Angilletta, Roberto

Corcione, Silvia.

DE ROSA, Francesco Giuseppe

Lupia, Tommaso

Scabini, Silvia

English

Institutional Research Information System University of Turin

Contents lists available at ScienceDirectEuropean Journal of Internal Medicinejournal homepage: www.elsevier.com/locate/ejimLetter to the EditorReal-life use of isavuconazole outside the hematological wardsA R T I C L E I N F OKeywords:IsavuconazoleMouldsAspergillosisInvasive fungal infectionsDear Editor,Real-world data on efficacy and safety of isavuconazole (ISV) aremostly based on cohorts of patients with hematological malignancies,stem cells or solid organ transplants (i.e., HSCT or SOT) [1,2].In these settings, invasive fungal infections (IFI) are responsible forconsiderable morbidity and mortality, although recent studies showedthat, aside of the classic risk factors, low doses of corticosteroids,chronic obstructive pulmonary disease (COPD), liver cirrhosis, systemicconnective tissue diseases, influenza infection, diabetes mellitus, andadvanced solid cancer represent a favorable environment for IFI,especially for invasive pulmonary aspergillosis (IPA) [3,4].According to the European Organization for Research andTreatment of Cancer/Mycosis Study Group (EORTC/MSG) [5], IPA iscategorized into proven, probable, possible and Blot et al. externally va-lidated this classification in the Intensive Care Unit (ICU) [6]. Althoughthe host factors described in EORTC/MSG statements were extended topatients with SOT, hereditary immunodeficiencies, connective tissuedisorders, and immunosuppressive agents, different groups of non-neutropenic patients with not negligible risk of IFI are still left out fromEORTC/MSG criteria [5].We report here a case series of patients treated with isavuconazolefor IFI outside the hematological wards in two referral hospitals inTurin, Italy. All adults receiving at least three doses of ISV from 1stMarch 2017 to 30th June 2019 were enrolled in the study. ISV wasadministered at the standard dosage of isavuconazonium sulfate372mg either intravenously or orally every 8 h for 48 h (loading dose),then once daily (maintenance dose).Exclusion criteria were ongoing or new-onset neutropenia, lym-phoproliferative disorders, or other hematological diseases.Diagnosis of proven, probable or possible IFI was defined according tohost risk factors, clinical and radiological features, detection of specificmarkers of fungal infections and mycological isolations, mostly relyingon EORTC/MSG [5]. Given the low sensibility and specificity of thefollowing criteria in non-hematological and non-transplanted patients,new risk and host factors have been used to define IFI according to therecent literature on this issue [7,8].Adverse effects, when reported, were considered as follows: increasein transaminases (aspartate aminotransferase– AST/GOT and alanineaminotransferase– ALT/GPT) levels> 1,5-fold the upper normal limits,increase Na+ (up to 145mEq/L) or decrease K+ (under 3,5mEq/L)levels, new-onset neurological signs (e.g., confusion, dizziness), neurovisual toxicity (e.g., color vision, decrease in visual acuity), gastro-intestinal symptoms (e.g., nausea, vomiting, diarrhoea, dyspepsia) andskin modifications. Drug and drug interactions were checked beforestart ISV.Outcomes were defined as follows: complete response, as the re-solution of all signs and symptoms and radiographic abnormalitiescompared with baseline; partial response, as a clinical and radiographicimprovement compared with baseline; no response, not consistent withany of the categories mentioned above [5].We performed descriptive statistics on the study population. Datawere analyzed using standard statistical methods: variables were de-scribed with medians [interquartile ranges (IQR)], and data analysiswas performed using SPSS software version 25.0 (IBM).Ten adults were included in the study (Table 1); the median age was69 year-old (range 42–79). Patients were all Caucasian, without pre-vious history of IFI: five (50%) were managed as outpatients in theInfectious Diseases clinic, 3 (30%) were enrolled during hospitalizationat Medical Ward, 2 (20%) at