clin infect dis. 2013 seddon 1676 84

M A J O R A R T I C L E

Preventive Therapy for Child Contacts ofMultidrug-Resistant Tuberculosis: A ProspectiveCohort Study

James A. Seddon,1,3,4 Anneke C. Hesseling,1 Heather Finlayson,2,5 Katherine Fielding,6 Helen Cox,7 Jennifer Hughes,7

Peter Godfrey-Faussett,3 and H. Simon Schaaf1,5

1Desmond Tutu Tuberculosis Centre and 2Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University,Tygerberg, South Africa; 3Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine,and 4Department of Paediatric Infectious Diseases, Imperial College London, United Kingdom; 5Tygerberg Childrens Hospital, Tygerberg, South Africa;6Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine,United Kingdom; and 7Mdecins Sans Frontires, Cape Town, South Africa

Background. Evidence is limited to guide the management of children exposed to multidrug-resistant (MDR)tuberculosis. We aimed to study the tolerability and toxicity of a standard preventive therapy regimen given to chil-dren exposed to infectious MDR tuberculosis, and explore risk factors for poor outcome.Methods. In this prospective cohort study in the Western Cape, South Africa, children

has implications for the community as children provide a reser-voir for future disease, with propagation of the epidemic bythose children who develop infectious tuberculosis. The rsttrials of isoniazid as preventive therapy for tuberculosis werecarried out >50 years ago [4], and isoniazid has been demon-strated to reduce the risk of progression from infection todisease in HIV-positive and HIV-negative children followingexposure to drug-susceptible tuberculosis [5, 6]. The majorityof international agencies and national tuberculosis programstherefore advise providing children

younger or breast-fed. Combination antiretroviral therapy wasroutinely initiated in all HIV-positive children following appro-priate evaluation. TST was completed by tuberculosis clinicpersonnel by injecting 2 tuberculin units intradermally (puri-ed protein derivative RT23, Statens Serum Institut) withresults read at 4872 hours; an induration of 10 mm (or 5mm if HIV positive) was regarded as positive.

Study Population and EligibilityAll children evaluated at TCH or community outreach clinicswere eligible if they had been in signicant contact with an in-dividual with an infectious case of pulmonary MDR tuberculo-sis (source patient) within the preceding 6 months and if thedrug susceptibility test of the isolate from the source patientshowed susceptibility to ooxacin. Children were enrolled ifthey had started preventive therapy from May 2010 throughApril 2011. Children were recruited following written, in-formed consent from their caregivers with assent from thechild where appropriate. The study was approved by the

Stellenbosch University and London School of Hygiene andTropical Medicine ethics committees.

Data CollectionChildren were seen by the study team at their routine clinicalappointments, as well as at any additional, unscheduled visits.At the initial interview, following screening for tuberculosisdisease, data were collected regarding demographic and clinicaldetails. At follow-up visits, after clinical assessment, parents/caregivers were interviewed concerning adherence and poten-tial drug-related adverse events using a structured question-naire. In addition, during the rst half of 2012, children weretraced and either recalled to the clinic or visited at their localclinic or home by the study team. Where this was not possible,local clinics and families were contacted to conrm that thechild was clinically well and was gaining weight. The date ofthis nal interaction was recorded. Follow-up time for the chil-dren, therefore, was a minimum of 12 months and up to 24months in some children.

Table 1. Classication of Adverse Events Used in Children Receiving Multidrug-Resistant Tuberculosis Preventive Therapy

AdverseEvent Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Joint, muscleor bonepain

