LETTERTOTHEEDITOR 415
Unusual
effectiveness
of
systemic
steroids
in
Whipple
disease
TotheEditor,Whipple’s disease is a rare disorder caused by the Gram-positive bacterium Tropheryma whipplei (TW), formerly knownasTropherymawhippelii,thatlocalizesinitiallyinthe laminapropriaofsmallbowelwithprominent gastrointesti-nalsymptomsandweightloss.1However,itcanalsocause awiderangeofclinicalmanifestations,duetoits spread-ingtoothersites(i.e.endocardium,lymphnodes,central neurologicsystem,serummembranes)2includingpulmonary manifestations.3,4
WedrawheretoattentionaquiteuniquecaseofWhipple diseasecomplicatedbylunginvolvementprobablyduetoan immunereconstitutionsyndrome.
Thisreferstoacaucasian77-year-oldmandiagnosedwith Whipple’s disease in2015 (relapsed in 2018)treated with doxycyclineandhydroxychloroquinethenwithheldbecause ofgastrointestinalintolerance.Inthepastmedicalhistory, he was diagnosed with a type 1 myelomonocytic chronic leukemia,peripheralaxonalneuropathy,dermatitisdueto a possible immune reconstitution syndrome, osteoporosis duetosteroidtherapy treatedwithvertebroplasty, hyper-tension, aortic insufficiency, bilateral glaucoma, benign prostatichypertrophyandintestinal-typegastric adenocar-cinomatreatedwithendoscopicresectionin2019.
He was admitted on September 2019 to the emer-gencyroomduetohighfeverthenightbefore,thoracalgia and arterial blood gases abnormalities (pO2 58mmHg, pCO2 29mmHg, pH 7.45); chest X-ray documented lung involvement with pleural effusion (Fig. 1). Vital parame-tersindicatedmildhypotension(90/50mmHg),tachycardia (115bpm), tachypnoea (30/min), no alteration in body temperature.Bloodtestsshowedanemia(6.8g/dl)mild ele-vation of C-Reactive Protein (2.8mg/dl), increased white cells (40.130mmc), Pro-calcitonin (34pg/ml), and creati-nine(1.6mg/dl),whiled-dimerwasinconsistentandcardiac enzymes were negative. The patient was transferred to our ward on oxygen (2L/min flow by nasal prongs), drug
Figure1 Chest-X-Rayatadmissioninemergencyroom show-ingleftlungparenchymalconsolidationandipsilateralpleural effusion.
regimenwithpiperacillin/tazobactamandprophylacticlow molecularweightheparinwasstarted,bloodtransfusionwas alsoperformed.Duetoclinicalsignsofmalabsorption, par-enteralnutritionwasinstituted.
Chestultrasoundconfirmedabilateral pleuraleffusion, largeronthe left,with extended B-lines. Bilateral apical opacitiesappeared at the chest-CT(Fig.2 upper panels). The wholebody exams performed tosearch for the most commonpathogens(bacteriaandrespiratoryviruses)were negative,andthebronchiolo-alveolarlavagealsoshowedno significantisolates.
Following an initial clinical improvement, the patient condition deteriorated with fever, tachypnea and wors-ening of arterial hypoxemia (pO2 40mmHg with 2L/min oxygen)and impendingfatigueof the respiratory system. Ceftazidimewas added, taking the history of TW disease intoaccount.Asecond chest-CTdocumentedthe worsen-ingofthelunginvolvement(Fig.2lowerpanels)sopatient wastransferredtoourrespiratoryintensivecareunit, oxy-gensupplementationwassetuptoFiO250%andantibiotic regimenwithcephalosporinwasstarted.
Thedecision toperformtrans-bronchial biopsiesofthe lung parenchymal consolidations with rigid bronchoscope wasthustakenwithpatientundersedationafterintubation; histologyisreportedinFig.3.Aftertheprocedure,asteroid therapywith1.5mg/kg ofmethylprednisolonewasstarted andarapidclinicalimprovementwithaparallelresolution oftherespiratory failurewasobserved overthe following days.Inagreementwiththeinfectiousdiseasesconsultant, thetherapy with doxycycline andhydroxychloroquine was started.Finally,thepatientwasdischargedwithoutany oxy-gensupplementationandsteroidtherapywasprolongedand graduallytaperedduringfollow-up.
