Rehabilitation, optimized nutritional care and boosting host internal milieu to improve long-term treatment outcomes in TB patients

University of Groningen

Rehabilitation, optimized nutritional care and boosting host internal milieu to improve

long-term treatment outcomes in TB patients

Akkerman, Onno W; Ter Beek, Lies; Centis, Rosella; Maeurer, Markus; Visca, Dina;

Muñoz-Torrico, Marcela; Tiberi, Simon; Migliori, Giovanni Battista

Published in:

International Journal of Infectious Diseases

DOI:

10.1016/j.ijid.2020.01.029

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Akkerman, O. W., Ter Beek, L., Centis, R., Maeurer, M., Visca, D., Muñoz-Torrico, M., Tiberi, S., & Migliori,

G. B. (2020). Rehabilitation, optimized nutritional care and boosting host internal milieu to improve

long-term treatment outcomes in TB patients. International Journal of Infectious Diseases, 92, S10-S14.

https://doi.org/10.1016/j.ijid.2020.01.029

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Rehabilitation,

optimized

nutritional

care,

and

boosting

host

internal

milieu

to

improve

long-term

treatment

outcomes

in

tuberculosis

patients

Onno

W.

Akkerman

,

Lies

ter

Beek

,

Rosella

Centis

,

Markus

Maeurer

,

Dina

Visca

,

Marcela

Muñoz-Torrico

,

Simon

Tiberi

,

Giovanni

Battista

Migliori

*

a

UniversityofGroningen,UniversityMedicalCentreGroningen,DepartmentofPulmonaryDiseasesandTuberculosis,Groningen,TheNetherlands

b

UniversityofGroningen,UniversityMedicalCentreGroningen,TBCentreBeatrixoord,Haren,TheNetherlands

c

ServiziodiEpidemiologiaClinicadelleMalattieRespiratorie,IstitutiCliniciScientificiMaugeriIRCCS,Tradate,Italy

d

ChampamalimaudFoundation,Immunosurgery,AvenidaBrasilia,Lisbon,Portugal

e

DivisionofPulmonaryRehabilitation,IstitutiCliniciScientificiMaugeri,IRCCS,Tradate,Italy

f_{DepartmentofMedicineandSurgery,RespiratoryDiseases,UniversityofInsubria,Varese-Como,Italy}

g_{TuberculosisClinic,InstitutoNacionalDeEnfermedadesRespiratoriasIsmaelCosioVillegas,CiudadDeMexico,Mexico} h

BlizardInstitute,BartsandTheLondonSchoolofMedicineandDentistry,QueenMaryUniversityofLondon,London,UnitedKingdom

i

DepartmentofInfection,RoyalLondonandNewhamHospitals,BartsHealthNHSTrust,London,UnitedKingdom

ARTICLE INFO

Articlehistory: Received8January2020

Receivedinrevisedform16January2020 Accepted16January2020 Keywords: Tuberculosis Pulmonaryrehabilitation Disease-relatedmalnutrition Immuneresponse ABSTRACT

Background:Theholisticmanagementoftuberculosis(TB)patientscanimprovelifeexpectancyandlost organfunction.

Rehabilitation:ChronicsequelaeareverycommonamongpatientswhosurviveTB,whichcanleadtoa furtherdeclineinlungfunction.Thereisstillnoguidancefor‘cured’patientswithimpairedlungfunction whoneedpulmonaryrehabilitation.Additionaltestsforevaluationshouldbegivenaftertheendof treatment,asrecentstudieshaveshownthegoodeffectofpulmonaryrehabilitationforTBpatients. Optimized nutritional care: Malnutrition is very common among TB patients and is related to malabsorption. Thelatter can causelower drugexposure, which may resultin treatment failure, increasingtheriskofdeath,andcanleadtoacquireddrugresistance.Malnutritionshouldbeassessed accordingtotheGlobalLeadershipInitiativeonMalnutrition(GLIM)criteriaandthediagnosisshould leadtoanindividualizedtreatmentplan,includingsufficientproteinsandpreferablyincombinationwith adequatetraining.

