Recrudescence of a high parasitaemia, severe Plasmodium falciparum malaria episode, treated by artesunate monotherapy

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Recrudescence of a high parasitaemia, severe Plasmodium falciparum malaria episode, treated by

artesunate monotherapy

S. Landre, A. L. Bienvenu, P. Miailhes, P. Abraham, M. Simon, A. Becker, A.

Conrad, G. Bonnot, Y. I. Kouakou, C. Chidiac, et al.

To cite this version:

S. Landre, A. L. Bienvenu, P. Miailhes, P. Abraham, M. Simon, et al.. Recrudescence of a high para- sitaemia, severe Plasmodium falciparum malaria episode, treated by artesunate monotherapy. Inter- national Journal of Infectious Diseases, Elsevier, 2021, 105, pp.345-348. �10.1016/j.ijid.2021.02.080�.

�inserm-03337970�

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Case Report

Recrudescence of a high parasitaemia, severe Plasmodium

falciparum malaria episode, treated by artesunate monotherapy

Sophie Landre

^a

, Anne-Lise Bienvenu

^b

, Patrick Miailhes

^a

, Paul Abraham

^c

, Marie Simon

^d

, Agathe Becker

^a

, Anne Conrad

^a

, Guillaume Bonnot

^e

, Yobouet Ines Kouakou

^e,f

,

Christian Chidiac

^a

, Gilles Leboucher

^b

, Thomas Rimmelé

^c

, Laurent Argaud

^d

, Stephane Picot

^e,f,

*

aServicedesMaladiesInfectieusesetTropicales,HôpitaldelaCroix-Rousse,HospicesCivilsdeLyon,69004Lyon,France

bServicePharmacie,GroupementHospitalierNord,HospicesCivilsdeLyon,69004Lyon,France

cAnesthesiologyandCriticalCareMedicine,HôpitalEdouardHerriot,HospicesCivilsdeLyon,Lyon,France

dServicedeMédecineIntensive-Réanimation,HôpitalEdouardHerriot,HospicesCivilsdeLyon,69437LyonCedex03,France

eUnivLyon,MalariaResearchUnit,UMR5246CNRS-INSA-CPE-UniversityLyon1,69100Villeurbanne,France

fInstituteofParasitologyandMedicalMycology,HôpitaldelaCroix-Rousse,HospicesCivilsdeLyon,69004Lyon,France

ARTICLE INFO

Articlehistory:

Received3February2021

Receivedinrevisedform18February2021 Accepted19February2021

Keywords:

Severemalaria Artesunate Resistance K13

Parasiteclearancetime

ABSTRACT

A patient presenting with severe malaria, with hyperparasitaemia, received 7-day artesunate monotherapy.Asevererecrudescencewasdetectedandattributedtohyperparasitaemia,monotherapy andapolyclonalinfectionwithoutKelch13genemutation.Asecondtreatmentwithartesunate,then quinine,followedbyartemether-lumefantrine,wassuccessful.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc- nd/4.0/).

Introduction

Artesunateistherecommendedinitialtreatmentforsevere malaria,followedby3daysofarteminisin-basedcombination therapy (ACT)(WorldHealthOrganization,2015).Artesunate monotherapy may lead to recrudescence of parasitemia in 40%–50% of cases within 28 days (Wellems et al., 2020).

This recrudescenceis related to parasite persistence due to induced dormancy and should be distinguished from drug resistance.

DecreasedartesunateefﬁcacywasdescribedinSouthEastAsia (Imwongetal.,2017).Thecombinationofpolymorphismsonthe Kelch 13 (K13) gene (Ariey et al., 2014) and pharmacology of artesunate(Kouakouetal.,2019)isinvolvedintherapeuticfailure.

Wereportaseveremalariacasewronglytreatedwithartesunate

monotherapy,followed bya recrudescence leadingtoa second severemalariaepisode.

Casereport

A65-year-oldmanreturnedtoFrancefromChad, wherehe hadstayedfor2yearswithoutmalariaprophylaxis.Aweeklater, hewasadmittedtohospital. Hepresentedwithalteredfebrile consciousness,mottledkneeswithhemodynamicinstability,and acuterespiratorydistress syndrome(ARDS), requiringinvasive mechanicalventilationandadmissiontoanintensivecareunit (ICU).Hehadamedicalhistoryoftype2diabetes,hypertension andobesity(BMI=36.8kg/m²).Biologicalparametersshoweda hyperlactatemia (lactate=4mmol/L), metabolic compensated acidosis(bicarbonates=17mmol/L;pH=7.47),andacutekidney injury (creatininemia=180

m

^mol/L). ^Platelet ^count ^was ²⁰^g/L,

hemoglobin 16.1g/dL, and proteins 5.4g/dL. Microscopy was positive for Plasmodium falciparum (675 000 parasites/

m

^L),

conﬁrming a severe malaria episode with respiratory failure

*Correspondingauthorat:MalariaResearchUnit,UMR5246CNRS-INSA-CPE- UniversityLyon1,F-69100Villeurbanne,France.