No adverseevent

Pain but nointerference withfunction ormovement

Moderate pain, affectingfunction but able to carryout normal activities

Severe pain limitingactivities

Disabling pain: unable tocarry out activities

Skin rashes No adverseevent

Small areas of redness/rash

Dry peeling or widespreadrash

Wet peeling, ulcers, orurticaria

Severe, widespread rash,necrosis needinghospitalization

Itchy skin No adverseevent

Slight itching inlocalized areas

Severe itching in localizedareas

Widespread itching overentire body

Uncontrollable scratchingneeding hospitalization

Headache No adverseevent

Mild: does not needtreatment

Transient/moderate: needsnonnarcotic treatment

Severe: responds tonarcotics

Intractable pain

Sleeping/mood

No adverseevent

Mild anxiety Moderate anxiety orproblems getting to sleep

Severe anxiety, problemsgetting to sleep, orrepeated waking

Psychosis, unable to sleepfor >1 hour

Lethargy No adverseevent

Activity reduced for4 normalfrequency for child

Liquid stool >8 normalfrequency for child

Jaundice No adverseevent

Jaundice detectableclinically: bilirubin1.11.5 ULN

Obvious clinical jaundice:bilirubin 1.62.5 ULN

Severe jaundice: bilirubin2.65 ULN

Hospitalization: bilirubin>5 ULN

Loss ofappetite/nausea

No adverseevent

Mild: still eating/drinking well

Moderate: decreasedappetite

Severe: little food taken No solid or liquid foodtaken

Abbreviation: ULN, upper limit of normal (as determined by reference range for age of child and assay used).

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Adherence was measured in 2 ways at each study visit. Therst was a 3-day recall and the second a 30-day visual analoguescore. Each of these 2 measures was scaled to give a score out of30. Scores derived from both measures from each visit wereadded to determine a total score for the whole period ontreatment [25, 26]. If this was >80% of a possible maximumthen adherence was recorded as good, with scores

Factors associated with increased risk of poor patient outcome(Table 6) were age 200 patient-years of follow-up, only 1 child died

and 6 developed incident tuberculosis. It is likely that the childwho died did not develop tuberculosis but died of some otherillness. Of the 6 children who developed incident tuberculosis,4 were not given the prescribed medications conscientiously,and no children given medications under daily observedtherapy developed tuberculosis. Risk factors for poor outcomeincluded young age (

exposed to multiple source cases had higher rates of pooroutcome is interesting. It may be that having multiple sourcecases increases the risk of mycobacterial transmission or it maybe that highly virulent strains circulate in some households. Itmay be that genetic factors render certain families more suscep-tible to tuberculosis or it may be that social factors such ascrowding, alcohol, drugs, nutrition, or adherence inuenceboth the adults and the children.Few studies have previously assessed preventive therapy for

child contacts of MDR tuberculosis, and no randomized con-trolled trials have been conducted [30]. One study in CapeTown examined 105 children; 41 were given a multidrug pre-ventive regimen tailored to the drug susceptibility test patternof the source case isolate [18]. Only 2 of the 41 treated patients(5%) developed tuberculosis disease compared to 13 (20%) ob-served without treatment. A study in Rio de Janeiro followed218 adult and child contacts of MDR tuberculosis; 45 had beengiven isoniazid [31]. There was no protective effect of the isoni-azid. A nal study in Chuuk, Federated States of Micronesia,examined 110 infected adult and child MDR tuberculosis con-tacts given a 12-month individually tailored multidrug preven-tive regimen under directly observed therapy. No patients givenpreventive therapy developed tuberculosis [32]. Guidelines vary[3335], as do expert opinion [36, 37] and published practice[11, 3841]. Some agencies advise careful follow-up alone [7, 42],some recommend isoniazid [43], some suggest 2 drugs to whichthe index patients tuberculosis strain is susceptible [12], and

some advocate specialist referral [44]. A Delphi survey ofexperts was unable to reach consensus [45], and 2 systematicreviews concluded that there was not enough evidence toinform policy development regarding MDR tuberculosis pre-ventive treatment [46]. A report from the European Centre forDisease Prevention and Control suggest that either tailored pre-ventive therapy with close follow-up or close follow-up aloneare acceptable options in the absence of better data [13].This is the largest study to date documenting the effect of a

standard preventive therapy regimen for children exposed toMDR tuberculosis. Follow-up was good, and both adherenceand adverse events were carefully documented. However, ourstudy had several limitations. Because this was an observationalstudy without a control group, it is not possible to concludewith certainty that this regimen is effective. It is possible thatthe number of children developing tuberculosis could havebeen similar had they been given isoniazid alone or even nomedications at all. However, the prechemotherapy data do notsupport this argument. In the absence of preventive therapy, ithas been shown that up to 50% ofM. tuberculosisinfected chil-dren