Protective immune responses: Under normalcircumstances,mostimmune cellsusea glucose-based mechanismtogenerateenergy.Thereforethepatient’snutritionalstatusisakeyfactorinshapingimmune responses.Disease-relatedmalnutritionleadstoproteolysisandlipolysis.Intheend,theidentificationof individualswhowillbenefitfromimmune-modulatorystrategiesmayleadtoclinicallyrelevantmarkers. ©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.This isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Introduction

Tuberculosis (TB) remains an important cause of mortality globally;however,verylittleissaidofthehundredsofmillionsof patients who survive the disease. Chronic sequelae are very common,whichcanrangefromreducedlungfunctionandpost-TB bronchiectasistoaspergillomaandnon-tuberculousinfections,all of which can further impact lung function. We are only now gainingabetterinsightintoTBasasystemicinflammatoryprocess and understandingthat patientsare morelikely tosuffer from vasculareventsafterTBcure.Ourex-TBpatientscanbeexpectedto bemorefragile(Choietal.,2017a)andarestilllikelytodie4years *Corresponding authorat: Serviziodi EpidemiologiaClinica delle Malattie

Respiratorie,IstitutiCliniciScientificiMaugeriIRCCS,ViaRoncaccio16,Tradate, Varese,21049,Italy.

E-mailaddresses:o.w.akkerman@umcg.nl(O.W. Akkerman),

l.ter.beek@umcg.nl(L.terBeek),rosella.centis@icsmaugeri.it(R.Centis),

markus.maeurer@gmail.com(M.Maeurer),dina.visca@icsmaugeri.it(D.Visca),

dra_munoz@hotmail.com(M.Muñoz-Torrico),simon.tiberi@bartshealth.nhs.uk

(S.Tiberi),giovannibattista.migliori@icsmaugeri.it(G.B.Migliori).

https://doi.org/10.1016/j.ijid.2020.01.029

1201-9712/©2020TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

earlier (Hoger et al., 2014) even though they are cured. The questionis,whyisthisthecaseandwhatcanbedoneaboutit? Thefollowingarticlediscussesthestateoftheartontheholistic management of TB patients aimed at recuperating lost organ functionandraisingpost-TBlife-expectancy,aswellastopicsfor futureresearchinthefield.Inparticularthereviewisfocusedon (1)thefunctionalevaluationofTBpatientsattheendoftreatment andrehabilitationofsequelae;(2)optimizationofnutritionalcare, and(3)newinsightsintotheprotectiveimmuneresponse. Methods

Anon-systematicreviewoftheliteraturewasconductedbythe membersofthewritingcommittee,soastoincludeusefulcore referencesthatmayhelpthereaderbetterunderstandthetopics covered. Thefollowing keywords wereused, without any time limitation: ‘tuberculosis’, ‘functional evaluation’, ‘pulmonary rehabilitation’,‘nutrition’,‘protectiveimmuneresponse’.MEDLINE wasusedasthesearchengine,focusingontheEnglish-language literatureonly.

RehabilitationforTBpatients

Functionalevaluationofpatientsandpulmonaryrehabilitation TB controlprogrammes haveprioritized early diagnosisand effective treatment of infectious cases to ensure rapid cure of individual patientsand interruption of thetransmission chain. GivenmostoftheglobalTBburdenislocalizedincountrieswith limitedeconomicresources,theimportanceofinvestigatingthe functionalstatusofthepatientsdeclared‘cured’toassesspotential abnormalitiesandcandidatesforpulmonaryrehabilitationhasnot gainedmuchattention(Amaraletal.,2015;Muñoz-Torricoetal., 2016;Spruitetal.,2013).