E-mailaddress:stephane.picot@univ-lyon1.fr(S.Picot).

https://doi.org/10.1016/j.ijid.2021.02.080

1201-9712/©2021TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o u r n a l h o m ep a g e : w w w . e l s e v i e r . c o m / l o c a te / i j i d

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(PaO2/FiO2<150mmHg), cardiovascular failure, acute kidney injuryandhyper-parasitaemia.

Artesunate intravenous (IV) regimen (2.4mg/kg) was initiated on day one and continued for 7 days. Continuous venovenoushemodialysis(CVVHD)wasperformedfortheﬁrst 72h,andnorepinephrinesupportwasrequiredfor10days.The patientwasdischargedfromtheICU4weeksafteradmission with a favorable outcome. Shortlyafterwards, he presented with hyperthermia, cough, and a pulmonary opacity at the chest X-ray. Because of a swallowing disorder, aspiration pneumoniawassuspected,andacefotaximemetronidazolebi- therapy was initiated. However, he remained febrile and experienced ARDS requiring his readmission to the ICU. He presented hemolysis (hemoglobin=6.4g/dL, undetectable haptoglobin, elevated LDH), low platelets (63G/L), and a lactatemiaof2.5mmol/L, withoutkidneydysfunction. Blood smearswerepositiveforP.falciparum(240000parasites/

m

^L),

leadingtoadiagnosisofseveremalariarecrudescence.Artesunate 2.4mg/kg wasinitiated for3 doses(H0,H12, H24)followedby

5daysofIVquinine(750mg/8h)toavoidthehemolyticprocess causedbyartesunate.AnoralACT(artemether-lumefantrine)was thengivenfor3days(Figure1A).

Methods

Themalariadiagnosiswasconfirmedthroughexaminationof 100 microscopic fields of 200 red blood cells for thin smears (Giemsa stains) following the requirements of the National Certification Program. The parasite clearance half-life (PC1/2) wasdeterminedusingT1/2=loge(2)/K.TheWorldwideAntimalari- al Resistance Network (WWARN) Parasite Clearance Estimator (PCE)wasnotusedbecausethe6-hourlybloodsamplingrequired wasnotstandardclinicalpractice.However,thePC1/2atadmission and recrudescence was calculated from 4 and 3 samples, respectively. Molecular tests wereperformed from fresh blood samples(Ponceetal.,2017).Real-timepolymerasechainreaction tests and direct sequencing of the Pfmsp1,Pfmsp2 and kelch13 geneswereconductedfromfrozensamples.

Figure1.A:Timelineofthe2malariaepisodeswithparasitemia(parasites/mL),antimalarialtreatmentsandhospitalizationwards.

B:GiemsastainedthinbloodﬁlmfromthebloodsampleatadmissionshowingPlasmodiumfalciparum(R:Ringstageparasite;T:Trophozoites).Magniﬁcation:1000.Scale bar=5m^M.

C:Oneofthe5%neutrophilswithengulfedhemozoinpigment.

S.Landre,A.-L.Bienvenu,P.Miailhesetal. InternationalJournalofInfectiousDiseases105(2021)345–348

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Results

The patientshoweda highparasitemiaoninitial admission with approximately 90% of ring stagesand 10% of developing trophozoites (Figure 1B). Five percent of leucocytes with phagocytosed hemozoin pigment were detected (Figure 1C).

After24h,anddespiteartesunatetreatment,theparasiticburden remained high (320 000 parasites/

m

^L). Parasitemia was 5000 parasites/

m

^L⁴⁸^h^laterând^negativeûntil^Day^28.^Theêstimated

PC1/2 was 6.8h, higher than the threshold of 5.5h for drug sensitivity(Ashleyetal.,2014).

The recrudescence was detected on Day 32. Three doses of artesunateledtoadecreaseinparasitemiaatDay33andnegative fromDay34to57afteraswitchtoIVquinine(topreventtheriskof post-artesunate delayed haemolysis) followed by 3 days of artemether-lumefantrine.The estimatedparasiteclearance time ofthesecondepisodewas1.7h.