with poor outcome adds support to the argument that thisregimen is effective in reducing the risk of progression from in-fection to disease. We included children irrespective of TSTstatus, consistent with national and provincial guidelines. Therationale for this is that TST is not a highly sensitive test for M.tuberculosis infection, especially in the young infant, HIV-posi-tive children, and malnourished children; nor is it highly specif-ic in settings where BCG is routinely given at birth such asours. By only including TST-positive children, a number of in-fected children would therefore have been excluded. Also, if aTST is negative at the time of initial assessment, there is achance that the child may have been infected but may onlyconvert their test later. Rather than use a 2-stage protocol withall children started on preventive therapy, which is thenstopped if a second TST at follow-up is negative, the localpolicy is for all exposed children to be treated. We employedthese operational entry criteria in our study. It could, therefore,be argued that some of the children in the study did not requiretreatment. As mycobacteria were not isolated from any of thechildren who developed tuberculosis, we were unable to deter-mine if this preventive therapy regimen resulted in increasedrates of uoroquinolone resistance. This is a potential concernand should be evaluated in future studies. A nal limitation of

the study is the duration of follow-up. All children were fol-lowed for a minimum of 12 months with some followed for 24months. Although the vast majority (>90%) of children whodevelop disease do so within 12 months of infection [4, 18], it isaccepted that some children might progress to disease after theperiod of observation.To conclusively determine the utility of preventive therapy

for child contacts of MDR tuberculosis, a clinical trial is war-ranted, one in which children are randomly and blindly as-signed to either a uoroquinolone-containing multidrugregimen or to isoniazid alone. However, until that time, clini-cians will continue to be confronted by children exposed toMDR tuberculosis. We have demonstrated this regimen to bewell tolerated and associated with limited toxicity. Also, clini-cians should be condent when managing a child exposed toMDR tuberculosis that providing this preventive therapyregimen results in reassuringly low rates of tuberculosis ordeath.

Notes

Acknowledgments. The authors thank Klassina Zimri, ZingiweMramba, and Ben Marais for their help in data collection. We also thankthe clinic team at Tygerberg Childrens Hospital for their assistance in the

Table 6. Assessment of Risk Factors for Poor Outcome (Death or Incident Tuberculosis Disease) in Children Exposed to Multidrug-Resis-tant Tuberculosis and Treated With a Preventive Therapy Regimen (N = 186)

Risk Factor No. of EventsYears of

ObservationIncidence Rate With 95%CI (Events per 1000 py) Rate Ratio (95% CI) P Value

Age>12 mo 2 175.5 11.4 (1.441.1) 1.0

012 mo 5 43.5 114.9 (37.3268.2) 10.1 (1.65105.8) .009

SexFemale 3 95.6 31.4 (6.591.7) 1.0

Male 4 123.4 32.4 (8.883.0) 1.03 (.177.05) 1.00

TSTNegative 4 132.1 30.3 (8.377.5) 1.0

Positive 2 84.8 23.6 (2.985.2) 0.78 (.075.43) 1.00

Source casesSingle 2 152.4 13.1 (3.2852.5) 1.0

Multiple 5 56.4 88.6 (36.9213.0) 6.75 (1.1170.9) .036

HIV statusNegative 5 201.5 24.8 (8.1579.1) 1.0

Positive 2 7.6 263.8 (31.9950.6) 10.6 (1.0164.9) .049

AdherenceGood 2 164.3 12.2 (1.544.0) 1.0 . . .

Poor 5 54.8 91.3 (29.6212.9) 7.50 (1.2378.7) .026

Type of deliveryDOT 0 31.5 0 (0117.1) . . . . . .

Other 7 187.6 37.3 (15.076.8) . . . .68

Abbreviations: CI, confidence interval; DOT, daily observed therapy; HIV, human immunodeficiency virus; py, person-years; TST, tuberculin skin test.




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running of the study (Helen Opperman, Elizabeth J. Perez, Sarah S. Faro,Rachel A. Solomon, Mary Petersen, Rina Plaatjies, Nadia J. Lackay, SharenDaniels, and Nertisha Newman).Financial support. This work was supported by a US Agency for Inter-

national Development Cooperative Agreement (TREAT TB, AgreementNo. GHN-A-00-08-00004-00 to J. A. S. and H. S. S.), the Sir Halley StewartTrust (to J. A. S.), and the National Research Foundation of South Africa(to H. S. S.).Disclaimer. The contents are the responsibility of the author(s) and do

not necessarily reect the views of the funders.Potential conicts of interest. All authors: No reported conicts.All authors have submitted the ICMJE Form for Disclosure of Potential

Conicts of Interest. Conicts that the editors consider relevant to thecontent of the manuscript have been disclosed.

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