Withamainfocusonchronicobstructivepulmonarydisease (COPD), the American Thoracic Society/European Respiratory Society(ATS/ERS)rehabilitationguidelinesindicatethat rehabili-tationisaneffectiveinterventioninchronicrespiratorydiseases, althoughTBis notindividuallymentioned.Recentevidencehas shownthatobstructiveand/orrestrictivefunctionalsequelaemay occur,potentiallyaffectingqualityoflife(QoL)(Amaraletal.,2015; Muñoz-Torrico et al., 2016).Currently, no guidance onspecific indicationsandproceduresregardingthestudyandrehabilitation of TB sequelaeis available (Amaral et al., 2015; Muñoz-Torrico etal.,2016),althoughTBrehabilitationwasrecentlyrecommended in the ATS/ERS/Infectious Disease Society of America (IDSA)/ Centers for Disease Control and Prevention (CDC) multidrug-resistant(MDR)-TBguidelines(Nahidetal.,2019).

Thepreliminarydataavailablesuggestthatpulmonary rehabili-tationiseffectiveinpatientswithaprevioushistoryofTBandwith impairedlungfunction.Asmoreandmorecountriesarepotentially abletofinanciallysupportrehabilitationforpatientswithpost-TB sequelae, well-designed prospective studies are necessary to identifytheindividualsneedingfurtherassessmentandtoclarify which rehabilitation models can be implemented to ensure a functionalrecovery(Viscaetal.,2019).

Theevidenceavailableonlungfunctionimpairment

AfewstudieshaveinvestigatedmechanicallungfunctioninTB patients.Alreadyin1961,HalletandMartindescribeda‘diffuse obstructivepulmonarysyndrome’amongTBpatientsadmittedto sanatoria(HallettandMartin,1961).WillcoxandFerguson(1989)

identifiedairwayobstructionin68%ofpatientscompletinganti-TB treatment, with an inverse relationship between the extentof chestradiographylesionsandforcedexpiratoryvolumeinthefirst

second (FEV1). Similarly, in South Africa, TB was found to be responsibleforlungfunctionimpairment(Hnizdoetal.,2000).Ina largepopulation-basedstudyinvolving14050participantsfrom 18 countries, a history of previous anti-TB treatment was associatedwithbothairflowobstructionandspirometry restric-tion,and itwas concludedthatTB isa majorcauseofCOPD in countrieswithahighTBprevalence(Amaraletal.,2015).

Worldwide,severalstudieshaveidentifiedTB(treatment)as apositivepredictorforlossoflungfunction.Theconclusionsofa South Korean study conducted between 2008 and 2012 recommended coupling regular lung function testing and smoking cessation aspreventive measures forchronic airway obstruction (Jung et al., 2015). A studyconducted in Indiain 2015 identified obstructive, restrictive, and mixed lung impairment disorders in TB patients after completing their treatment(SailajaandNagasreedhar,2015).InChina,treatedTB was identified as an independent risk factor for airflow obstruction (Lametal.,2010).InPapuaNewGuinea,effective management(earlydiagnosisandadequatetreatment)of MDR-TBpatientswasconsideredessentialtopreventpost-treatment sequelae(Ralphetal.,2013).

Furthermore, a multicentre population-based study in Latin Americainvolvingover5500patientsinfivecitiesrevealedthat (self-reported)historyofpreviousanti-TBtreatmentwassigni fi-cantlyassociatedwithairflowobstruction(Menezesetal.,2007). InMexico,70patientscuredofpulmonaryTBwereinvestigated, andfrequentobstructiveabnormalitieswerefound,withimpaired QoL (de la Mora et al., 2015). Last, in Texas, United States, pulmonaryfunctionwasevaluatedtwice, after20 weeksandat the end of anti-TB treatment, and TB treatmentwas identified as an independent risk factor for COPD, both in smokers and non-smokers(Vecinoetal.,2011).

Therefore, it wasrecently suggested thatlung function be assessed by performing spirometry, plethysmography, DLCO (diffusion for carbon oxide), arterial blood gas analyses, and evaluatingthecapacitytoperformexerciseviathe6-minwalk test (6MWT).Itispossible todescribe thelesions with chest radiography and computed tomography before and after treatment. Clearly,the clinical assessmentof infectiouscases implies adequate infection control measures are in place (Migliorietal.,2019).

