate and L5 top plate, as well as bone marrow oedema of bothvertebral bodies (more marked on the left) with enhancement afterintravenous gadolinium. No epidural or paravertebral abscessFig. 2 a MRI of L4 lumbar vertebra, horizontal, fat-suppressedand after i.v. gadolinium; bMRI of lumbosacral transition, frontal,fat-suppressed and after i.v. gadolinium. Left-accentuated enhance-ment of L4 and L5 vertebral bodies with streaky paravertebralenhancement, more marked on the left. No abscess formation.Erosive alterations of the L4/L5 end plates with enhancement,central enhancement in the height-reduced disc. Degenerativespinal canal stenosis444ces. The histology of the biopsy material from duode-num, terminal ileum and colon was normal, apart fromregenerative epithelial fragments and granulation tissuein the area of the small ileocaecal valve ulcer. In par-ticular, no PAS-positive inclusions in macrophages weredetected.In contrast, broad-spectrum PCR [9] revealed T.whipplei DNA in material from the L4/L5 disc puncturebiopsy. This result was conﬁrmed by two diﬀerent spe-cies-speciﬁc real-time PCR assays targeting the 16SrDNA and an open reading frame of unknown function,respectively [10]. Biopsies from terminal ileum andcolon, as well as a stool sample, were also positiveusing the speciﬁc assay targeting the 16S rDNA, butno T. whipplei DNA was found in an EDTA bloodsample.Antibiotic therapy with sulphamethoxazole and tri-methoprim (800 mg plus 160 mg twice daily; additionalfolic acid substitution) led to normalisation of theinﬂammatory parameters within 1 month, and the pa-tient was asymptomatic and fully able to work 5 monthsafter starting therapy.DiscussionTo our knowledge, only three cases of Whipples diseasewith spondylodiscitis as the main manifestation havebeen reported [9, 11, 12]. There seems to be an accu-mulation of cases of Whipples disease with unusualpresentation in the Zurich area and eastern Switzerland,as 3 of the 4 spondylitis cases as well as at least 7 othercases have been observed in this geographical areawithin a short time (four cases of endocarditis, one eachwith involvement of the CNS, the bone marrow and thejoints, respectively) [11, 13, 14, 15]. In one of these 7patients, PAS-positive bacteria were detected in bonemarrow biopsy material [15]. We assume that the highincidence of Whipples disease found in the Zurich areais not related to a peculiar epidemiologic situation butrather to the increased use of molecular methods for theanalysis of unclear infections, especially the broad-spectrum PCR on usually sterile specimens.A notable feature of our case is the absence of gas-trointestinal symptoms and arthralgia. In recent yearsthere has been an increasing number of reports of vari-ous organ manifestations of Whipples disease withoutclinical or histological evidence for an involvement ofthe gastrointestinal tract [9, 11, 13].The indication for invasive exploration was based onseveral red ﬂags for a secondary form of low back painthat had been refractory to treatment for 1 year. Apartfrom lower lumbar pain at night and on percussion,signs of systemic disease developed, with loss of appetite,weight loss and night sweats combined with elevatedinﬂammatory parameters and a left shift in the diﬀer-ential blood count. The signal alteration in a magneticresonance tomography scan of the lumbar spine wascompatible with spondylodiscitis. Repeated blood cul-tures failed to show microbial growth and there was noevidence of any underlying neoplastic disease.After we failed to detect any pathogen in the L4/L5disc puncture biopsy material by histological examina-tion and conventional culture, the specimen was exam-ined by broad-spectrum PCR. Sequencing of theamplicon revealed T. whipplei in the material from thedisc puncture biopsy. We did not attempt to cultureT. whipplei using cell cultures because at the time thespecimens were taken, Whipples disease was not sus-pected clinically. This illustrates the usefulness of broad-spectrum PCR, which detects any bacterium if present insuﬃcient numbers. The presence of T. whipplei wassubsequently conﬁrmed with two independent species-speciﬁc PCR assays with DNA from the disc puncturebiopsy, as well as by a positive PCR from duodenumand colon biopsies, respectively. Despite positive PCRresults, the histological ﬁndings in material from theduodenum, terminal ileum, colon and disc puncturebiopsy were normal, and in particular there were noPAS-positive inclusions in macrophages.T. whipplei seems to be a rather common environ-mental organism and is detectable in the gastrointestinaltract of a signiﬁcant proportion of asymptomatic carri-ers. In a prospective study with elective gastroscopy in105 patients without signs of Whipples disease, positiveresults were obtained by PCR ampliﬁcation in 11.4% ofgastric juice aspirates and 4.8% of duodenal biopsies[16]. These results were conﬁrmed in a follow-up study,with 6 of 14 initially positive subjects being also positivein saliva [17]. Similarly, T. whipplei DNA was detectedby PCR in the saliva of 35% of 40 