Please cite this article in press as: Cerri S, et al. Janus-faced amiodarone-induced pneumopathy. Pulmonol. 2019. https://doi.org/10.1016/j.pulmoe.2019.07.003
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LETTER
TO
THE
EDITOR
Janus-faced
amiodarone-induced
pneumopathy
TotheEditor,
Several forms of pulmonary disease can occur among patients treated with amiodarone (usually delivered as an antiarrhythmic drug). Computed tomography findings indicativeofamiodarone-inducedlungdiseaseinclude high-attenuation parenchymal-pleural lesions and nonspecific pulmonary infiltrates. Only a few cases in the literature havedescribedtheoccurrenceofamiodarone-induced pul-monarydiseaseaspulmonarynodules.Theauthorsdescribe apatientshowingbilateral,peripheral,predominantlybasal ground-glassandreticularopacitiesconsistent witha non-specific interstitialpneumonia(NSIP) radiological pattern. This was followed by theoccurrence of two nodules that progressivelydecreasedinsizeafteroralsteroidshadbeen
Figure1 PanelsAandB.CTscanimagesshowingpredominantlybasal,bilateral,peripheralground-glassopacitieswithassociated reticularabnormalitiesconsistentwithanon-specificinterstitialpneumonia(NSIP)radiologicalpattern.PanelsCandD.Histological appearanceatdifferentmagnificationsoftransbronchialbiopsiesshowingareasoforganizedfibrosiswithfibrinousexudatesand significantamountofinflammatorycellsandwithnoevidenceofmalignantcells.
givenand therefore they were interpreted as an unusual manifestation of amiodarone-related pulmonary toxicity (APT).
A79-year-oldman,anon-smokerandwhohadahistory ofatrial fibrillation, wastreated withamiodarone 400mg dailyfor3years.Duringthelast2monthsoftreatment,he presentedwithexertionaldyspneaanddrycough. Respira-toryfunctiontestsrevealedarestrictiveventilatorypattern withamoderatereductionincarbondioxidelungdiffusion (DLCO)(14.3mL/min/mmHg,55%ofpredictedvalue).Chest computed tomography (CT) showed bilateral, peripheral, predominantly basal ground-glass and reticular opacities consistentwitha NSIP radiologicalpattern (Fig.1, panels AandB). Thebronchoalveolarlavageshowedasignificant amountoffoamymacrophages.Transbronchiallungbiopsy oftherightlowerlobewasperformedandthehistological examinationrevealedthepresenceofseptalwideningwith
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Please cite this article in press as: Cerri S, et al. Janus-faced amiodarone-induced pneumopathy. Pulmonol. 2019. https://doi.org/10.1016/j.pulmoe.2019.07.003
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Figure2 PanelsA andB.CTscanimagesshowingtheresolutionoftheground-glassandreticularopacitiesafteramiodarone withdrawalandtheonsetoftwolargenodulesof25mmand11mm,respectively,whichensuedintherightcostophrenicsulcus. PanelsCandD.Follow-upCTimagesshowing asubstantialreductioninsizeoftherightcostophrenicnodules18months after amiodaronewithdrawal.
typeII pneumocyteshyperplasia,areasoforganized inter-stitialfibrosiswithsporadic fibrinousexudates,fibroblasts andcollagendepositionnexttoaggregatesofinflammatory cellsandconsiderable amountoffoamyhistiocyets.These findingswereconsistentwithadiagnosisofAPT(Fig.1, pan-els C and D). Other etiologies of interstitial lung disease (ILD)werecarefullyruledout.Amiodaronewassuspended whileprednisone40mgdailyandoral anticoagulantswere given, with rapid clinical and functional recovery. At 40 days,ground-glassandreticularopacitieshadalmost com-pletelyresolved onCTscanwhile twosoft-tissuenodules of25and11mm, respectively,wereidentifiedintheright costophrenicsulcus(Fig.2,panelsAandB).Bothlesions pre-sentedelevateddensityonCTscanimageswithHounsfield Unit(HU)valuesrangingfrom46to50.Thepatient under-wenta new bronchoscopywith bronchoalveolar lavageof the right lower lobe, but microbiological and cytological investigationswereunremarkable.Atuberculinskintestand blood serologicalmarkers for autoimmunity,inflammatory andinfectious diseasewere alsoperformed withnegative results. Moreover a supplemental investigation was con-ductedexcludingtheonsetofnewdrugtreatment,trauma or exposure to environmental agents. Given their rapid onset,the elevated HUvaluesand theexclusion of other coherent etiologies, the nodules were interpreted as an unusualsubacute manifestation of APT. As physical insult topulmonaryparenchymaisknowntoincrease susceptibil-ity to toxicityeven if low dose amiodarone treatment is
used,1 surgical lung biopsy wasnot performed and radio-logical follow-upwasstarted. At18months, follow-upCT showed a considerable reduction in the size of both lung nodules(Fig.2,panelsCandD)andtheclinicalconditionof thepatientwasunremarkable.