time of discharge from the ICU. Amongcomorbidities, there were: history of malignancy (5; 50%), chronicpulmonary disease (3; 30%) or diabetes mellitus (2, 20%); five patients(50%) had a history of recent corticosteroid immunosuppressivetherapy (in the previous 30 days).Aspergillosis was the frequent primary diagnosis (N=9, 90%), andone patient was affected by pulmonary mucormycosis. Eight patients(8/9, 88,8%) had a microbiological diagnosis of Aspergillus spp. infec-tion, and the remaining was treated according to clinical symptoms andbiomarkers positivity. Besides, one adult (1/1, 100%) has reported amicrobiological diagnosis of Mucor spp. infection (Table 1). Clinicalsymptoms (e.g., fever, cough, purulent sputum) were present in allpatients. Regarding radiological findings, nodules (dense, well-cir-cumscribed lesions, with or without “halo” sign) were described in 6patients (60%), two patients reported a tree-in-bud pattern (20%), ca-vitation alone and cavitation with fungus ball in one patient each, re-spectively (14,3%). Regarding biomarkers, serum galattomannan (GM)resulted positive in two (20%) patients, whilst GM on (bronchoalveolarlavage) BAL was positive in 50% of cases, confirming the usefulnesshttps://doi.org/10.1016/j.ejim.2019.09.005Received 23 August 2019; Accepted 9 September 2019European Journal of Internal Medicine xxx (xxxx) xxx–xxx0953-6205/ © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.also in non-neutropenic patients [9].ISV was started according to moulds' microbiological susceptibility.Seven patients (70%) switched to ISV from triazole or polyene mostly toreduce drug to drug interactions, only three patients switched due toadverse reactions.The median time of administration of ISV was 3 (range 2–5) weeks:seven patients (63,6%) reported a clinical cure, defined as resolution ofsymptoms complained, three patients died before the end of therapy,and one patient did not clinically improve during ISV treatment andwas switched to polyene. No patient discontinued ISV treatment due totoxicity.Uusually IFI have been a major concern among hematological set-ting and neutropenic patients [3,4,7,8]. In this case series we high-lighted the increasing relevance of IFI also in non-neutropenic patients,usually admitted to internal medicine wards, with a mild degree ofimmunosuppression and without classic predisposing risk factors. Datafrom literature revealed an increasing incidence of IFI, especially IPA,outside hematological wards, with estimated incidence from 0.3%–19%[4]. In this population, IPA diagnosis is usually challenging due to thelack of standardized classification and the non-specificity of signs andsymptoms along with the relatively low diagnostic capacity of thecomplementary tests [8,9]. Clinical symptoms and changes in radi-ological CT findings even if aspecific may be the first trigger to suspectIFI in these patients, more than serum biomarkers that could be usefulto support the clinical suspect, but they lose their sensitivity and spe-cificity in non-hematological setting [7,8]. Moreover, in our case series,ISV was generally well tolerated and, according to literature short termISV appears safe and associated with treatment response in 70% ofcases [2].In conclusion, IA has to be considered outside the hematologicalward, although achieving a diagnosis of IA is challenging, and diag-nostic criteria are urgently needed. The use of ISV in these groups ofpatients seems to be a good option for the treatment of IFI.Author contributionsS·S, T.L. and S.C. conceived the ideas; S·S and T.L. collected andanalyzed the data; S·S, T.L., S.C. and F.G.D.R led the writing.Declaration of Competing InterestNone to declare.AcknowledgementsThe authors wish to thank Prof. G. Di Perri and Dr. F. Cattel for thesupport in drafting the manuscript.References[1] Hoenigl M, Prattes J, Neumeister P, Wölfler A, Krause R. Real-world challenges andunmet needs in the diagnosis and treatment of suspected invasive pulmonary as-pergillosis in patients with haematological diseases: an illustrative case study.Mycoses 2018;61(3):201–5.