Theevidenceavailableonpulmonaryrehabilitation

TB is clearly mentioned among the conditions for which pulmonary rehabilitation is useful according to the ATS/ERS guidelinesand theSouth AfricanCOPDmanagement guidelines (Spruitetal.,2013).Inarecentstudy(Viscaetal.,2019),pulmonary rehabilitationwaseffectiveinpatientswithaprevioushistoryof anti-TBtreatment.Patientswithimpairedlungfunctionreporteda signi_ficant improvement in 6MWT, Borg dyspnoeaand fatigue scores, FEV1, forced vital capacity (FVC), mean arterial oxygen partial pressure (PaO2), and median arterial blood oxygen saturation(SaO2)(Viscaetal.,2019).

In a recent editorial and in studies conducted in Benin, Zimbabwe, and Uganda (Chin et al., 2019; Fiogbe et al., 2019; Harriesand Chakaya, 2019;Joneset al.,2017), theissueof the feasibilityofpost-treatmentfunctionalassessmentofTBpatients and subsequentpulmonary rehabilitationwas discussed,witha focus ontheperspectiveof low-incomecountries.In Uganda,a pulmonaryrehabilitationpackagesupervisedbyphysiotherapists andrequiringminimumequipmentinitiatedatthehealthfacility level,withaerobicandresistanceexerciseslatermanagedathome, was demonstratedto befeasible and associated with clinically importantimprovementsinQoL,exercisecapacity,andrespiratory outcomes(Jonesetal.,2017).

Arecentreview(Hogeretal.,2014)recommendedthatfuture evaluation of post-treatment sequelae include the following (Figure 1): detailed information onpatient characteristics(age, sex, ethnicity, etc.), TB disease (history of previous treatment, bacteriological status and pattern of drug resistance, previous drugsandregimenswithadverseevents),andpathophysiological status(spirometrywithbronchodilatorresponse),assessmentof lung volumes (plethysmography), DLCO, arterial blood gases analysis,6MWT,radiologicalevaluation,QoLevaluation,rationale andthefeaturesoftherehabilitationplan(withclear pre-/post-test comparisons), and a cost evaluation. Furthermore, studies shouldquantifytheproportionofpatientsneedingrehabilitation amongthosecompletingtreatment.Thiswillallowtheneedfor pulmonaryrehabilitationtobeestimatedandadequatelyplanned attheprogrammaticlevel.

OptimizednutritionalcareforTBpatients Thehistoryofnutritionalcare

Nutritional care has been an important component of TB treatment throughout the history of European civilization. Lackingadequatedrugs,Hippocrates’TBtreatmentconsistedof resting,praying, drinking milk, exercise,andavoidingextreme weather conditions (Madkour et al., 2004). At the end of the nineteenthcentury,inthefirstsanatoriumforTBpatients,amore specificnutritional regimenwasimplementedinTBtreatment. Thisdietwas“amixofmeatwithplentyofvegetables”(Kinghorn, 1921).Furthermore,totreatsymptomslikenightsweats,cognac wasused(Kinghorn,1921).Inthefirstrandomizedtrialtesting thepotentialofstreptomycininjections,thecontrolstandardof care consisted of nutrition and bed rest (Streptomycin in TuberculosisTrialsCommittee,1948).In2013,theWorldHealth Organization(WHO)publishedthefirstguidelinesonnutritional care and support specifically for patients with TB. In these guidelines, the WHO stressed thatall patients with active TB are entitled to individualized nutritional assessment and management,includingcounsellingandtherapy(World Health Organization,2013).

