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Leukemia & Lymphoma

ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20

Epidemiology of invasive fungal infectionsduring induction therapy in adults with acutelymphoblastic leukemia: a GRAALL-2005 study

Clara Mariette, Emmanuelle Tavernier, Didier Hocquet, Anne Huynh,Françoise Isnard, Faezeh Legrand, Véronique Lhéritier, Emmanuel Raffoux,Hervé Dombret, Norbert Ifrah, Jean-Yves Cahn & Anne Thiébaut

To cite this article: Clara Mariette, Emmanuelle Tavernier, Didier Hocquet, Anne Huynh,Françoise Isnard, Faezeh Legrand, Véronique Lhéritier, Emmanuel Raffoux, Hervé Dombret,Norbert Ifrah, Jean-Yves Cahn & Anne Thiébaut (2016): Epidemiology of invasive fungalinfections during induction therapy in adults with acute lymphoblastic leukemia: aGRAALL-2005 study, Leukemia & Lymphoma, DOI: 10.1080/10428194.2016.1204652

To link to this article: http://dx.doi.org/10.1080/10428194.2016.1204652

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ORIGINAL ARTICLE: CLINICAL

Epidemiology of invasive fungal infections during induction therapy in adultswith acute lymphoblastic leukemia: a GRAALL-2005 study

Clara Mariettea, Emmanuelle Tavernierb, Didier Hocquetc, Anne Huynhd, Francoise Isnarde, Faezeh Legrandf,V�eronique Lh�eritierg, Emmanuel Raffouxh, Herv�e Dombreth, Norbert Ifrahi, Jean-Yves Cahna andAnne Thi�ebauta

aDepartment of Hematology and UMR 5525 CNRS-UJF, University Hospital, Grenoble, France; bDepartment of HematologySaint-Etienne, University Hospital, Saint-Etienne, France; cInfection Control Department, University Hospital, Besancon, France;dDepartment of Hematology, University Hospital, Toulouse, France; eDepartment of Hematology, University Hospital, Saint-Antoine,France; fDepartment of Hematology, University Hospital, Nice, France; gDepartment of Hematology Group for Research on Adult AcuteLymphoblastic Leukemia (GRAALL), Coordination Office, Pierre B�enite, France; hDepartment of Hematology, University Paris Diderot,Institut Universitaire d’H�ematologie (IUH), University Hospital Saint-Louis, Assistance Publique Hopitaux de Paris (AP-HP), Paris, France;iDepartment of Hematology and Inserm U 892/CNRS 6299, University Hospital, Angers, France

ABSTRACTLittle data have been published concerning invasive fungal infections during treatment of acutelymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the mul-ticenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed forthe occurrence of IFI using the EORTC modified criteria. These patients did not routinely receiveantifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developedIFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candid-iasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosiswas 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serumwas tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median timebetween induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes.Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortalityafter diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33.The median delay between induction chemotherapy initiation and attributable death related toIC was 15 days. These findings may help to optimize the future management of ALL patients,and as in AML advocate systematic monitoring and the development of prophylactic or preemp-tive antifungal treatments.

ARTICLE HISTORYReceived 14 January 2016Revised 8 June 2016Accepted 18 June 2016

KEYWORDSAcute lymphoblasticleukemia; invasive fungalinfections; invasiveaspergillosis; invasivecandidiasis

Introduction

Invasive fungal infections (IFI) are a major cause ofmorbidity and mortality in patients with hematologicalmalignancies, especially in acute myeloblastic leukemia(AML) and after allogeneic hematopoietic stem celltransplantation (HSCT). Mold infections are frequentand most of the time they are due to Aspergillus, butIFI due to rare and emergent filamentous fungi arealso increasing (0.3–16% of the mold infections).[1,2]Candida remains the major pathogen in yeast infec-tions, especially Candida albicans (46–56%),[3,4] butcases of non-albicans species are growing,[4] 35–47%for C. glabrata, and 14–31% for C. parapsilosis.[5,6] Theepidemiology of these complications has been mainlyreported for AML with an incidence of IFI between 2and 49%,[7–11] 4.4–7% for invasive aspergillosis

