Bernardelli, Giuditta

Brugioni, Lucio

Cerri, Stefania

Clini, Enrico

Fontana, Matteo

Tonelli, Roberto.

English

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

ARTICLE IN PRESS+ModelPULMOE-1451; No. of Pages 3Pulmonol. 2020;xxx(xx):xxx--xxxwww.journalpulmonology.orgLETTER TO THE EDITORUnusual effectiveness of systemicsteroids in Whipple diseaseFieloTcnsceoCiiwgrlwhtherapy  with  1.5  mg/kg  of  methylprednisolone  was  startedand  a rapid  clinical  improvement  with  a  parallel  resolutionTo  the  Editor,Whipple’s  disease  is  a  rare  disorder  caused  by  the  Gram-positive  bacterium  Tropheryma  whipplei  (TW),  formerlyknown  as  Tropheryma  whippelii,  that  localizes  initially  in  thelamina  propria  of  small  bowel  with  prominent  gastrointesti-nal  symptoms  and  weight  loss.1 However,  it  can  also  causea  wide  range  of  clinical  manifestations,  due  to  its  spread-ing  to  other  sites  (i.e.  endocardium,  lymph  nodes,  centralneurologic  system,  serum  membranes)2 including  pulmonarymanifestations.3,4We  draw  here  to  attention  a  quite  unique  case  of  Whippledisease  complicated  by  lung  involvement  probably  due  to  animmune  reconstitution  syndrome.This  refers  to  a  caucasian  77-year-old  man  diagnosed  withWhipple’s  disease  in  2015  (relapsed  in  2018)  treated  withdoxycycline  and  hydroxychloroquine  then  withheld  becauseof  gastrointestinal  intolerance.  In  the  past  medical  history,he  was  diagnosed  with  a  type  1  myelomonocytic  chronicleukemia,  peripheral  axonal  neuropathy,  dermatitis  due  toa  possible  immune  reconstitution  syndrome,  osteoporosisdue  to  steroid  therapy  treated  with  vertebroplasty,  hyper-tension,  aortic  insufficiency,  bilateral  glaucoma,  benignprostatic  hypertrophy  and  intestinal-type  gastric  adenocar-cinoma  treated  with  endoscopic  resection  in  2019.He  was  admitted  on  September  2019  to  the  emer-gency  room  due  to  high  fever  the  night  before,  thoracalgiaand  arterial  blood  gases  abnormalities  (pO2  58  mmHg,pCO2  29  mmHg,  pH  7.45);  chest  X-ray  documented  lunginvolvement  with  pleural  effusion  (Fig.  1).  Vital  parame-ters  indicated  mild  hypotension  (90/50  mmHg),  tachycardia(115  bpm),  tachypnoea  (30/min),  no  alteration  in  bodytemperature.  Blood  tests  showed  anemia  (6.8  g/dl)  mild  ele-vation  of  C-Reactive  Protein  (2.8  mg/dl),  increased  whitecells  (40.130  mmc),  Pro-calcitonin  (34  pg/ml),  and  creati-nine  (1.6  mg/dl),  while  d-dimer  was  inconsistent  and  cardiacenzymes  were  negative.  The  patient  was  transferred  toour  ward  on  oxygen  (2  L/min  flow  by  nasal  prongs),  drugregimen  with  piperacillin/tazobactam  and  prophylactic  lowPlease  cite  this  article  in  press  as:  Fontana  M,  et  al.  UnusuaPulmonol.  2020.  https://doi.org/10.1016/j.pulmoe.2020.02.00molecular  weight  heparin  was  started,  blood  transfusion  wasalso  performed.  Due  to  clinical  signs  of  malabsorption,  par-enteral  nutrition  was  instituted.odhttps://doi.org/10.1016/j.pulmoe.2020.02.0072531-0437/© 2020 Sociedade Portuguesa de Pneumologia. Published by BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)igure  1  Chest-X-Ray  at  admission  in  emergency  room  show-ng left  lung  parenchymal  consolidation  and  ipsilateral  pleuralffusion.Chest  ultrasound  confirmed  a  bilateral  pleural  effusion,arger  on  the  left,  with  extended  B-lines.  Bilateral  apicalpacities  appeared  at  the  chest-CT  (Fig.  2  upper  panels).he  whole  body  exams  performed  to  search  for  the  mostommon  pathogens  (bacteria  and  respiratory  viruses)  wereegative,  and  the  bronchiolo-alveolar  lavage  also  showed  noignificant  isolates.Following  an  initial  clinical  improvement,  the  patientondition  deteriorated  with  fever,  tachypnea  and  wors-ning  of  arterial  hypoxemia  (pO2  40  mmHg  with  2  L/minxygen)  and  impending  fatigue  of  the  respiratory  system.eftazidime  was  added,  taking  the  history  of  TW  diseasento  account.  