MalnutritionanditsimplicationsforTB

Malnutrition is defined by theEuropean Society for Clinical NutritionandMetabolism(ESPEN)as“astateresultingfromlackof intakeoruptakeofnutritionthatleadstoalteredbody composi-tion (decreased fat-free mass) and body cell mass leading to diminished physicaland mental function and impaired clinical outcome from disease” (Cederholm et al., 2017). In general, malnutrition is reported to have a huge impact on patient outcomes and healthcare costs (Muscaritoli et al., 2017). Disease-relatedmalnutritionischaracterizedbyalossoffat-free mass;therefore,normal weight,overweight,andobesepatients withTBcanbemalnourished(Patonetal.,2004).Thisimpliesa declineinmusclefunction,whichleadstodependencyandless participationinsocietyforthepatient.Regainingphysicalfunction shortensthetimeneededforrecoveryandenablespatientswith TBtoresumework(Cederholmetal.,2017;Patonetal.,2004).The prevalenceofmalnutritioninpatientswithTBiscalculatedtobe 70%,andinthispopulation,malnutritionisassociatedwitha two-foldhigherriskofdyingfromTB(Bhargavaetal.,2013).

Malnutritionisconsideredanimportantpotentiallyreversible risk factor for TB treatment failure (Choi et al., 2017b). It is hypothesized that pharmacokinetic variability, resulting from changesin malabsorption (Montaltoet al., 2008), caninfluence efficacy.PatientswithTBmaysufferfrommalabsorptionbecauseof malnutrition,whichcanbeincreasedbypossiblecomorbiditiessuch asdiabetesandHIV/AIDS.Subsequently,decreasedabsorptionof anti-TBdrugsislikelytoresultinlowdrugexposure.Thismayleadto unfavourableoutcomesbytreatmentfailureandthedevelopmentof drugresistance(TerBeeketal.,2019).

Nutritionalassessment,therapy,andmonitoring

Malnutritionisnotdisease-specificbutisa‘nutritiondisorder’ (Cederholm et al., 2017). As low body mass index (BMI) is a hallmarkofchronicmalnutritionthatinvolvesthelossofbothfat andmuscletissue,aBMI<18.5kg/m2_{maybeusedasameasurefor} generalpublichealthpurposes(Cederholmetal.,2015).However, inclinicalpractice,usingBMIexclusivelyisoflessrelevancefor nutritional assessment, since in disease-related malnutrition,

Figure1.Summaryofthecoreinterventionsattheendofanti-tuberculosistreatmentandduringpulmonaryrehabilitation.

DLCO:diffusingcapacityofthelungforcarbonmonoxide;SatHB%:haemoglobinsaturationasapercentage;PaO2/PaCO2:arterialbloodtensionofoxygenandcarbondioxide;

muscle mass is mainly lost (Cederholm et al., 2015). A gold standard for malnutrition is not available, which complicates consensusonhownutritionalassessmentanditsvalidationshould beconducted.However,in2018,consensusdiagnosticcriteriafor malnutritionwerepublishedbyESPENandtheAmericanSociety for Parenteral and Enteral Nutrition (ASPEN) to accommodate uniformityinnutritionalassessment,i.e.the‘GLIMcriteria’(Global Leadership Initiative onMalnutrition) (Cederholmet al., 2019). Thesecriteriaarebothphenotypic(weightloss,lowBMI,reduced musclemass)andaetiological(reducedfoodintakeor assimila-tion,diseaseburden/inflammatorycondition),andareprecededby validatedscreeningformalnutritionrisk(Cederholmetal.,2019). After diagnosing malnutrition, an individualized treatment planneedstobedeveloped.Thistailoredtreatmentplanneedsto bebasedonsufficientproteins(anddistribution)andenergyfrom either regular foods or medical nutritional supplements if necessary,andpreferablyincombinationwithtraining(Ockenga etal.,2006).Thenutritionalcounsellingandmeasurementsthat areperformedtoassessmalnutritionshouldberepeatedregularly duringthe treatmentand (pulmonary) rehabilitationperiod, to allowadjustmentofthenutritionaltreatmentplanifnecessary. Newinsightsfromprotectiveimmuneresponses —cross-fertilizingconceptsforanti-MTBimmunesurveillance