(IA) [7,12,13] and 4.1–5.5% [7,8] for invasive candidiasis(IC). In patients with HSCT, an incidence of IA from 2.5to 12% has been reported,[14–17] and of 4.7%for IC.[5]

Much less is known about the role of IFI during thetreatment of acute lymphoblastic leukemia (ALL).However, these patients, often with severe neutropeniaand prolonged treatment with corticosteroids, presenta risk of developing further fungal infections.[19]Among the relatively scarce data available describingthe incidence of IFI in this population we found anoverall incidence of 6.5% and the majority are IA andIC,[7] an incidence of IA of 2.2% [12] or 3.8%,[7] andan incidence of IC of 1.9%.[7] In another study, amongthe patients who developed an IA, 15.4% present anALL. But these previous studies described

CONTACT Dr Clara Mariette cmariette@chu-grenoble.fr Clinique Universitaire d’H�ematologie, CHU de Grenoble, CS 10217, Grenoble 38043, France� 2016 Informa UK Limited, trading as Taylor & Francis Group

LEUKEMIA & LYMPHOMA, 2016http://dx.doi.org/10.1080/10428194.2016.1204652

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heterogeneous groups of patients with various risk fac-tors and developing IFI.

Furthermore, no standard of care has been definedfor antifungal prophylaxis in ALL patients, even if thequestion is increasingly raised.[20,21]

In order to design adequate prospective studies, wefirst performed a retrospective study on the incidence ofIFI during the induction treatment of ALL patients. In ourlarge randomized trial, we described a homogeneousgroup of adult ALL patients with IFI complications.

Patients and methods

Patients

Most of the patients treated for ALL in France from2006 to 2012 were included in the trial set up in 2005by the GRAALL investigators. This trial was a prospectivemulticenter randomized phase III clinical trial(ClinicalTrials.gov: NCT00327678). We used this cohortof patients to perform a retrospective study describingthe epidemiology of IFI in ALL patients. We analyzed allpatients enrolled in GRAALL-2005 between 15/05/2006and 26/10/2012 who developed an IFI prior to their allo-graft. Informed consent was obtained from all patientsat inclusion in the main clinical trial.

GRAALL-2005 treatment

After inclusion in the GRAALL trial, patients weretreated by three different sub-protocols according totheir ALL characteristics: GRAALL-2005 (Figure 1A),GRAALL-Rituximab-2005 (GRAALL-R-2005) for CD20þALL, or GRAAPH-2005 (Figure 1B) for Philadelphia(Phþ) chromosome-positive ALL. All patients received7 days of corticosteroids, and then continued for 8 or

14 days, and chemotherapy according to their proto-col. In GRAALL-R-2005, patients were randomized toreceive, or not, rituximab. In GRAAPH-2005, all patientsreceived a combined imatinib/chemotherapy regimen.No antifungal prophylaxis was recommended in any ofthe protocols.

Fungal infections

In order to identify IFI cases, all databases of adverseevents and infectious complications were analyzed. Wecompleted missing data by searching all the patient’sfiles.

All hematology centers apply recommendations ofEORTC/MSG concerning IFI diagnosis: galactomannanassay performed twice weekly and CT chest performedin case of febrile neutropenia resistant to large spec-trum antibiotics and/or positive galactomannan assay.

Consensus modified criteria proposed by theEuropean Organization for Research and Treatment ofCancer/Mycoses Study Group (EORTC/MSG) were usedto define retrospectively all IFI.[22] Multiple episodesoccurring in the same patient were counted as separ-ate infections, unless they were caused by the samefungal agent.