healthy persons [18],with results remaining positive in a repeat test. In con-trast, T. whipplei DNA has not so far been reportedfrom usually sterile locations (joints, cerebrospinal ﬂuid)from persons without Whipples disease. Gene sequencesspeciﬁc for T. whipplei were also found in 25 of 38eﬄuent water samples from ﬁve diﬀerent sewage plantsin southern Germany [19]. Whether these ﬁndings in-deed indicate environmental occurrence of the organismis debatable, as it may as well simply reﬂect fecalexcretion. T. whipplei may be a commensal bacteriumthat leads to systemic infection only under special, as yetundeﬁned circumstances, such as macrophage dysfunc-tion. Despite this possible widespread environmentaloccurrence, a positive ﬁnding of speciﬁc DNA by PCRin the context of an infection of a normally sterile bodysite can be considered diagnostic.The recent sequencing of the complete T. whippleigenome provides new insights into the biology of thispathogen, with the possible perspective of new diag-nostic strategies [20].In summary, the possibility of Whipples disease mustbe suspected in the case of a culture negative spondy-lodiscitis, even if there are no gastrointestinal symptomsand no arthralgia present. Compared to histologicaldetection of non-acid-fast PAS-positive macrophageinclusions, PCR ampliﬁcation of the speciﬁc 16S rRNAgene sequences of T. whipplei is more sensitive and445allows early diagnosis and the introduction of long-termantibiotic therapy.Acknowledgement This work was supported by a grant fromthe Swiss National Science Foundation (No. 32–61602.00) toM. Altwegg.References1. Durand DV, Lecomte C, Cathe´bras P, Rousset H, Godeau P,and the SNFMI Research Group on Whipple Disease (1997)Whipple disease: clinical review of 52 cases. Medicine 76:170–1842. Dutly F, Altwegg M (2001) Whipples disease and ‘‘Tropherymawhippelii’’. Clin Microbiol Rev 14:561–5833. Marth T, Raoult D (2003) Whipples disease. Lancet 361:239–2464. Raoult D, Birg ML, La Scola B et al. (2000) Cultivation of thebacillus of Whipples disease. N Engl J Med 342:620–6255. Schoedon G, Goldenberger D, Forrer R et al. (1997) Deacti-vation of macrophages with interleukin-4 is the key to theisolation of Tropheryma whippelii. J Infect Dis 176:672–6776. Wilson KH, Blitchington R, Frotingham R, Wilson JA (1991)Phylogeny of the Whipples-disease-associated bacterium.Lancet 338:474–4757. Relman DA, Schmidt TM, MacDermott RP, Falkow S (1992)Identiﬁcation of the uncultured bacillus of Whipples disease. NEngl J Med 327:293–3018. Ramzan NN, Loftus E Jr, Burgart LJ et al. (1997) Diagnosisand monitoring of Whipple disease by polymerase chain reac-tion. Ann Intern Med 126:520–5279. Altwegg M, Fleisch-Marx A, Goldenberger D, Hailemariam S,Schaﬀner A, Kissling R (1996) Spondylodiscitis caused byTropheryma whippelii. Schweiz Med Wochenschr 126:1495–149910. Maibach RC, Altwegg M (2003) Cloning and sequencing anunknown gene of Tropheryma whipplei and development oftwo LightCycler PCR assays. Diagn Microbiol Infect Dis(in press)11. Hirsbrunner-Erni R, Altwegg M, Diener PA, Villiger PM(2000) Whipples disease with normal intestinal histology: rarityor reality? [in German] Schweiz Med Wochenschr 130:1820–182612. Goldenberger D, Lucchini R (2000) Identiﬁcation of theWhipples disease-associated bacterium ‘‘Tropheryma whippelii’’from vertebral body L4 and direct sequencing of the almostcomplete 16S rRNA gene. Annual Meeting of the Swiss Societyof Microbiology, Zurich, p. 13313. Gubler JGH, Kuster M, Dutly F et al. (1999) Whipple endo-carditis without overt gastrointestinal disease: report of fourcases. Ann Intern Med 131:112–11614. Bra¨ndle M, Ammann P, Spinas GA et al. (1999) RelapsingWhipples disease presenting with hypopituitarism. ClinEndocrinol 50:399–40315. Walter R, Bachmann SP, Schaﬀner A, Ru¨egg R, Schoedon G(2001) Bone marrow involvement in Whipples disease: rarelyreported, but really rare? Br J Haematol 112:677–67916. Ehrbar HU, Bauerfeind P, Dutly F, Koelz HR, Altwegg M(1999) PCR-positive tests for Tropheryma whippelii in patientswithout Whipples disease. Lancet 353:221417. Dutly F, Hinrikson HP, Seidel T, Morgenegg S, Altwegg M,Bauerfeind P (2000) Tropheryma whippelii DNA in saliva ofpatients without Whipples disease. Infection 28:219–22218. Street S, Donoghue HD, Neild GH (1999) Tropheryma whip-pelii DNA in saliva of healthy people. Lancet 354:1178–117919. Maiwald M, Schuhmacher F, Ditton HJ, von Herbay A (1998)Environmental occurrence of the Whipples disease bacterium(Tropheryma whippelii). Appl Environ Microbiol 64:760–76220. Bentley SD, Maiwald M, Murphy LD et al. (2003) Sequencingand analysis of the genome of the Whipples disease bacteriumTropheryma whipplei. Lancet 361:637–644446

Spondylodiscitis as the first manifestation of Whipple's disease -a removal worker with chronic low back pain

http://doc.rero.ch/record/309677/files/10067_2003_Article_786.pdf

Spondylodiscitis as the first manifestation of Whipple's disease -a removal worker with chronic low back pain

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library