A  second  chest-CT  documented  the  worsen-ng  of  the  lung  involvement  (Fig.  2  lower  panels)  so  patientas  transferred  to  our  respiratory  intensive  care  unit,  oxy-en  supplementation  was  set  up  to  FiO2  50%  and  antibioticegimen  with  cephalosporin  was  started.The  decision  to  perform  trans-bronchial  biopsies  of  theung  parenchymal  consolidations  with  rigid  bronchoscopeas  thus  taken  with  patient  under  sedation  after  intubation;istology  is  reported  in  Fig.  3.  After  the  procedure,  a  steroidl  effectiveness  of  systemic  steroids  in  Whipple  disease.7f  the  respiratory  failure  was  observed  over  the  followingays.  In  agreement  with  the  infectious  diseases  consultant,Elsevier Espan˜a, S.L.U. This is an open access article under the CC.ARTICLE IN PRESS+ModelPULMOE-1451; No. of Pages 32  LETTER  TO  THE  EDITORFigure  2  The  first  chest-CT  performed  in  the  ward  demonstrated  bilateral  lung  opacities  with  the  appearance  of  ground-glass  inthe upper  lobes  (see  upper  panel  1  in  different  slices  a  to  c).The  second  chest-CT  performed  after  patient’s  worsening  demonstratedprogression of  the  lung  parenchimal  opacities,  with  consolidations  and  reticolo-nodular  interstitial  thickening  (see  lower  panel  2  indifferent slices  a  to  c).Figure  3  Histologic  specimen  shows  a  non-caseating  granulomatous  inflammation  (left  panel);  the  PAS-stain  was  positive  (rightp ativetsggictbadtsatccWanel) but  the  PCR  detection  for  Tropheryma  whipplei  was  neghe  therapy  with  doxycycline  and  hydroxychloroquine  wastarted.  Finally,  the  patient  was  discharged  without  any  oxy-en  supplementation  and  steroid  therapy  was  prolonged  andradually  tapered  during  follow-up.The  clinical  manifestation  of  Whipple’s  disease  involv-ng  lung  parenchyma  in  our  patient  follows  other  very  rareases  in  the  past  literature.4 As  for  the  other  manifesta-ions  involving  different  sites,2 diagnosis  is  confirmed  at  thePlease  cite  this  article  in  press  as:  Fontana  M,  et  al.  UnusuaPulmonol.  2020.  https://doi.org/10.1016/j.pulmoe.2020.02.00iopsy  stain  both  by  finding  the  pathogen  with  PCR  methodnd  with  the  PAS  positivity.1However,  the  case  here  reported  was  atypical:  first,  weid  not  find  PCR  positivity  for  TW  in  the  biopsy  (despitetbts.he  PAS  positivity);  second,  patient  clinically  improved  onceystemic  steroid  therapy  was  instituted,  although  steroidsre  not  a  cornerstone  of  disease  treatment.5 Indeed,  sincehen,  patient  continued  to  deteriorate  and  lung  infiltratesontinued  to  worsen  despite  antibiotic  treatment  withephalosporins,  an  effective  first-line  therapy  in  severehipple’s  disease.1In  the  clinical  history  of  this  patient  we  have  foundl  effectiveness  of  systemic  steroids  in  Whipple  disease.7hat  he  had  a  dermatological  manifestation  probably  causedy  an  immune  reconstitution  syndrome  after  starting  theherapy  for  Whipple’s  disease.  The  immune  reconstitutionyndrome  in  Whipple  disease  is  extremely  rare  but  reported IN+ModelR12345678MEaDMbMcMdU∗ESUniversitaria  di  Modena,  Policlinico,  Director,  PneumologyARTICLEPULMOE-1451; No. of Pages 3LETTER  TO  THE  EDITOR  in  the  literature6 with  a  positive  PAS  staining,  but  nega-tive  PCR  for  TW,  probably  due  to  the  previous  clearanceof  the  pathogen  with  antibiotic  therapy.7 That  was  exactlywhat  happened  in  our  patient  with  lung  involvement.  Prob-ably,  steroid  therapy  might  have  played  a  role  in  limitingimmune  reconstitution.  