Test used for galactomannan assay was Platelia,Bio-Rad.[23–25]

Results

Patients

Among 969 ALL patients enrolled in 59 French hema-tology centers, 76 (7.8%) developed IFI before allogen-eic stem cell transplantation: 32 (3.3%) IA, 37 (3.8%) IC,and seven other fungal infections. Out of these 76 IFI,

PDN: prednisone; IT: intrathecal; DNR: daunorubicin; VCR: vincristin; CPM: cyclophosphamide; aspa : L-asparaginase; MR : minimal residual disease; w: weeks; HDAC: high-dose cytarabine; HDMTX: high-dose methotrexate; HDCPM: high-dose cyclophosphamide; DXM: dexamethasone; 6MP: 6-mercaptopurine; VP16: etoposide; G-CSF: granulocyte colony stimulating factor; SCT: stem cell transplantation

IM: imatinib; CVAD: cyclophosphamide, doxorubicin, vincristine and dexamethasone; PBSC: peripheral blood stem cell; MUD: matched unrelated donor; MAC: myeloablative conditioning; CY: cyclophosphamide; TBI: total body irradiation; RIC: reduced-intensity conditioning

(B) GRAAPH-2005 protocol(A) GRAALL-2005 protocol

Figure 1. ALL treatment: GRAALL-2005 and GRAAPH-2005 protocols.

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65 (85.5%) occurred during the induction course ofchemotherapy, therefore 6.7% of the 969 patientsdeveloped IFI during induction chemotherapy. Themedian age of the GRAALL-2005 study population was30 years and that of patients who developed IFI was47 years (range, 18–60).

Invasive aspergillosis

Thirty-two (3.3%) of the 969 patients developed IA(42% of all IFI) before allograft and 26/969 (2.7%) dur-ing induction chemotherapy. The majority 26/32 (81%)of these infections appeared during the first course ofinduction chemotherapy; four (12.5%) others occurredduring consolidation chemotherapy.

IA during induction

During induction, we found 14 IA (2.4%) in GRAALL-2005 patients (593 patients enrolled), 11 (5.8%) inGRAALL-R-2005 patients (191 patients enrolled), andone (0.4%) in GRAAPH-2005 patients (270 patientsenrolled). In GRAALL-R-2005, IA was diagnosed in fivepatients randomly assigned to receive rituximab and insix patients in the control group.

Over all three protocols, the age at diagnosis was<25 years for two patients (7.7%), between 25 and 45years for 10 patients (38.5%), and >45 years for 14patients (53.8%) patients (Table 1). The median timebetween the first day of neutropenia and IA diagnosiswas 18 days (range, 1–76) and between the first day ofinduction chemotherapy and IA diagnosis was 20 days(range, 2–71). Four patients with IA (15.4%) hadreceived prophylactic antifungal drugs: fluconazole(n¼ 1), caspofungin (n¼ 1) and liposomal amphotericin

B (n¼ 2). All of the 26 patients had pulmonary localiza-tion and three of them had a secondary site of infec-tion (two skin and one sinus).

Diagnosis of IA was classified as probable in 22(84.6%) and proven in four (15.4%). Of these patients,four had a standard chest X-ray: one with diffuse andbilateral infiltrates, four with alveolar condensation andfour were normal. Lung CT scan was performed in allthe 26 cases (100%) showing 15 halo signs, 15 nodularlesions, three pleural effusions, one atelectasis and oneair crescent sign (some combine several signs) (Table 2).An assay for Aspergillus antigen in serum by galacto-mannan test was performed in all the cases (100%) andwas positive in 24 (92%) cases. Bronchoalveolar lavagewas performed for 11 patients (42.3%): direct examin-ation was positive for six patients, culture was positivein four patients. BAL galactomannan was performed infour cases and was positive in two (50%) of them.Biopsies were positive (presence of hyphae on histopa-thologic direct microscopic examination) in four cases:pulmonary biopsy in three and cutaneous biopsy in one(Table 3). Of the five Aspergillus isolates identified at thespecies level, Aspergillus fumigatus was isolated in fourcases, Aspergillus flavus in one and co-infection withMucor was identified in one patient. Overall 12-weekmortality after diagnosis of IA was 5/26 (19.2%) andattributable mortality related to the infection was 4/26(15.4%). The median delay between induction chemo-therapy and attributable death related to the IA was31 days (range, 27–46).