Amiodarone,oneofthemostwidelyusedantiarrhythmic agents,is knowntocauseadverselung effectsin approxi-mately5%oftreatedpatients.2Severalriskfactorsforthe development of lung complications have been identified: the pre-existence of lung disease and/or respiratory fail-urerequiringhighoxygenmixtures,lowerrespiratorytract infections, olderage, treatmentduration andahistory of cardiothoracicsurgery.3 Sincethepatienthadbeen taking amiodaronefor2yearsbeforedevelopingrespiratory symp-toms, a dose accumulation effect might be suspected in thiscase.2,3Formostpatients,thediagnosisof amiodarone-induced pneumopathy relies on imaging.4 According to availableliterature,lunginvolvementpresentsawiderange ofpossiblemanifestations:fromasymptomaticlipoid pneu-monia, which is usually named the ‘amiodarone effect’, to the ‘amiodarone toxicity’ spectrum, which embraces different clinical entitiessuchas eosinophilicpneumonia, chronic organizingpneumonia (COP),acutefibrinous orga-nizingpneumonia(AFOP),nonspecificinterstitialpneumonia (NSIP)-likeandidiopathicpulmonaryfibrosis(IPF)-like inter-stitial pneumonia, desquamative interstitial pneumonia (DIP), acute respiratorydistress syndrome(ARDS), diffuse alveolarhemorrhageand,morerarely,isolatedormultiple
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LETTERTOTHEEDITOR 3
nodular or mass-like lesions.2,4,5 Amiodarone-related pul-monarynodulesusuallygeneratehighattenuationareason CTscansduetotheincorporationofiodine-richamiodarone into type II pneumocytes.6 In this form, the radiological presentation of drug-induced toxicity might mimic malig-nant neoplasms.7 In most cases, patients respond well to the withdrawal of amiodarone with the addition of corticosteroid treatment, with symptomsand radiological abnormalities resolving within several months due to the longhalf-lifeoftheamiodaronemetabolites.8
The peculiarity of our case was the sequential occur-renceofreversibleinterstitialNSIP-likelungabnormalities followed by nodular high-densityopacities. Moreover, the onset of lung nodules occurred after the withdrawal of amiodarone and once corticosteroid treatment had been started.Severalhypothesesonthelate-onsetoflung nod-ulescouldbemade.Alate-onsetdirecttoxicinjurytolung parenchymaand/oraslowimmunologicreactionshouldnot beexcluded.2Howevergiventhatthenoduleswerelocated inthesamelobewherethefirstbiopsyhadbeenperformed, apossibleincreaseinlungsusceptibilitytoamiodaronetoxic effectafterphysicalinsultmightbesuspected.1
To thebestofourknowledge,thisisthefirstcaseof a biphasicmanifestationofamiodarone-relatedlungtoxicity with large reversible nodules following interstitial abnor-malities. The broad imaging manifestations of APT may accountforsometemporalheterogeneity.
Funding
The authorsdeclarethat nofundingwasreceivedfor this paper.
Consent
to
publish
data
Informed consent to publish data was obtained by the patient.
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgments
We want to thank Professional Editor Colin Woodham for languageediting.
References
1.Schwaiblmair M, Berghaus T, Haeckel T, et al. Amiodarone-induced pulmonary toxicity: an under-recognized and severe adverseeffect?ClinResCardiol.2010;99:693---700.
2.PapirisSA,TriantafillidouC,KolilekasL,MarkoulakiD,ManaliED. Amiodarone:reviewofpulmonaryeffectsandtoxicity.DrugSaf. 2010;33(July1(7)):539---58.
3.Ernawati DK,Stafford L, HughesJD. Amiodarone-induced pul-monarytoxicity.BrJClinPharmacol.2008;66(July(1)):82---7. 4.Ott MC, Khoor A, Leventhal JP, et al. Pulmonary
tox-icity in patients receiving low-dose amiodarone. Chest. 2003;123:646---51.
5.Van Mieghem W, Coolen L, Malysse I, et al. Amiodarone and the development of ARDS after lung surgery. Chest. 1994;105:1642---5.
6.ChouriN,LanginT,LantuejoulS,etal.Pulmonarynoduleswith theCThalosign.Respiration.2002;69:103.
7.PiccioneWJr,FaberLP,RosenbergMS.Amiodarone-induced pul-monarymass.AnnThoracSurg.1989;47:918---9.
8.LanctotKL,NaranjoCA.ComparisonoftheBayesianapproach andasimplealgorithmfor assessmentofadversedrugevents. ClinPharmacolTher.1995;58:692---8.
S.Cerri,R.Tonelli
CenterforRareLungDiseases,RespiratoryDiseaseUnit, UniversityHospitalofModenaandUniversityofModena andReggioEmilia,Modena,Italy
P.Faverio
RespiratoryUnit,UniversityofMilanoBicocca,S.Gerardo Hospital,Monza,Italy
N.Sverzellati
SectionofRadiology,UnitofSurgicalSciences,
DepartmentofMedicineandSurgery(DiMeC),University ofParma,Parma,Italy
E.Clini∗
CenterforRareLungDiseases,RespiratoryDiseaseUnit, UniversityHospitalofModenaandUniversityofModena andReggioEmilia,Modena,Italy
F.Luppi
RespiratoryUnit,UniversityofMilanoBicocca,S.Gerardo Hospital,Monza,Italy
∗Corresponding author at: University of Modena & Reggio Emilia,AziendaOspedaliera-UniversitariadiModena, Pneu-mologyUnit,LargodelPozzo71,41125Modena,Italy.
E-mailaddress:enrico.clini@unimore.it(E.Clini). 29May2019