Genotypingofsamplescollectedatadmission(Day5),Day7 and Day 32for Pfmsp1 (SupplementaryFigureS1) revealedthe presenceof2clonesofP.falciparum:onedisappearedaftertheﬁrst treatmentwhilethesecondwasresponsiblefortherecrudescence.

Nopolymorphismwasdetectedforthe3samplesintheK13gene (SupplementaryFigureS2).

Discussion

This patient presented a recrudescence of a severe malaria episode. For the ﬁrst episode, he received a 7-day therapy of intravenous artesunate with 3 doses (300mg for 126kg body weight)givenat12-hintervals,thenonceadayfor6days.Hedid notreceivetheoralfollow-ontreatmentwithanACTneededto avoidrecurrences.

Thisnon-immunepatientwithhighparasitaemiaatadmission receivedaprolongedartesunatetreatment(7days)whichshould havecovered3parasitelifecycles.Itisknownthatpatientswith hyperparasitaemia have an increased risk of recrudescence (Luxemburgeret al.,1995).Theneedforfrequentmicroscopical measuresofbloodparasitaemiaduringthetreatmentofmalaria withhighparasiteburdenshouldbeunderscored.

Artemisinin resistance was described (Ashley et al., 2014;

Dondorpetal.,2009),manifestedinanincreaseinPC1/2(>5.5h).

TherewasadelayedestimateofPC1/2duringtheﬁrstepisodeof severemalaria,butthisvalueshouldbeconsideredwithcaution because the WWARN PCE was not used. The K13 genes of P.falciparumidentiﬁedfromtheinitialandrecrudescenceepisodes werewild-type,eliminatingadrug-resistantPlasmodium.

The patient may havebeen infected by at least 2 clones of P. falciparum. It can be suspected that part of the parasite populationwascuredbyartesunatemonotherapy,whileanother partslowlydecreasedtosubpatentlevelsandsurvived,despitethe 7-dayartesunatetreatment.Thereisstrongevidencethata3-day oral ACT, following the initial artesunate regimen, could have preventedthesevererecurrence.Practitionersshouldbeawareof the recrudescence risk of severe or non-severe malaria with hyperparasitaemia(Luxemburgeretal.,1995).

Whywastherecurrencealsoaseveremalariacase?Thepatient received artesunate treatment according to the summary of productcharacteristics(SPC).Thepatient’sweightmaynothave impactedthedistributionvolumesinceartesunateishydrophilic andmainlydistributedinleantissue.Accordingtotheartesunate SPC, dose adjustment for renal impairment was unnecessary despite dihydroartemisinin (DHA) metabolites excretion in the urine.TheimpactofCVVHDonartesunateexcretionintheurine was notevaluated,butanincrease inartesunateexcretionmay have occurred. Artesunate is highly bound to proteins, and hypoproteinemia mayincreasetheamountof drugremovedby

renal replacement therapy. Unfortunately, the artesunate/DHA dosage used was not available. Age, obesity, hypertension and diabetesprobablyalsocontributedtothesuccessiveepisodesof severemalaria.Aretrospectivestudyinadultsfoundthatobesity was associated with severe malaria, independently and in associationwithothermetabolicriskfactors,suchashypertension, dyslipidemia and diabetes (Wyss et al., 2017). Multiple P. falciparum genotype infection has also previously been associatedwithmalariaseverity(Nicastrietal.,2008).

Itisofutmostimportancetousetherecommended3-day oralACTafterartesunateintravenoustreatment(evena7-day treatment)andperformtherapeuticdrugmonitoring,ensuring optimaldrugexposureandavoidingclinicalfailure.Frequent, repeatedmicroscopicexaminationofbloodsmearsisneeded for earlydetection ofrecrudescence, particularlyin casesof highparasitaemia.Antimalarialstewardshipactions(Bienvenu et al., 2019) could help to promote these good clinical practices.

Authorscontribution

AllauthorscontributedequallyinStudydesign,Datacollection, DataanalysisandWriting.

Ethicalapproval

Informedconsentwasobtainedfromthepatientatadmission.

Fundingsource None.

Conﬂictofinterest

Theauthorsdeclarenoconﬂictofinterest.

Acknowledgments Notapplicable.

AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,in theonlineversion,atdoi:https://doi.org/10.1016/j.ijid.2021.02.080.

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