Invasive candidiasis

Thirty-seven (3.8%) out of 969 patients developed IC(39.8% of the IFI) before allograft. Almost all, 33/37

Table 1. Characteristics of patients with IA or IC diagnosed during induction chemotherapy.Characteristic IA (n¼ 26) IC (n¼ 33) Other IFI (n¼ 6)

DemographicsAge in years, median (range) 51 (22–57) 53 (18–60) 47 (27–59)

Gender: male/female 15/11 11/22 2/6Substudy

GRAALL-2005 14 12 0GRAALL-R-2005 11 12 4GRAAPH-2005 1 9 2

Neutropenia at IFI diagnosis (neutrophil count �500/mm3) 23 (88.5%) 22 (66.7%) 5 (83.3%)Median time between first day of neutropenia and IFI diagnosis in days (range) 18 (1–76) 19 (0–49) 19(4–35)Median time between first day of induction chemotherapy and IFI diagnosis in days (range) 20 (2–71) 20 (9–36) 19 (14–23)Hospitalization conditions

Laminar airflow 10 13 2Positive pressure chamber 6 5 1High-efficiency particulate air filtration 1 2 1Conventional room 5 6 1Home care 1 1 0Unknown 3 6 1

Therapy the month before IFIGCSF 7 (26.9%) 15 (45.5%) 4 (66.7%)Antifungal drug for IFI prophylaxis 4 (15.4%) 7 (21.2%) 3 (50%)

IA: invasive aspergillosis; IC: invasive candidiasis; IFI: invasive fungal infections; GRAALL: Group for Research on Adult Acute Lymphoblastic Leukemia;GRAAPH: Group for Research on Adult Acute Lymphoblastic Leukemia Philadelphia positive; GCSF: granulocyte colony-stimulating factor.

INVASIVE FUNGAL INFECTIONS IN ALL 3

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(89.2%) of these infections emerged during the firstcourse of induction chemotherapy. Two (5.4%) othersoccurred during consolidation chemotherapy and twomore occurred later.

IC during induction

During induction, we observed 12 IC (2%) in GRAALL-2005 protocol patients (593 patients enrolled), 12(6.3%) in GRAALL-R-2005 patients (191 patientsenrolled), and nine (3.3%) in GRAAPH-2005 patients(270 patients enrolled). In the GRAALL-R-2005 protocol,IC was diagnosed in four patients randomly assignedto receive rituximab and in eight patients in the con-trol group.

The age at diagnosis was <25 years for fourpatients (12.1%), between 25 and 45 years for eightpatients (24.3%), and >45 years for 21 (63.6%) patients(Table 1). The median time between the first day ofneutropenia and IC diagnosis was 19 days (range,0–49) and between the first day of induction chemo-therapy and IC diagnosis was 20 days (range, 9–36).Seven patients with IC (21.2%) had received antifungaldrug prophylaxis: fluconazole (n¼ 2), posaconazole(n¼ 1), amphotericin B (n¼ 3) and liposomal ampho-tericin B for one.

Among these patients, 27 (81.8%) had candidemiaand six (18.2%) had spleen and liver infection. Thediagnosis of IC was classified as probable in four cases(12.1%) and proven in the remaining 29 cases (87.9%).Blood cultures were positive in 27 cases, spleen biopsyculture positive in one case after splenectomy and liverbiopsy culture positive in one case. Of the 27 Candidaisolates identified at the species level, Candida albicanswas the most common (16 out of 27, 59.3%), Candidatropicalis in five (18.5%), Candida krusei in three(11.1%), Candida kefyr in two (7.4%) and Candida glab-rata in one (3.7%). Overall 12-week mortality after diag-nosis of IC was 8/33 (24.2%) and attributable mortalityrelated to the infection was 7/33 (21.2%). Themedian delay between induction chemotherapy and

attributable death related to the IC was 15 days (range,11–49). Species-specific attributable death related tothe IC was 3/16 (18.8%) for infections caused byC. albicans and 3/5 (60%) for C. tropicalis. No deathwas attributed to C. krusei or C. glabrata.