[2] DiPippo AJ, Kontoyiannis DP. Lack of toxicity with long term isavuconazole use inpatients with hematologic malignancy. Clin Infect Dis 2019. https://doi.org/10.1093/cid/ciz159. [2019 Mar 7. pii: ciz159].[3] Russo A, Falcone M, Vena A, Vena A, Venditti C, Mancini C, et al. Invasive pulmonaryaspergillosis in non-neutropenic patients: analysis of a 14-month prospective clinicalexperience. J Chemother 2011;23:290–4.[4] Bassetti M, Bouza E. Invasive mould infections in the ICU setting: complexities andsolutions. J Antimicrob Chemother 2017;72:i39–47.[5] De Pauw B, Walsh TJ, Donnelly JP, et al. European Organization for Research andTreatment of cancer/InvasiveFungal infections cooperative group. Revised defini-tions of invasive fungal dis- ease from the European Organization for Research andTreatment of cancer/invasive fungal infections cooperative group and the NationalInstitute of Allergy and Infectious Diseases mycoses study group (EORTC/MSG)consensus group. National Institute of Allergy and Infectious Diseases mycoses studygroup (EORTC/MSG) consensus group. Clin Infect Dis 2008;46:1813–21.[6] Blot SI, Taccone FS, Van den Abeele AM, Bulpa P, Meersseman W, Brusselaers N,Table1HostFactors,MicrobiologicalFeatures,RadiologicalFindingsandTreatmentDurationinMouldsInfections.PatientClinicalRiskFactorsForMouldsSiteofInfectionRadiologicalFindingsSampleSpecimenMouldGMserumGMBALBDGTreatment(wks)Outcome1BreastCancerPost-surgicalEndophtalmitisNormalChestX-RayVitreousAspergillusspp.NegativeNotAvailableNotAvailable3ClinicalResponse2Bronchiectasis,BreastCancerPulmonaryAspergillosisNodules,Tree-in-budSputumAspergillusspp.NegativeNotAvailableNotAvailable4ClinicalResponse3LungCancerPulmonaryAspergillosisNodules,Ground-glasshaloSputumAspergillusfumigatusNegativeNegativeNotAvailable4ClinicalResponse4AnorexiaNervosa,CervicalCancerPulmonaryMucormycosisNodulesPulmonarybiopsyMucorspp.NegativeNegativeNotAvailable2Deceased5ChronicRhinosinusitisFungalRhinosinusitisNormalChestX-RayNasalMucosaAspergillusfumigatusNegativeNotAvailableNotAvailable4ClinicalResponse6AsthmaPulmonaryAspergillosisNodules,Ground-glasshaloSputumA.fumigatus,A.nigerNegativeNotAvailableNotAvailable4ClinicalResponse7LungTransplant,ICUPulmonaryAspergillosisCavitationBALAspergillusfumigatusNegative3.99Negative2Deceased8Burn(TBSA>90%),HEDisseminatedAspergillosisNodulesSkinSwabandCVCA.fumigatus,A.flavus3.38NotAvailable>5004Deceased9DM,COPD,LungCancerPulmonaryAspergillosisNodules,Tree-in-budBALAspergillusfumigatusNegative4,6NotAvailable1ClinicalResponse10DM,RA,Leflunomide,CTS(>5mg/die)FungusBallCavitationwithfungusballNotIsolatedNotIsolated1,65NotAvailable3503ClinicalResponseICU:IntensiveCareUnit;TBSA:TotalBodySurfaceArea;COPD:ChronicObstructivePulmonaryDisease;DM;DiabetesMellitus;RA:RheumatoidArthritis;GM:Galattomannan;BDG:1,3BetaD-glucan;Wks:weeks,HE:Haemodyalisis,CTS:corticosteroid.Letter to the Editor European Journal of Internal Medicine xxx (xxxx) xxx–xxx2et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically illpatients. Am J Respir Crit Care Med 2012;186:56–64.[7] Bassetti M, Peghin M, Vena A. Challenges and solution of invasive Aspergillosis innon-neutropenic patients: a review. Infect Dis Ther 2018;7(1):17–27.[8] Danion F, Rouzaud C, Duréault A, Poirée S, Bougnoux ME, Alanio A. Why are somany cases of invasive aspergillosis missed? Med Mycol 2019;57:S94–103.[9] Meersseman W, Lagrou K, Maertens J, et al. Galactomannan in bronchoalveolar la-vage fluid: a tool for diagnosing aspergillosis in intensive care unit patients. Am JRespir Crit Care Med 2008;177:27–34.Silvia Scabini1, Tommaso Lupia⁎, Roberto Angilletta,Francesco Giuseppe De Rosa, Silvia CorcioneDepartment of Medical Sciences, Infectious Diseases, University of Turin,Turin, ItalyE-mail address: tommaso.lupia89@gmail.com (T. Lupia).⁎ Corresponding author.1 These authors equally contributed to this work.Letter to the Editor European Journal of Internal Medicine xxx (xxxx) xxx–xxx3

Real-life use of isavuconazole outside the hematological wards.

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Real-life use of isavuconazole outside the hematological wards.

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