In  addition,  due  to  his  hematolog-ical  pathology,  this  patient  was  exposed  to  another  risk  ofa  immune-mediated  complication  i.e.  the  alteration  of  themonocytes  function  connected  to  an  abnormal  phagocytosisand  proliferation  of  TW.8 The  fluctuation  in  the  number  ofwhite  blood  cells  that  we  observed  during  admission  couldhave  led  to  the  development  of  an  aberrant  response  toantibiotics  and  the  elimination  of  the  pathogen.6 At  dis-charge,  specific  therapy  for  Whipple’s  disease  was  continuedbecause  of  the  risk  of  relapse,  of  worsening  when  systemicsteroids  or  other  immunosuppressants  are  administered,  andof  manifestations  due  to  the  immune  reconstitution  whensteroid  therapy  is  suspended  rapidly.1To  the  best  of  our  knowledge,  this  specific  manifestationinvolving  the  lung  has  not  been  previously  described  and  itsheds  light  on  whether  steroid  therapy  could  be  added  insome  cases  of  Whipple’s  disease  to  avoid  the  risk  of  furthercomplications,  such  as  immune-reconstitution  syndrome.FundingThe  authors  declare  that  no  funding  was  received  for  thispaper.Consent to  publish dataInformed  consent  to  publish  data  was  obtained  by  thepatient.Conflicts of interestThe  authors  have  no  conflicts  of  interest  to  declare.Please  cite  this  article  in  press  as:  Fontana  M,  et  al.  UnusuaPulmonol.  2020.  https://doi.org/10.1016/j.pulmoe.2020.02.00AcknowledgmentsWe  want  to  thank  Professional  Editor  Colin  Woodham  forlanguage  editing.UE8 PRESS3eferences. Fenollar F, Lagier JC, Raoult D. Tropheryma whipplei and Whip-ple’s disease. J Infect. 2014;69:103--12.. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic tropherymawhipplei: clinical presentation of 142 patients with infectionsdiagnosed or confirmed in a reference center. Medicine (Balti-more). 2010;89:337--45.. Kelly CA, Egan M, Rawlinson J. Whipple’s disease presenting withlung involvement. Thorax. 1996;51:343--4.. Urbanski G, et al. Whipple disease revealed by lung involvement:a case report and literature review. Chest. 2012;141:1595--8.. Mahnel R, et al. Immunosuppressive therapy in Whipple’s diseasepatients is associated with the appearance of gastrointestinalmanifestations. Am J Gastroenterol. 2005;100:1167--73.. Moos V, et al. Immunopathology of immune reconstitutioninflammatory syndrome in Whipple’s Disease. J Immunol.2013;190:2354--61.. Feurle GE, et al. The immune reconstitution inflammatory syn-drome in Whipple disease: a cohort study. Ann. Intern. Med.2010;153:710--7.. Marth T, Neurath M, Cuccherini BA, Strober W. Defects ofmonocyte interleukin 12 production and humoral immunity inWhipple’s disease. Gastroenterology. 1997;113:442--8..  Fontanaa,  S.  Cerri a,  G.  Bernardelli b,  L.  Brugioni c,.  Clini a,∗,  R.  Tonelli a,dUniversity  Hospital  of  Modena,  Respiratory  Diseases  Unit,epartment  of  Medical  and  Surgical  Sciences,  University  ofodena  Reggio  Emilia,  ItalyUniversity  Hospital  of  Modena,  Pathologic  Anatomy  Unit,odena,  ItalyUniversity  Hospital  of  Modena,  Internal  and  Emergencyedicine  Unit,  Modena,  ItalyClinical  and  Experimental  Medicine  PhD  Program,niversity  of  Modena  Reggio  Emilia,  ItalyCorresponding  author  at:  University  of  Modena  and  Reggiomilia,  Chair  of  Respiratory  Medicine,  Director  Post-doctoralchool  in  Respiratory  Medicine,  Azienda  Ospedaliera-l  effectiveness  of  systemic  steroids  in  Whipple  disease.7nit,  Largo  del  Pozzo  71,  41125  Modena,  Italy.-mail  address:  enrico.clini@unimore.it  (E.  Clini). February  2020

Unusual effectiveness of systemic steroids in Whipple disease.

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Unusual effectiveness of systemic steroids in Whipple disease.

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