Other infections

Fusarium sp. was isolated in two patients: one in BALand one in cutaneous biopsy. Geotrichum sp. was iso-lated in two patients in blood culture, Zygomycetes inone patient in BAL and pulmonary biopsy,Scedosporium sp. in one patient in BAL and cutaneousbiopsy and Sporopachydermia was isolated in onepatient in blood culture. Six (85.7%) of these infectionsoccurred during induction chemotherapy. Threepatients died due to their IFI: one due to fusariosis andtwo due to Geotrichum infection.

Discussion

In this cohort of 969 adult ALL patients, we found 76cases of IFI in a 6-year period (2006–2012). Few reportsof IFI in adult ALL patients are published and it pro-vides an opportunity to further study and understandthe epidemiology of IFI in these patients.

Our data confirm that aspergillosis and candidiasisare responsible of the majority of the IFIs in patientswith acute leukemia.[8,10,26]

The incidence of IA of 3.3%, and 2.7% during induc-tion chemotherapy, was in the range previouslyrecorded in ALL patients,[7,12,27] and not far from theresults found in AML patients [7,12,13] or in HSCTpatients.[15,17] Most IA occurred early after the end ofthe induction course, emphasizing the need to refocuson preventative strategies. Only 50 (77%) of thepatients were neutropenic at time of IFI diagnosis,GCSF was recommended during induction chemother-apy in the GRAALL trial from day 18.

The median time between the first day of neutro-penia and IA diagnosis was 18 days (range, 1–76), and

Table 2. Diagnostic procedure for the patients with IA (possible, probable and proven).Procedure Performed n¼ 26 (%) Finding n (%)

Lung CT scan 26 (100) Abnormal 26/26 (100)Halo sign 15/26 (58)Nodule 15/26 (58)Air crescent sign 1/26 (4)Pleural effusion 3/26 (12)

Serum galactomannan antigen test 26 (100) Positive 24/26 (92)Sputum examination 1 (4) Positive culture and direct examination 1/(100)BAL fluid examination 11 (42) Direct examination positive 6/11 (55)

Culture positive 4/11 (36)BAL fluid galactomannan 4 (15) Positive for galactomannan 2/4 (50)Bronchial or lung biopsy 4 (15) Positive 3/4 (75)Skin biopsy 2 (8) Positive 1/2 (50)

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INVASIVE FUNGAL INFECTIONS IN ALL 5

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was similar to that observed in AML patients.[12] Thediagnosis of IA was proven in 15.4% of cases. A criticalreview of recent data found similar results: 13% amongpatients treated for hematological malignancies,[12]11.5% in the PATH Alliance Registry cohort [16] and15% in the SAIF cohort.[17] Considerable progress hasbeen made between 2006 and 2012 with regard tonew diagnostic tools in the field of IFIs, including thewidespread introduction of CT scans and the galacto-mannan test. The use of the galactomannan test inserum or BAL, contributed to 66.7% of IA diagnoses,while it contributed to 73% and 16% in HSCT and SOTrecipients, respectively, in the PATH Alliance Registrycohort [16,18] and to 71% in a hematology cohort.[12]In our study, very few galactomannan test are per-formed on BAL: only four and half are positive. A. fumi-gatus remains the most frequently isolated species.Unlike other authors we did not observe an increase ininfections due to A. terreus,[28] but the number ofidentifications at the species level was low.