The clinical manifestation of Whipple’s disease involv-inglungparenchymainourpatientfollowsotherveryrare casesin the past literature.4 As for the other manifesta-tionsinvolvingdifferentsites,2diagnosisisconfirmedatthe biopsystainbothbyfindingthepathogenwithPCRmethod andwiththePASpositivity.1
However,thecaseherereportedwasatypical:first,we did not find PCR positivity for TW in the biopsy (despite thePASpositivity);second,patientclinicallyimprovedonce systemicsteroidtherapy wasinstituted,although steroids arenotacornerstoneofdiseasetreatment.5Indeed,since then,patientcontinuedtodeteriorateandlunginfiltrates continued to worsen despite antibiotic treatment with cephalosporins, an effective first-line therapy in severe Whipple’sdisease.1
In the clinical history of this patient we have found thathehadadermatologicalmanifestationprobablycaused by an immune reconstitution syndrome after starting the therapyfor Whipple’s disease.The immunereconstitution syndromeinWhipplediseaseisextremelyrarebutreported in the literature6 with a positive PAS staining, but nega-tive PCR for TW, probably due to the previous clearance ofthepathogenwithantibiotictherapy.7Thatwasexactly whathappenedinourpatientwithlunginvolvement. Prob-ably, steroidtherapy might have played a rolein limiting immunereconstitution.Inaddition,duetohis hematolog-icalpathology,thispatientwasexposedtoanotherriskof aimmune-mediatedcomplicationi.e.thealterationofthe monocytesfunctionconnectedtoanabnormalphagocytosis
416 LETTERTOTHEEDITOR
Figure2 Thefirstchest-CTperformedinthewarddemonstratedbilaterallungopacitieswiththeappearanceofground-glassin theupperlobes(seeupperpanel1indifferentslicesatoc).Thesecondchest-CTperformedafterpatient’sworseningdemonstrated progressionofthelungparenchimalopacities,withconsolidationsandreticolo-nodularinterstitialthickening(seelowerpanel2in differentslicesatoc).
Figure3 Histologicspecimenshowsanon-caseatinggranulomatousinflammation(leftpanel);thePAS-stainwaspositive(right
panel)butthePCRdetectionforTropherymawhippleiwasnegative.
andproliferationofTW.8The fluctuationinthenumberof whiteblood cellsthatweobservedduringadmissioncould have led to the development of an aberrant response to antibiotics and the elimination of the pathogen.6 At dis-charge,specifictherapyforWhipple’sdiseasewascontinued becauseoftheriskofrelapse,ofworseningwhensystemic steroidsorotherimmunosuppressantsareadministered,and ofmanifestations duetothe immunereconstitutionwhen steroidtherapyissuspendedrapidly.1
Tothebestofourknowledge,thisspecificmanifestation involvingthelunghasnotbeenpreviouslydescribedandit shedslight onwhether steroidtherapy couldbe addedin somecasesofWhipple’sdiseasetoavoidtheriskoffurther complications,suchasimmune-reconstitutionsyndrome.
Funding
The authorsdeclare thatnofundingwasreceivedfor this paper.
Consent
to
publish
data
Informed consent to publish data was obtained by the patient.
Conflicts
of
interest
LETTERTOTHEEDITOR 417
Acknowledgments
We want tothank Professional Editor Colin Woodham for languageediting.
References
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2.LagierJC,LepidiH,RaoultD,FenollarF.Systemictropheryma whipplei:clinical presentationof 142patientswithinfections diagnosedorconfirmedinareferencecenter.Medicine (Balti-more).2010;89:337---45.
3.KellyCA,EganM,RawlinsonJ.Whipple’sdiseasepresentingwith lunginvolvement.Thorax.1996;51:343---4.
4.UrbanskiG,etal.Whipplediseaserevealedbylunginvolvement: acasereportandliteraturereview.Chest.2012;141:1595---8.
5.MahnelR,etal.ImmunosuppressivetherapyinWhipple’sdisease patientsis associatedwiththeappearance ofgastrointestinal manifestations.AmJGastroenterol.2005;100:1167---73.
6.Moos V, et al. Immunopathology of immune reconstitution inflammatory syndrome in Whipple’s Disease. J Immunol. 2013;190:2354---61.
7.FeurleGE,etal.Theimmunereconstitutioninflammatory syn-drome in Whipple disease: a cohortstudy. Ann. Intern. Med. 2010;153:710---7.
8.Marth T, Neurath M, Cuccherini BA, Strober W. Defects of monocyte interleukin 12productionand humoral immunity in Whipple’sdisease.Gastroenterology.1997;113:442---8.
M.Fontanaa,S.Cerria,G.Bernardellib,L.Brugionic, E.Clinia,∗,R.Tonellia,d
aUniversityHospitalofModena,RespiratoryDiseasesUnit,
DepartmentofMedicalandSurgicalSciences,Universityof ModenaReggioEmilia,Italy
bUniversityHospitalofModena,PathologicAnatomyUnit,
Modena,Italy
cUniversityHospitalofModena,InternalandEmergency
MedicineUnit,Modena,Italy
dClinicalandExperimentalMedicinePhDProgram,
UniversityofModenaReggioEmilia,Italy
∗Correspondingauthorat:UniversityofModenaandReggio
Emilia,ChairofRespiratoryMedicine,DirectorPost-doctoral School in Respiratory Medicine, Azienda Ospedaliera-Universitariadi Modena, Policlinico, Director, Pneumology Unit,LargodelPozzo71,41125Modena,Italy.
E-mailaddress:enrico.clini@unimore.it(E.Clini). 8February2020
https://doi.org/10.1016/j.pulmoe.2020.02.007
2531-0437/©2020SociedadePortuguesadePneumologia. PublishedbyElsevierEspa˜na,S.L.U.Thisisanopenaccessarticle undertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