Newinsightsfromcancerresearchandbiologicaltherapyare guiding innovative immunological therapies targeted against definedmoleculartargets.Anovel pathwayhasbeensuggested onhowdisease-relatedmalnutritionismediated,andisacommon findinginTBpatients.Nutritionalstatusisakeyfactorinshaping immuneresponses.Undernormalcircumstances,mostimmune cells use a glucose-based mechanism to generate energy. In nutrient-deficientstates,alternativesourcesareusedtogenerate energy,suchasproteinsandfattyacids.Baazimetal.showedthat infection-induced cachexia is not only mediated by tumour necrosisfactoralpha(TNF-α),interleukin(IL)-1β,andIL-6leading to proteolysis and lipolysis, but also by antigen-specific CD8+ T-cells that mediate cachexia by adipose tissue remodelling (Baazim et al., 2019) (Figure 2).Furthermore, thecontainment of tissue infections requires the involvementof tissue resident immunecells(Trmcells).Thesecellsareenrichedinthelungand are thought to mediate an important line of defence against invading pathogens (Behr et al., 2018). Bhlh40 is a key factor mediatingcontainmentof infectiouspathogens (ortransformed cells)(Lietal.,2019).MicewithreducedBhlhle40 cellsexhibit reducedsurvivalininfluenza-positiveanimals;increasedBhlhle40

expression results inincreasedinterferon-gammaproduction in theTh1compartment.Thesemaybepromisingclinicallyrelevant markerstoidentifyindividualswhomaybenefitfrom immune-modulatorystrategiestargetingthebiologicalpathwaysassociated withlong-termprotectiveimmuneresponses.

Conclusions

InthisreviewontheholisticapproachtoTBpatients,wehave discussedtherecentevidenceontheimportanceofevaluating functional status at the completion of treatment in order to identifycandidatesforpulmonaryrehabilitation.Wehaveshown thatpulmonaryrehabilitationiseffectiveinimprovingfunctional parameters,thecapacitytoperformexercise(walkingtest),and quality of life. We have described the recent evidence and implicationsattheimmunologicallevel,identifyingprioritiesfor futureresearch.Wehavealsodiscussedthedamageproducedby malnutrition and the importance of assessing the nutritional status.Theimportanceofaddressingmalnutritioncorrectlyand in a timely fashion is essential in reducing morbidity and mortality.

Fundingsources

Thisresearchdidnotreceiveanyspecificgrantfromfunding agenciesinthepublic,commercial,ornot-for-profitsectors. Ethicalapproval

Approvalwasnotrequired. Conflictofinterest

Nocompetinginterestdeclared. Acknowledgements

ThisarticleispartoftheactivitiesoftheGlobalTuberculosis Network(GTN;CommitteesonTBTreatment,WorkingGroupon PulmonaryRehabilitation, and GlobalTB Consilium) and of the WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate,ITA-80,2017-2020-GBM/RC/LDA.Thisarticleispartofa supplemententitledCommemoratingWorldTuberculosisDayMarch 24th,2020:“IT’STIMETOFIND,TREATALLandENDTUBERCULOSIS!” published withsupportfrom anunrestricted educational grant fromQIAGENSciencesInc.

Figure2. ImmuneresponsesinMycobacteriumtuberculosisinfection.TissueresidentT-cells(Trm)andtumourinfiltratingT-cells(TIL)exhibitincreasedBhlhle40expression; however,thisisnotthecaseforperipheral(CD8+)T-cells.GAL(granuloma-associatedlymphocytes;Tullyetal;2005)correspondtoTIL.IncreasedBhlhle40isassociatedwith increasedimmuneeffectorfunctions,increased‘mitochondrialfitness’,andincreasedcompetencetocontainpathogensortransformedcells(lightgreenarrow).Incontrast, decreasedBhlhe40expressionislinkedwithlossofimmunecompetence(darkgreenarrow).ImmunecellsmayberecruitedintothegranulomaviaTrmresources,fromthe peripheralcirculation,orfromlymphnodes.TCF1+PD1+T-cellshavestem-likepropertiesandarecrucialinlong-termimmunememory.Antigen-specificCD8+T-cellsare vitalforimmunesurveillance,butmayalsoberesponsibleformediatingcachexia.

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