The overall 12-week mortality after diagnosis of IAof 19.2% with an attributable 12-week mortality relatedto the IA of 15.4% is markedly improved from previ-ously reported rates.[7,12,17,26] This may be due toearlier diagnosis, partly owing to greater awarenessand thus more frequent clinical suspicion, better non-invasive diagnostic methods, prompt initiation of treat-ment with effective, well-tolerated antifungal therapies,and/or changes in clinical practices. It has been sug-gested that the late diagnosis of IA can lead to poorprognosis.[29]

Our data confirm that yeast infections are less com-mon than mold infections in ALL patients. Candida spp.were still the predominant yeast pathogens with anincidence of 3.8%, and 4.8% during induction chemo-therapy, which is lower than previously reported:12.5% in ALL [7] or hematological malignancies, canceror SOT patients.[18,30–33] In our cohort we observed achanging Candida spp. distribution, with the emer-gence of non albicans species. C. non albicans repre-sented half of the Candida isolates identified at thespecies level, as described previously.[7,8] Mortality inpatients with candidemia has been reported to rangefrom 30% to 81%.[7,26,34–36] However, we observedlower attributable 12-week mortality related to the ICin patients, in the range of 19%, probably due to theadvances in diagnostic and therapeutic practices.Nevertheless, IC worsens the prognosis of patients, andin our study, attributable mortality related to IC ishigher than those related to IA.

We observed more IFI in the GRAALL-R-2005 cohort.This might raise the question as to the role of rituxi-mab in the development of IFI, although IFI was

observed predominantly in the patients randomlyassigned to the control group (without rituximab). Inthe GRAALL-R-2005 subgroup, preliminary data hasbeen presented showing excess toxic mortality.Currently, this toxic mortality is attributed to age andindeed, patients in the GRAALL-R protocol were olderthan those in the other protocols.[37]

A randomized clinical trial has compared posacon-azole versus fluconazole or itraconazole prophylaxis inpatients treated for AML. A lower incidence of IFI (2%)was observed in the posaconazole arm than in the flu-conazole or itraconazole arm (8%) (p< 0.001) with anincidence of IA of 1% and 7%, respectively.[38]Therefore, posaconazole prophylaxis is efficient in AMLpatients in whom the incidence of IFI and AI is high.Furthermore, a German pharmacoeconomic analysisfavored drug prophylaxis for AML patients in terms ofcost-effectiveness.[39] However, in patients with ALL,the incidence of IFI and IA is lower, which raises thequestion as to the effectiveness of prophylaxis withposaconazole in this disease, and its benefit at themedico-economic level. Moreover, posaconazole usetogether with vincristine in induction may exacerbatetoxicity from the latter and require dosage adjustment.We cannot be sure that posaconazole is the best indi-cation for prophylaxis in ALL as opposed to AML.[40]

A double blind randomized study (AmBiGuard trial)undertaken of antifungal prophylaxis with liposomalamphotericin B (L-AMB) during ALL induction chemo-therapy has been conducted and reported in the lastASH (American Society of Hematology) meeting.[41]7.9% subjects in the L-AMB group and 11.7% subjectsin the placebo group developed proven or probable IFI(p¼ 0.24). Overall mortality was similar: 7.2% in the L-AMB group vs. 6.8% in the placebo group as was theincidence of serious adverse events. The authors con-cluded that L-AMB given twice weekly reduces theincidence of IFI although this did not reach statisticalsignificance.

Despite the limitations related to its retrospectivenature, our study provides useful information. It con-firms that fungal infections, particularly IA and IC,remain an important cause of morbidity and mortalityin adult ALL patients, especially in the early post-induc-tion chemotherapy period. Overall mortality appears tobe improved from that seen in previous reports. Ourfindings should contribute to the improvement of themanagement of adult ALL patients at high risk of IFIand should inform the development of future monitor-ing. In our retrospective study, the incidence of IFI(6.7%) is lower than in the placebo arm of theAmBiGuard trial (11.7%). All of these data support

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diagnosis and curative therapeutical strategy ratherthan prophylactic strategy.

We believe that a reasonable option during induc-tion chemotherapy for ALL is to favor a preemptive orempirical antifungal strategy. A clinical trial on the pre-emptive and empirical antifungal management of ALLpatients at high risk of IFI is needed.

Acknowledgements

We thank Dr. Alison Foote (Grenoble Clinical ResearchCenter) for critically editing the manuscript.

Potential conflict of interest: Disclosure forms providedby the authors are available with the full text of this article athttp://dx.doi.org/10.1080/10428194.2016.1204652.

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